Abstract
Proteoglycans and selected extracellular matrix constituents are emerging as intrinsic and critical regulators of evolutionarily conversed, intracellular catabolic pathways. Often, these secreted molecules evoke sustained autophagy in a variety of cell types, tissues, and model systems. The unique properties of proteoglycans have ushered in a paradigmatic shift to broaden our understanding of matrix-mediated signaling cascades. The dynamic cellular pathway controlling autophagy is now linked to an equally dynamic and fluid signaling network embedded in a complex meshwork of matrix molecules. A rapidly emerging field of research encompasses multiple matrix-derived candidates, representing a menagerie of soluble matrix constituents including decorin, biglycan, endorepellin, endostatin, collagen VI and plasminogen kringle 5. These matrix constituents are pro-autophagic and simultaneously anti-angiogenic. In contrast, perlecan, laminin α2 chain, and lumican have anti-autophagic functions. Mechanistically, each matrix constituent linked to intracellular catabolic events engages a specific cell surface receptor that often converges on a common core of the autophagic machinery including AMPK, Peg3 and Beclin 1. We consider this matrix-evoked autophagy as non-canonical given that it occurs in an allosteric manner and is independent of nutrient availability or prevailing bioenergetics control. We propose that matrix-regulated autophagy is an important outside-in signaling mechanism for proper tissue homeostasis that could be therapeutically leveraged to combat a variety of diseases.
Keywords: proteoglycans, angiogenesis, cancer, endothelial cells, receptor tyrosine kinases
Introduction
Proteoglycans are key constituents of the extracellular matrix (ECM) that exert many functions, some of which are ‘intrinsic” to their inherently complex chemical structure: specialized protein cores with unique covalently attached, post-translational modifications of intricate glycosaminoglycan chains [1–4]. The multifunctional nature of proteoglycans, based on their intrinsic chemical diversity, drives many regulatory processes encompassing all aspects of mammalian biology [2,5–25]. One of the most important roles of the extracellular matrix, as both an insoluble and soluble constituent, is to regulate the growth of new blood vessels from preexisting ones, commonly known as the angiogenic cascade [26,27]. This dynamic process contributes to the development and progression of malignant tumors, rheumatoid arthritis and wound healing among others [28–31]. Often, the arbiters of extracellular matrix remodeling and the main sources of abnormal matrix production are activated fibroblasts [32] which are involved in regulating matrix biomechanics [33], matrix processing [34,35], fibrotic diseases, and various forms of cancer [36–38]. An emerging new property of dysregulated proteoglycans and processed matrix molecules is their ability to evoke autophagy and sometimes to interfere with this intracellular catabolic process. Given the rapidly expanding field of proteomics, the delineation of the matrisome in various species [39–49] and the new concept of spatial-omics [50], we predict that alterations in the matrisome could affect intracellular catabolism and cell behavior, especially in cancer [51–56].
Autophagy is an evolutionarily conserved catabolic process that non-selectively targets cytosolic components such as long-lived proteins, protein aggregates, lipids, and superfluous and/or damaged organelles for lysosomal degradation and the subsequent release of nutrients for the biosynthesis of new macromolecules [57,58]. Autophagy is tightly regulated involving multiple signaling arms for optimal coordination [59–61]. Generally, these signaling pathways involve the global suppression of anabolism (mTORC1) and concurrent activation of catabolism (Vps34/AMPK) for proficient and sustained autophagy [62,63] (Fig. 1). Importantly, by adeptly balancing opposing biological demands, autophagy integrates prevailing bioenergetics and cellular metabolism for direct effects on downstream behaviors such as gene expression, proliferation, and migration [64].
Fig. 1.
Autophagic signaling hub evoked by extracellular matrix components. Schematic representation of the intricate network of ECM molecules, receptors, and intracellular downstream effectors that regulate autophagy. Decorin, biglycan, endorepellin, collagen VI, kringle 5, and endostatin activate autophagy through binding to different cognate receptors or cell adhesion molecules. Laminin α2, instead, inhibits autophagy through the PI3K/AKT signaling pathway. Decorin, via binding to EGFR and Met, also induces mitophagy in cancer cells and inhibits angiogenesis. Peg3 is shown as the master regulator of autophagy as induction of its expression correlates with increased levels of LC3-positive autophagosomes. Please see the text for a detailed analysis of the illustrated signaling pathways.
Given the nexus from which autophagy operates to maintain cellular homeostasis, this catabolic pathway is perceived as a critical process gone awry in many diseases. Dysregulated autophagy is defined as either inadequate or as a supra-physiological process of autophagic flux that is overtly detrimental to normal tissue function [65–70]. Dysregulated autophagy has been observed in many pathological processes including cancer [71–74]. During the later stages of tumorigenic growth and progression, autophagy is potently tumor suppressive [75–79]. The oncosuppressive properties and therapeutic benefits of autophagic activation align with the extensively documented functions of soluble proteoglycans in suppressing cancer and angiogenesis [2,4,80–90].
Mechanistically, several proteoglycan family members and select ECM proteins utilize specific cell surface receptor complexes to transduce germane biological information onto a common core of autophagic machinery composed of Peg3, Beclin 1, and LC3 in a diverse array of cell types, tissues, and microenvironments (Fig. 1). A menagerie of matrix components including decorin, endorepellin, collagen VI, plasminogen kringle 5, endostatin, laminin α2, and biglycan are archetypical regulators that evoke or inhibit autophagic progression (Fig. 1). Notably, decorin also evokes tumor cell mitophagy in a mitostatin dependent manner downstream of Met signaling (Fig. 1) [91]. Given the focus of this review on autophagy, for more information on decorin please refer to a recently-published article concerning the role of decorin in tumor cell mitophagy [92]. Autophagic regulation by matrix factors is independent of the canonical nutrient-dependent mechanisms that have become dogma for activating autophagy. It is important to note that ECM-mediated autophagy has been discussed elsewhere [93,94]. Nevertheless, these previous studies chiefly focused on anoikis dependent autophagy, via an integrin-dependent mechanism. Therefore, in this review, we will focus on soluble, matrix-derived molecules, primarily proteoglycans, that each possesses an intrinsic ability to modulate autophagy. We thereby propose that proteoglycans [95,96] and other processed forms of matrix molecules [97,98] represent a dynamic and therapeutically untapped repertoire of versatile factors that brandish autophagy as a potent inhibitor of tumorigenesis and pathological angiogenesis (Fig. 1). Collectively, these proteoglycan neofunctions [87,99] cast this group as a suitable and propitious candidate towards the development of novel protein therapies for the fight against cancer [100].
Peg3 executes proteoglycan-driven autophagy to suppress tumorigenesis
Decorin-evoked endothelial cell autophagy occurs via a non-canonical signaling cascade that initiates irrespective of nutrient bioavailability or cellular energy levels [88]. This process is dependent on cell surface receptor tyrosine kinases [95,101,102], such as vascular endothelial growth factor receptor 2 (VEGFR2) [103]. The pro-autophagic information encoded by the leucine rich repeats of decorin is decoded by a proximal signaling apparatus composed of VEGFR2 and AMP-activated protein kinase (AMPK) that converges on Paternally expressed gene 3 (Peg3), a master regulator of endothelial cell autophagy [104]. Peg3 orchestrates a broad autophagic program culminating in long-term, stable changes in gene expression to both suppress angiogenesis and tumorigenesis [105].
Peg3, a key signaling node that integrates pro-autophagic and anti-angiogenic signals, is part of an exclusive transcriptomic signature of differentially expressed genes within the M. musculus tumor microenvironment of orthotopically implanted triple negative breast cancer xenografts following systemic decorin treatment [103,106,107]. PEG3 spans a ~30-kb genomic region on human chromosome 19q13.4 [108], or the proximal arm of chromosome 7 in mice (Fig. 2A), and is a member of ~70 imprinted genes. Interestingly, Dcn is also an imprinted gene in pigs [109] and mice [110]; however, DCN exhibits bi-allelic expression in humans, suggesting similar modes of regulation in the former genomes. The 2-Mbp PEG3 locus is found within a KRAB-A (Krüpple-associated box-A) zinc finger-rich gene cluster harboring more than 50 individual zinc finger genes [111]. Accordingly, it encodes a Cys2-His2 Krüpple-like zinc finger-containing transcription factor [112–114] (Fig. 2B). The 12 Cys2-His2 Krüpple-type motifs (Fig. 2E) are clustered into groups and each finger coordinates a metal ion that stabilizes a ββα fold [115]. Every finger is separated by a Krüpple-link, consisting of ~7 conserved amino acids [115]. An individual zinc finger can insert into the major groove of DNA and recognize ~4 bases; working in tandem, the zinc fingers of Peg3 can recognize a large sequence of DNA [116], thus imbuing a high degree of specificity and variety for promoter binding sites (Fig. 2 B,E). In response to stimuli, Peg3 translocates into the nucleus [117] and binds to the promoter of target genes in a sequence-specific manner, conferred by combinatorial zinc finger binding [118,119].
Fig. 2.
Transcriptomic and domain organization of H. sapiens PEG3. (A) PEG3 genomic organization and architecture denoting untranslated regions, non-coding exons, and the open reading frame responsible for encoding Peg3. This schematic representation of the PEG3 mRNA is to scale. (B). Peg3 protein and domain organization schematically depicting the architecture and arrangement of the N-terminal protein-protein interaction domains (SCAN, KRAB-A) and the 12 C2H2 C-terminal zinc finger domains. This schematic representation of the Peg3 protein is to scale. (C-E) Representative ribbon diagrams rendered in PyMOL from the corresponding Protein Data Bank (PDB) identifiers for the PEG3 SCAN domain (C), a KRAB-A domain (D), and a C2H2 zinc finger domain (E). Please refer to the text for additional information.
Peg3 is a large (~165 kDa) multi-domain protein dominated by the presence of 12 C2H2 zinc fingers (Fig. 2A,B), which are encoded by a single exon [111]. A majority of zinc finger containing proteins, especially transcription factors, frequently possess other functional domains. Indeed, the N-terminus of Peg3 harbors a SCAN domain, encoded by exon 3 [111] (Fig. 2 B,C), that coordinates protein-protein interactions. The SCAN domain, named for the founding members of a ~65 gene family (SREZBP, Ctfin51, AW-1, and Number 18) with a highly conserved structure [120], coordinates selective oligomerization as it mediates homotypic and heterotypic interactions [121,122]. The crystal structure of the Peg3-SCAN domain shows that Peg3 can form self-oligomers via hydrogen bonding at the SCAN interface [123] (Fig. 2 C). Topologically, these Peg3 molecules bind in antiparallel orientation and Peg3 molecules may subsume this homodimeric configuration to localize and aggregate within specific genomic compartments and/or loci to regulate gene expression [123] (Fig. 2C). Currently, there are four isoforms of Peg3, with each potentially having various degrees of DNA binding specificity and SCAN-SCAN interactions [123].
Soluble decorin and rapamycin trigger the expression of PEG3 [103] (Fig. 3) which in turns activates the autophagic program. Notably, Dcn itself is subject to autophagic regulation in cardiac tissue following starvation [124] and acts as an extracellular nutrient sensor to maintain cardiac physiology [125]. Nuclear control of autophagy, highlighted in part by the FOXO family of transcription factors [126,127] coupled with stable epigenetic changes, such as H4 Lys acetylation via hMOF acetyltransferase [128] are critical factors for prolonged autophagy [129]. Peg3 expression is further fine-tuned post-transcriptionally by APeg3, an evolutionarily conserved antisense non-coding RNA [130].
Fig. 3.
Peg3 is a master regulator of autophagy that integrates anti-angiogenic signals. Schematic representation of the downstream signal transduction events initiated by the binding of decorin to the ectodomain of VEGFR2 on the surface of endothelial cells. The signals emanating from this high-affinity interaction are conveyed by AMPK to regulate Peg3. Peg3 is critical for executing the pro-autophagic and anti-angiogenic properties inherent to decorin for potent oncosuppression. Please refer to the text for additional, mechanistic details.
Functionally, Peg3 has been implicated in regulating a myriad of biological processes such as progenitor and adult cell stemness [131–133], maternal behavior and reproduction [134–137], metabolism [138,139], p53-mediated apoptosis [140–142], brain ischemia/hypoxic injury [143], TNF-α/NFκB signaling [144], post-myocardial infarction fibrosis [145], corneal neovascularization [146,147] and cancer [148,149]. However, recent evidence has emerged showing that mutations in the Peg3 locus do not perturb maternal or nursing behaviors [150]. Moreover, the role of Peg3 in regulating TNF-α signaling has also been disputed [151], suggesting a deeper, context-dependent role of Peg3 in regulating inflammation. Despite these ascribed roles, the precise molecular mechanism(s) whereby Peg3 contributes to these multiple biological functions has yet to be discovered.
Our research has been focused on the role of Peg3 at the intersection of autophagy and cancer. Lack of autophagy is linked to an increase in angiogenesis and tumorigenesis, as shown by the loss of the classic autophagy gene, Becn1 [71,74,152]. Mice deficient in autophagy develop multiple liver tumors [153]. We utilized genomically stable endothelial cells as a representative cell type for the tumor microenvironment, the compartment that showed significant and exclusive expression of Peg3. Further reinforcing this rationale, independent microarray datasets indicated that Peg3 is a marker for endothelial progenitors [154]. We discovered that Peg3 parses and integrates the signals conveyed by decorin to evoke autophagy and suppress angiogenesis [103,104] and ultimately to inhibit cancer (Fig. 1). As a traditional tumor suppressor gene, PEG3 promoter is highly susceptible to hypermethylation, or subject to loss of heterozygosity, with important oncogenic ramifications [155]. Administration of cyclophilin A blocks excessive promoter methylation and prevents deposition of additional inactive histone marks along the Peg3 locus [155]. Biallelic Peg3 promoter hypermethylation has been extensively documented in a diverse array of solid tumors including intraepithelial and invasive cervical cancer [156], gynecological cancer [157], gliomas [158–160], ovarian [161,162], and breast cancer [113,160]. Recently, PEG3 was identified as one of 10 master transcription factors that govern and regulate signaling pathways in human breast cancer [149]. Intriguingly, Peg3 non-canonically suppresses Wnt/β-catenin signaling in gliomas to impair growth [159], via a mechanism that is functionally similar to how decorin impedes Wnt/β-catenin signaling in HeLa cells [163].
Decorin evokes endothelial cell autophagy
Decorin interfacing with the VEGFR2 ectodomain results in prolonged phosphorylation of the α catalytic subunit of AMPK at Thr172, a key phosphosite denoting activation of the master energy sensor kinase [164] (Fig. 3). AMPK is evolutionarily conserved and orchestrates a plethora of metabolic processes, including autophagy [63] with complex roles in tumorigenesis [165]. Canonically, AMPK stimulates autophagy following bioenergetic stress when AMP:ATP ratios are critically elevated [166]. However, proteoglycan-mediated AMPK-activation occurs under nutrient-rich conditions and is independent of bioenergetic profiles [92]. Impaired positive VEGFR2 signaling via pharmacological or genetic means impairs decorin-evoked autophagic initiation vis-à-vis phosphorylated AMPK [103]. The precise mechanism of action that decorin utilizes to transduce signals from VEGFR2 to AMPK is currently obscure (Fig. 3). It is plausible that an intermediate kinase complex such as the LKB1/STRAD1/MO25α heterotrimer used for canonical AMPK activation in response to nutrient depletion [167] could be situated between decorin/VEGFR2 and AMPK (Fig. 3). A leading candidate is CAMKK2, a kinase capable of phosphorylating and activating AMPK via a nucleotide-independent manner in response to cytosolic Ca2+ oscillations [63]. Notably, decorin mobilizes cytosolic Ca2+ [168,169] downstream of RTKs, suggesting an activation mechanism for CAMKK2 to phosphorylate AMPK. This would provide a plausible rationale for the nutrient-independent mode of autophagic initiation utilized by decorin and potentially for other proteoglycans [170–175]. Alternatively, AMPK could be simply a direct target of VEGFR2 kinase, without the need for an intermediary kinase or other signaling effector(s) (Fig. 1).
Distally to the decorin/VEGFR2/AMPK interaction, autophagy initiation proceeds with the formation of the phagophore assembly site (PAS), which consists of Vps34, a non-oncogenic p110 class III PI3K, in complex with ULK1/2, Atg13, Beclin 1, and/or FIP200 [62,70,176,177]. Peg3 associates with Beclin 1, an integral scaffolding component along with Vps34 that is required for initial autophagosome biogenesis [178,179] (Fig. 3). Whether AMPK directly promotes the physical association of Peg3 with various Beclin1/Vps34 nodes or subcomplexes in response to decorin requires further studies. However, it is known that decorin requires the kinase activities of Vps34 and AMPK [180] (Fig. 3). Pharmacologically targeting of Vps34 with 3-methyladenine or AMPK with Compound C (Dorsomorphin) abrogates autophagy [103], Vps34/Beclin 1 formation [181], and Peg3 induction [103,107]. Concurrently, AMPK diametrically opposes mTORC1 via ULK1/2 [63], which drives cell growth, size, and numerous anabolic reactions [164], thereby positioning mTOR as a potent anti-autophagic and pro-tumorigenic effector [182–186]. Decorin attenuates the mTORC1 signaling axis (Fig. 3) by decreasing phosphorylated mTOR at Ser2448 (signifying active mTOR), Akt at Ser476, and its predominant downstream effector, p70S6K at Thr389 [180], potentially via activation of AMPK and/or downstream phosphatases. However, the role of mTOR as strictly anti-autophagic and thus more tumorigenic is much more nuanced as it also aids in the physiological termination of autophagy [187]. The ability of decorin to reprogram RTK signaling toward a pro-autophagic program aligns with the anti-oncogenic role of Beclin 1, where EGFR/Akt can phosphorylate and inactivate Beclin 1 for increased tumorigenesis and chemoresistance [188,189].
The core of Peg3 functionality manifests downstream of these signaling pathways, despite being implicated in the more upstream signaling complexes tasked with autophagic initiation (Fig. 3). Peg3 localizes to large cytosolic structures, reminiscent of autophagosomes in human and murine microvascular and macrovascular endothelial cells. These structures were empirically confirmed as autophagosomes by co-localizing Peg3 with Beclin 1 and/or LC3 [103] (Fig. 3), two well-established autophagosomal markers [62]. The presence of Peg3 co-localizing with Beclin 1 and LC3 indicates a critical role in the later stages of the autophagic process. This concept is strongly reinforced by the fact that Peg3 is indispensable for decorin-evoked endothelial cell autophagy by triggering and maintaining the transcription of BECN1 and MAP1LC3A [103,104]. Peg3 undergoes nuclear translocation (Fig. 3) for target gene activation following autophagic stimuli [117]. Mechanistically, Peg3 is both necessary and sufficient [103,117] to maintain basal BECN1 mRNA levels and to ensure the overall bioavailability of Beclin1 and LC3 when the endothelial cells respond to autophagic stimuli. Indeed, genetic silencing of Peg3 wholly ablates autophagy and renders the cells insensitive to autophagic cues. These findings reinforce the oncosuppressive role of Peg3 as it directly controls the expression of Beclin 1, whose absence results in increased angiogenesis and tumorigenesis [73,190]. Indeed, the expression of Becn1 is considered a favorable prognosticator in colon cancer [191].
The antiparallel orientation of Peg3 homodimers via the SCAN domain may be important for transcriptionally active chromatin by configuring the appropriate three-dimensional genomic architecture via a scaffolding function. As Peg3 is also found in the cytoplasm, it is plausible that Peg3 via the C2H2 zinc finger domains may drive the formation and/or stabilization of multi-subunit protein complexes including PAS (e.g., Vps34/Beclin1/Peg3 positive complexes) and autophagosome maturation (e.g. the Peg3/LC3 positive structures). Emerging evidence suggests that transcription factors harboring C2H2 zinc fingers, including YY1, Sp1, Zif268, and Miz-1 utilize these domains for widespread protein-protein interactions in addition to their canonical role as DNA binding motifs [192]. It is also plausible that decorin employs this mechanism via the combinatorial formation of pro-autophagic condensates seen with LC3/Peg3, while simultaneously counteracting the release of anti-autophagic factors such as Bcl-2 from Beclin 1 [72,180,193,194]. Currently, it is unknown whether Peg3 drives these interactions directly, and/or which domain(s) are involved in mediating the formation of the complex condensates where Peg3 is found. Of exons 3–9 that comprise the ORF for Peg3, only exons 3 (SCAN domain) (Fig. 2C), 7 (KRAB-A domain) (Fig. 2D), and 9 (all 12 of the C2H2 zinc fingers) (Fig. 3E) have been functionally mapped. The molecular determinants responsible for driving these disparate multi-protein complexes, and the sustained transcriptional responses, may reside in the unknown domains of Peg3 encoded by the remaining exons. As decorin relies on VEGFR2/AMPK, the post-translational modifications governing the precise spatiotemporal patterns of Peg3 throughout this autophagic cascade, from proximal signaling complexes to distally mature autophagosomes, remains unexplored.
The benchmark standard for rigorously determining autophagic involvement is to analyze the magnitude of flux of cellular cargo through the pathway [58,195–197]. Administering small molecule inhibitors that impede the final step, e.g. fusion of the mature autophagosome with a lysosome to form the terminal autophagolysosome for cargo degradation and nutrient recycling (Fig. 3) [65,70]. Pharmacological compounds such as bafilomycin A1 (BafA1) or chloroquine (CQ) inhibits this terminal step, permitting an analysis of the accumulated cargo. Mechanistically, BafA1 inhibits the lysosomal H+ ATPase to prevent the mature autophagosomes from fusing with lysosomes, thereby increasing the abundance of LC3-II or p62 as quantifiable markers for determining autophagic flux. A lysosomotropic agent, CQ was initially thought to prevent lysosomal acidification [198]. However, it was recently found that CQ inhibits flux by decreasing autophagosome-lysosome fusion [199], similar to that of BafA1. Genetically, autophagic flux can be measured by transiently silencing or wholly ablating key proteases, such as Atg5 [200] that disrupt the physiological processing of LC3-I into LC3-II [195]. Using a confluence of these methodologies, we discovered that decorin, via Peg3, greatly enhances autophagic flux, resulting in excessive and oncosuppressive autophagy [117]. Peg3 alone is sufficient to drive endothelial cell autophagic flux as determined by increases in GFP-LC3 in combination with BafA1 [117]. It is not known whether Peg3 itself is an autophagic substrate or if Peg3 is found on both the outer and the inner autophagic membrane (Fig. 3). In the case of LC3, it is found on both the outer and inner membranes [201–203], which has functional implications as the LC3 species found on the inner membrane do become degraded [204,205], in contrast to the outer membrane fraction which is recycled for subsequent rounds of autophagosome maturation [206]. As LC3 binds JIP-1, a scaffolding protein responsible for the transport of autophagosomes during maturation [207], it is possible that Peg3 could also be recycled. These properties of LC3 confer its characteristics as an autophagic substrate.
Congruent with the role of the nucleus in promoting autophagic longevity [208], is the transcription factor EB (TFEB), a major driver of autophagic flux that is often referred to as the master regulator of lysosome biogenesis [209–211]. TFEB binds CLEAR-box sequences in the proximal promoters of many lysosomal genes to stimulate their expression for lysosomal biogenesis, a key facet to support long-term autophagy [210–213]. TFEB is kept inactive via mTORC1-mediated phosphorylation that permits 14-3-3 scaffolding proteins to bind and sequester it within the cytosol [208,211,214]. Following the transduction of autophagic stimuli, TFEB is rapidly dephosphorylated by the phosphatase calcineurin and translocates into the nucleus where it seeks CLEAR box containing loci and augments their transcription [213]. As decorin is a potent-pro-autophagic stimulant capable of long-term autophagy via differential modulation of the VEGFR2/AMPK/mTOR axis, we found that TFEB responds accordingly [215]. Importantly, depletion of Peg3 significantly blunts the nuclear translocation of TFEB as well as the transcriptional induction of TFEB (Fig. 3). This may promote a positive feedforward loop as TFEB stimulates its own expression [216]. Mechanistically, increasing amounts of Peg3 proportionately heightens TFEB expression in a saturable manner, suggesting interactions of Peg3 with the TFEB promoter [215]. Therefore, Peg3 functions as an upstream driver of TFEB [217]. Compromising the VEGFR2/AMPK axis with SU5416 or Compound C, respectively, abolishes TFEB induction and nuclear translocation. This places TFEB as a major downstream effector of the decorin/VEGFR2/Peg3 autophagic cascade to sustain prolonged autophagy via continued lysosomal biogenesis [215].
As decorin activates AMPK in a prolonged fashion and considering the role of the nucleus (Peg3, TFEB) in promoting autophagy, it is not unreasonable to posit that decorin may modulate epigenetic modifications as an additional regulatory layer to achieve excessive autophagy. Intriguingly, this may be exerted by AMPK signaling via modulation of the SKP2/CARM1 pathway [218]. In this pathway, AMPK positively regulates CARM1 (co-activator-associated arginine methyltransferase) via FOXO3a-mediated transcriptional repression of the SKP2/SCF ubiquitin ligase complex that otherwise targets CARM1 for proteasomal degradation [218]. Accumulated CARM1 engages in transcriptional co-activator functions for TFEB to induce a cohort of lysosomal genes for sustained autophagy. It would be intriguing to determine if decorin, downstream of VEGFR2/AMPK, would increase chromatin occupancy of CARM1 with TFEB and/or decrease activity of the SKP2/SCF ubiquitin ligase complex. Moreover, as Peg3 is involved in evoking TFEB expression, it will be important to determine whether CARM1 is also modulated downstream of Peg3. The discovery of the Peg3/TFEB axis in regulating lysosomal biogenesis is a major step towards understanding the oncosuppressive relationship of decorin and catabolism (Fig. 3).
Decorin evokes VEGFA clearance via autophagy
Decorin is the archetypical small leucine rich proteoglycan involved in a variety of physiological and pathological conditions [219–231]. Moreover soluble decorin [232] is a ligand for several growth factors such as TGF-β [233–237] and Activin C [238], as well as various receptors that potently suppress cancer growth, metastasis and rampant tumor angiogenesis [101,239–258]. Decorin is also involved in Lyme disease [259,260] and as a soluble proteoglycan is potently pro-autophagic in endothelial cells [103]. Uniting both physiognomies instead of perceiving them as single, disparate forms of decorin bioactivity provides a more refined caricature between proteoglycan-evoked autophagy and angiostasis [261]. The conceptual advance is functional dichotomy, where soluble matrix components are both pro-autophagic and concurrently anti-angiogenic; conversely, components that are anti-autophagic are correspondingly pro-angiogenic (Fig.3).
There is also recent evidence that VEGFA itself is involved in regulating autophagy. For example, silencing VEGFA suppresses autophagy through activation of the mTOR pathway [262], whereas VEGFA triggers autophagy in endothelial cells via AMPK [263]. Moreover, inhibition of VEGFA enhances the chemo-sensitivity of ovarian cancer cells by suppressing VEGFA-mediated autophagy [264]. Again, this is another example of the recurrent theme of an outside-in signaling network involving growth factors and ECM molecules- VEGFA is a heparan-sulfate bound growth factor.
The precise molecular underpinning of decorin effects has recently emerged from the discovery that decorin directly promotes degradation of intracellular endothelial VEGFA via autophagy [265], thereby linking autophagy and angiogenesis. This process required the same VEGFR2/AMPK signaling pathway for the mobilization of VEGFA into Beclin 1 or LC3-positive autophagosomes. The anti-angiogenic predilection of pro-autophagic AMPK signaling in nutrient rich conditions was further determined via its activation by saturating amounts of AICAR; this an AMP analog that mimics reduced cellular energy levels decreased intracellular VEGFA levels [266]. Enigmatically, VEGFA catabolism is independent of mTOR signaling as pharmacological blockade with two selective mTOR inhibitors, Torin 1 [267] or INK128 [184], does not perturb intracellular VEGFA. Collectively, there is a delegation of tasks within the signaling pathways governing autophagy that allows context-dependent, targeted degradation of cellular cargo by specific stimuli.
The clearance of VEGFA is wholly dependent on Peg3. Genetic modulation of Peg3 via over-expression or depletion by way of RNAi demonstrated the necessity and sufficiency of Peg3 for marshalling VEGFA into LC3-positive autophagosomes. Augmented expression of Peg3 alone resulted in a sharp increase in dually positive VEGFA/LC3-positive autophagosomes; conversely, loss of Peg3 abrogated this association in response to autophagic stimuli, such as decorin [265]. Further corroborating the connection between autophagy and angiogenesis, VEGFA was found to be a basal substrate for autophagic degradation. The terminal autophagy inhibitors BafA1 or CQ application, or silencing ATG5, a key protease for LC3 processing, resulted in rapid accumulation of intracellular VEGFA. The basal incorporation of VEGFA into these mature autophagosomes is dependent on Peg3, its loss reduced the number of basal autophagosomes that stained positive for LC3/VEGFA. The addition of decorin enhanced VEGFA autophagic degradation by increasing flux [265], potentially in a Peg3 dependent manner [117] (Fig. 3). The small GTPase RAB24 represents a new molecular effector for basal and decorin-evoked VEGFA autophagic clearance [265]. Importantly, RAB24 has already been implicated as a housekeeper for basal autophagic processes [268–270]; it is possible that Peg3 controls RAB24 expression given Peg3 in maintaining basal levels of BECN1 [103,117,265]. Physiologically, VEGFA is subject to autophagic clearance in vivo. Mice that were starved for 2 days experienced a sharp decrease in the overall levels of cardiac and aortic VEGFA. This decrease was significantly abrogated by systemic administration of CQ [265].
Peg3 is integral in orchestrating an integrated transcriptional program that manifests as excessive autophagy concurrent with angiogenic suppression. This proceeds via the physical formation of mature autophagosomes (BECN1, MAP1LC3A) and a sustained response by increasing critical lysosomal biogenesis targets (TFEB) that ultimately encapsulates potent pro-angiogenic growth factors (VEGFA). However, we are only beginning to comprehend the depth of Peg3 in coordinating these responses. A recent computational analysis of Peg3 null endothelial cells posited Peg3 as essential for the endothelial niche and identified a large cohort of differentially expressed genes pertinent for angiogenesis [154]. Notably Thbs1, which encodes thrombospondin-1 a key matricellular protein that evokes angiostasis [271–274], was among the genes decreased upon Peg3 ablation [154]. This is congruent with our findings that over-expression of Peg3 in porcine aortic endothelial cells promotes Thbs1 expression and subsequent thrombospondin-1 secretion [117]. Peg3 may reprogram the endothelial secretome to combinatorically favor the synthesis and excretion of soluble pro-autophagic and anti-angiogenic factors, vis-à-vis von Willebrand factor [275].
Endorepellin evokes protracted autophagy in endothelial cells
Endorepellin is a soluble matrix molecule and is the C-terminal domain of one of the largest proteoglycans, perlecan [276], which is encoded by a large gene with a complex promoter structure responsive to various cytokines and growth factors [100,277–282] and susceptible to various proteases [283,284]. As a whole, perlecan is ubiquitously expressed in both vascular and avascular tissues [285–287] and is highly conserved across species [288–292]. Via its multiple interactions with various ligands and extracellular molecules [293–297] perlecan plays a central function in skeletal muscle and cardiovascular development [298], in regulating developmental [299,300] and tumor angiogenesis [29,301–306], in the uptaking of atherogenic lipoproteins [307], in the blood-brain barrier [308], and in directing cartilage and neural crest development [309,310]. Remarkably, depleting perlecan in the stroma of pancreatic cancer combined with chemotherapy prolongs mouse survival, suggesting that targeting the pancreatic microenvironment could be a useful anti-cancer therapy [311]. Moreover, perlecan is required to prevent thrombosis after deep vascular injury [312], and its overexpression independently predicts poor survival in patients with acute myeloid leukemia [313]. Most of these properties embedded in the parent molecule can be partially explained by its ability to concentrate growth and pro-angiogenic factors. Indeed, perlecan is unique in its structure as it is one of the few proteoglycan protein cores that harbor three closely-spaced heparan sulfate chains at its N-terminus [277,314].
Although endorepellin is a proteolytic derivative of perlecan, they have opposing physiological roles [315]: the parent molecule is pro-angiogenic, whereas endorepellin is anti-angiogenic both in vitro and in vivo [276,316–320]. Moreover, we discovered that soluble endorepellin promotes autophagy [170], whereas perlecan functions as an autophagic inhibitor via activation of the mTORC1 pathway in the soleus muscle of the mice [321]. Endorepellin activates endothelial cell autophagy in the absence of nutrient deficiency or energy depletion, the two canonical autophagic stimuli [322,323]. Endorepellin mimics nutrient deficiency by activating AMPKα at Thr172 while simultaneously blocking mTOR [170], known to be activated following nutrient deprivation [324]. Mechanistically, endorepellin deploys non-canonical phosphorylation of VEGFR2 at Tyr1175, a crucial endothelial cell RTK to induce AMPKα and to inhibit mTOR [170,174]. This action unleashes PEG3 (Figs.1 and 2), a tumor suppressor protein, and master regulator of autophagy [103,104,170]. Under the effect of endorepellin, Peg3 physically interacts with LC3 and Beclin 1 to assist autophagosome formation (Fig. 3). In the absence of Peg3, endorepellin loses its ability to transcriptionally induce autophagy [170].
Endorepellin activates anti-angiogenic pathways
In agreement with their often-opposing roles in autophagy, perlecan and endorepellin once again face-off in the arena of angiogenesis. While the parent molecule, perlecan, utilizes its heparan sulfate chains to sequester growth factors and cytokines to promote angiogenesis, endorepellin lacks such chains and is an angiogenic inhibitor [276]. Intriguingly, endorepellin exerts its anti-angiogenic effect on the endothelial cells at two levels. The first is transient dual receptor antagonism that blocks pro-angiogenic pathways [325]. The second level is more long term and manifests as single receptor activation inducing anti-angiogenic pathways [326].
At the transient level, within a span of 5–10 min of simultaneous binding of endorepellin to VEGFR2 and the α2β1 integrin it potently inhibits angiogenesis via a mechanism we defined as dual receptor antagonism [174,319,320,327]. Structurally, endorepellin contains three laminin-like globular domains (LG1-3) [328,329], separated by EGF-like repeats [314]. The proximal LG1 and LG2 domains interact with IgG3–5 of the VEGFR2 ectodomain, whereas the C-terminal LG3 domains engages the α2β1 integrin receptor, which in turn recruits the SHP-1 tyrosine phosphatase on its cytoplasmic tail [305,316,319,319,330]. The heterotrimeric complex (endorepellin/VEGFR2/α2β1) brings the SHP-1 phosphatase in close functional juxtaposition with the VEGFR2 cytoplasmic tail [320]. SHP-1 dephosphorylates VEGFR2 at Tyr1175 among other residues [320] thereby impairing VEGFA expression and secretion [325]. The LG1/2 domains bind VEGFR2 and allosterically blocks VEGFA from binding to the IgG2–3 VEGFR2 pocket by occupying the adjacent site, IgG3–5 [319]. This prevents VEGFA-dependent VEGR2 phosphorylation at Tyr1175 and impedes the subsequent binding and activation of phospholipase Cγ (PLCγ) and Src homology 2 domain-containing adaptor protein (Shb) [320,327,331–334], two key adaptor proteins that bind phosphorylated VEGFR2. Upon loss of PLCγ and Shb binding, endorepellin attenuates three VEGFA-induced pro-angiogenic pathways, namely the PLCγ/calcineurin/RACK1/NFAT1, the PLCγ/PI3K/PDK1/AKT/mTOR, and Shb/PKC/JNK/AP1 pathways Endorepellin-induced obstruction of each angiogenic pathway ultimately blocks the expression of NFAT1, HIF1A, and AP1, respectively, thus causing widespread and durable angiogenic inhibition. In contrast to the transient or short-term endorepellin-mediated dephosphorylation of VEGFR2 is the long-term, downstream effects of endorepellin-based VEGFR2 phosphorylation at Tyr1175 [178]. Activation of VEGFR2 snowballs into a cascade of stress of stress signaling, autophagy, and mitochondrial depolarization, all of which ultimately leads to angiostasis [91,170,173].
Endorepellin evokes protracted stress signaling in endothelial cells
Endothelial cell stress signaling is a vital pathway recently discovered to be activated by endorepellin. Previously, it was considered that stress could only be induced in a cell by harmful external stimuli such as UV radiation, toxic chemicals, nutrient deprivation, and osmotic stress [173]. Recently, we (and others) have shown that stress could also be induced in cells by ligand-receptor interaction in the absence of any external stimuli or protein misfolding [173,335]. Endorepellin activates the canonical stress axis of PERK/eIF2α/ATF4/GADD45α in the endothelium via direct binding and phosphorylation of VEGFR2 at Tyr1175 [173] (Fig. 4A). This leads to inhibition of angiogenesis as shown in ex vivo aortic rings assays (Fig. 4B) [336]. PERK, which is the foremost molecule of the axis and presents itself as a homodimer on the endoplasmic reticulum, autophosphorylates at Thr980 within two hours of endorepellin exposure. PERK activation subsequently leads to eIF2α phosphorylation at Ser51, increased translation of ATF4, and upregulation of GADD45α protein. ATF4 and GADD45α translocate into the nucleus (Fig. 4A), where, presumably, they block pro-angiogenic processes [173]. While the role of cytoplasmic GADD45α in blocking STAT3 phosphorylation at Ser727 and subsequently blocking VEGFA transcription is recognized [337], the nuclear function of GADD45α is still unclear in the context of angiogenesis.
Fig. 4.
Stress pathway concurrently stimulates autophagy and inhibits angiogenesis. (A) Schematic of endorepellin-based activation of the stress signaling pathway (PERK/eIF2α/ATF4/GADD45α) via VEGFR2 phosphorylation at Thr980. GADD45α inhibits mTOR that leads to angiostasis via two routes: autophagic degradation of HAS2 and dephosphorylation of Stat3. (B) Representative confocal images of ex vivo aortic rings treated every other day for 7 days with vehicle (PBS), endorepellin (200 nM) or tunicamycin (10 μg/ml). Images were captured after staining with the isolectin IB4, an endothelial marker, or after immunoreaction with antibodies against P-PERK (green) or GADD45α (green).
Endorepellin promotes autophagic degradation of HAS2
Earlier we discussed a general mechanism concerning endorepellin-induced endothelial cell autophagy. Here we shed light on a critical autophagic substrate, HAS2, a key enzyme involved in the synthesis of HA with multiple functions in homeostasis and disease [338–353]. A role of HA has been proposed in the formation and homeostasis of the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers endothelial cell lumen and functions as a barrier to circulating cells [354]. The endothelial glycocalyx is highly enriched in HA, and this glycosaminoglycan is increased on laminar shear and reduced when exposed to oscillatory flow [355]. Loss of the glycocalyx impairs endothelial stability and adaptive vascular remodeling [356,357]. Moreover, inhibition of HA expression hampers the stimulus for reperfusion after arterial occlusion [358]. This line of research is directly linked to the biology of HA and stress signaling, as this unsulfated linear glycosaminoglycan is involved in cancer, inflammation and angiogenesis [359]. Under nutrient-rich conditions, endorepellin activates AMPKα, which inhibits mTOR and leads to downstream autophagic catabolism of HAS2 [360]. This catabolic effect is consistently observed across different cell types and species in vitro and in vivo in several tissues from fasted mice [360]. The possibility of proteasomal degradation of HAS2 was ruled out by inhibiting proteasomal activity via MG132 with no significant alterations in total levels of HAS2 or synthesized HA [361], thus reinforcing the hypothesis that endorepellin causes autophagic degradation of HAS2. The intracellular catabolism of HAS2 by autophagy could play a role not only in normal endothelial protein homeostasis, but also at atheroprone sites with abnormal shear stress or in vascular remodelling such as tumor angiogenesis. This is a novel idea that offers a molecular mechanism through which matrix molecules or enzymes involved in their synthesis would regulate in vivo angiogenesis.
Crosstalk between endorepellin-induced autophagy and anti-angiogenic pathways
Many independent groups have demonstrated that matrix-derived angiogenic inhibitors such as endorepellin, decorin (see above), and endostatin (see below) induce autophagy (Fig. 1) [103,170,362]. This indicates that engaging endothelial autophagy might be a common mechanism for matrix-derived anti-angiogenic molecules to exercise their effects. We identified two critical proteins, GADD45α and HAS2, that connect autophagy to angiogenic pathways (Fig. 4A).
GADD45α canonically arrests the cell cycle upon DNA damage due to UV radiation, toxic chemicals, osmotic fluctuations, or other types of stress [363]. However, in a more diverse role, GADD45α inhibits angiogenesis and modulates autophagy [337,364]. Our recent study detailed the anti-angiogenic role of GADD45α in constricting blood vessel growth in ex vivo aortic ring assays [173,336]. Similarly, GADD45α suppresses tumor angiogenesis in nude mice [337]. In these tumors, GADD45α suppresses STAT3 phosphorylation by physically interacting and blocking its activator, mTOR. STAT3 inhibition further downregulates VEGFA expression and thus inhibits angiogenesis [337]. Whether GADD45α and the physical interaction with mTOR is required or impacts tumor autophagy, as mTOR is a potent autophagic inhibitor, needs further investigation.
GADD45α explicitly promotes autophagy in skeletal muscles during muscular atrophy caused by stressful conditions such as muscular starvation, immobility, or denervation [364]. Despite evidence in favor of GADD45α in mediating autophagic induction, other reports suggest otherwise. For example, in cancer cells, GADD45α inhibits autophagy by disrupting BECN1-PIK3C3 complex formation, thus demonstrating a tissue-specific role of GADD45α in autophagic induction [365]. It is apparent that GADD45α plays a crucial role in modulating autophagy and concurrently inhibiting angiogenesis, thereby establishing a robust link between angiogenesis and autophagy.
The second molecule, HAS2, is a critical enzyme that generates HA [341,361,366,367], a much-hyped matrix molecule that structurally helps water retention in the microenvironment, but also signals to the existing vasculature via a plethora of cell surface receptors to stimulate angiogenesis [338,359,368–370]. Very recently, we discovered that HAS2 is degraded via autophagy, which directly diminishes HA secretion in vitro and ex vivo [360]. Another supporting study found that activating AMPK through metformin, commonly used to treat diabetes, downregulates HA secretion in vascular smooth muscle cells [371], further suggesting an AMPK-dependent downregulation of HAS2. More importantly, HAS2 may partake in autophagosomal biogenesis and not only be a substrate of autophagy [360]. We found that HAS2 binds ATG9A [360], which transports lipids from the plasma membrane, endoplasmic reticulum, Golgi apparatus, and the mitochondria to the growing autophagosome [78,372–375]. Using super-resolution microscopy, we observed an increase in co-localization of HAS2 and ATG9A, which we further corroborated with immunoprecipitation studies [360]. In alliance with the core autophagic machinery, ATG9A undergoes phosphorylation by ULK1, a post-translational modification essential for LC3 recruitment and autophagosomal formation [376]. Thus, by exclusively binding ATG9A and aiding in the transport of structural components, HAS2 facilitates autophagosome formation [360]. This transcending behavior of HAS2, where it oscillates between an angiogenic inducer and an autophagosome constructor and substrate, highlights it as a critical link between the two pathways.
Endostatin, plasminogen kringle 5, and collagen VI evoke endothelial cell autophagy
Akin to the mechanism for endorepellin, the C-terminal domain of the collagen XVIII α1 chain is proteolytically processed by cathepsin L [377] to yield a soluble and potently angiostatic component known as endostatin [378,379]. Liberated endostatin evokes anti-proliferative [380], pro-apoptotic [381,382], and anti-migratory [383] effects on endothelial cells without competing for heparan sulfate or FGF2 binding [384]. Endostatin is currently being evaluated, with clinical success, as a neoadjuvant first-line therapy referred to as endostar when combined with traditional chemotherapeutics for breast cancer [385], advanced solid tumors [386], well-differentiated pancreatic neuroendocrine tumors [387], and non-small cell lung cancer [388]. Notably, combinatorial treatment of Lewis lung carcinoma xenografts with anti-PD-1 and endostar results in a remarkable synergistic effect through the suppression of the PI3K/AKT/mTOR signaling pathway, which ultimately improves the tumor microenvironment and activates autophagy [389]. Endostatin activates autophagic gene expression through X-box-binding protein 1 (XBP1) in an inositol-requiring enzyme 1α (IRE1α)-dependent manner [390]. Moreover, endostar evokes cell death of hepatoma cells by autophagic induction [391], suggesting that endostar might act on tumor cells directly.
The information encoded by endostatin is transduced via high-affinity interactions with the α5β1 integrin (Fig. 1) [392] to induce endothelial cell autophagy in multiple models, human umbilical vein endothelial cells, and EAhy926 human endothelial cells (Fig. 1) [362,393]. Endostatin also binds VEGFR2 [394], and this may represent a variation of “dual-receptor antagonism” utilized by endorepellin [171] (see above) to realize anti-angiogenic and pro-autophagic effects. Moreover, collagen type XVIII/endostatin co-localizes with perlecan within basement membranes in vivo [395], potentially raising the possibility that these proteolytic fragments may work synergistically in the vascular niche. Thus, endostatin is a member of the ever-growing collection of soluble molecules that are concurrently pro-autophagic and anti-angiogenic members. In an empirical example that further corroborates this concept, a mutated form of endostatin known as P125A endostatin exhibits higher-affinity binding and enhanced autophagic effects via the pro-autophagic Vps34/Beclin 1/LC3 complex [362,393]. Autophagosomal biogenesis and subsequent maturation evoked by P125A endostatin is pharmacologically inhibited by 3-MA in a mechanism similar to decorin (Fig. 3) and endorepellin in endothelial cells [362]. Considering the molecular similarities of endostatin on autophagosome formation, it is plausible that endostatin might also regulate Peg3 (Fig. 1) and/or TFEB for sustained autophagic progression. Moreover, endostatin differentially and combinatorically promotes the binding of Beclin 1 with multiple protein complexes that favor autophagic progression and disfavors the association of Beclin 1 with inhibitive complexes. Indeed, Bcl-2 and Bcl-xL which are known anti-autophagic proteins, are precluded from binding and sequestering Beclin 1 [362], much like the effect of decorin on Beclin 1/Bcl2 interactions (see above) [107].
Kringle 5 and angiostatin (kringle 1–4) are endogenous inhibitors of angiogenesis derived from the proteolytic processing of plasminogen [396]. Kringle 5 plays an important role in inhibiting endothelial cell proliferation as well as activating autophagic and apoptotic behaviors [397,398]. Angiogenesis involves the formation of capillaries that sprout from existing blood vessels [336,399]. Since blood capillaries are chiefly composed of endothelial cells, kringle 5 is heavily involved in the suppression of FGF2-stimulated endothelial cell proliferation [400]. Murine kringle 5 triggers cell cycle arrest by limiting the transition of C-PAE cells from entering the S phase from G0 phase [401]. Treatment with recombinant kringle 5 causes cell detachment, shrinkage, and granulation. Mechanistically, kringle 5 evokes apoptosis as detected by TUNEL staining and Annexin V FITC assays. More recently, researchers have discovered that kringle 5 via cell surface expressed glucose regulated protein 78 (GRP78) [402] induces autophagy and apoptotic death in endothelial and tumor cells [397,403,404] by upregulating Beclin 1 (Fig. 1). Upon long term treatment with kringle 5, caspase-7 is processed and activated downstream of GRP78 for apoptosis. Plasminogen kringle 5 evokes endothelial cell apoptosis by triggering a voltage-dependent anion channel 1 (VDAC1) positive feedback loop [405]. Specifically, kringle 5 increases the protein level of VDAC1, a surface receptor on endothelial cells [406], thereby evoking mitochondrial apoptosis in endothelial cells [405]. A similar effect on mitochondrial apoptosis has been reported by kringle 5-evoked subcellular distribution of pro-apoptotic proteins [407]. Moreover, plasminogen kringle 5 suppresses gastric cancer via regulation of HIF-1α and GRP78 [408], and a peptide derived from kringle 5 inhibits VEGFA-mediated VEGFR2 activation, thereby preventing the breakdown of the blood-retinal barrier in diabetic mice [409]. Finally, in addition to GRP78, kringle 5 binds to the laminin α3 chain in human endothelial cells suggesting the existence of another specific receptor for kringle 5 [410]. Again, this is a recurrent theme for a functional outside-in signaling network regulating vital intracellular processes.
Collagen VI is a protein found in the ECM that is secreted by fibroblasts in a variety of tissues that aids in self-renewal of satellite cells and in muscle regeneration [411]. Collagen VI has been implicated in cancer [412], muscular dystrophies [413–415], and Col6a1−/− mice have been proposed to represent a good experimental animal model to study muscle decline in aging [416]. As autophagy plays a pivotal role in maintaining skeletal muscle homeostasis and may represent an underlying pathological mechanism for muscular dystrophy [417], collagen IV was recently found to play an integral role in autophagic activation [418] (Fig. 1). In murine fibroblasts derived from Col6a1−/− mice, there is impaired autophagosomal clearance and lack of Parkin-dependent mitophagy, indicative of a severe defect in autophagic machinery [419]. The mitophagy defect is consistent and may be mechanistic with respect to the documented mitochondrial dysfunction in myopathic mice deficient in collagen VI [420]. Moreover, Col6a1−/− exhibit impaired autophagic flux, with a correlation to lower induction of Bcl-2 interacting protein-3 (Bnip3) [418]. The myofiber degeneration phenotype in the collagen VI knockout mice was rescued through pharmacological restoration of autophagy, indicating that collagen VI is essential for autophagy in muscle cells [418]. Similar results were found in neural cells, with Col6a1−/− mice displaying spontaneous apoptosis and defective autophagy after analysis of brain sections [421]. Notably, the myopathic phenotype of Col6a1−/− mice is improved by pterostilbene, a polyphenol similar in structure to resveratrol that evokes in vivo autophagic flux in skeletal muscle [422]. Due to the mounting evidence that autophagy plays an integral role in promoting angiostasis in growing neoplasms, collagen VI may provide a crucial avenue for cancer research and tumor angiogenesis (see review by Castagnaro et al in this Special issue).
There is also evidence that autophagy might be linked to the proper secretion and folding of various collagens. For example, defective collagen proteostasis and matrix formation are involved in the pathogenesis of lysosomal storage disorders [423]. Another example is provided by collagen VII which plays a role in fibrosis and wound healing [424,425]. Lack of collagen VII causes various forms of epidermolysis bullosa [426–428] and leads to alterations of intracellular protein composition and perturbation of autophagy [429]. Mutations of PLOD3, which encodes lysyl oxidase 3, can also cause a complex syndrome of epidermolysis bullosa with abnormal anchoring fibrils and deficiency of collagen VII [430]. Thus, collagen VII can be affected via multiple pathways and importantly, a microenvironment deficient in collagen VII favors cancer initiation [431]. There is also a link between cellular stress/autophagy and proper collagen secretion, as administration of the chaperone 4-phenylbutyrate alleviates cellular stress and concurrently stimulates autophagy in osteogenesis imperfecta cells [432]. These findings are supported by a recent observation that autophagy plays a key regulatory role in facilitating collagen I synthesis and regulating osteoblastic differentiation in periodontal ligament cells [433].
The cell adhesion molecule IGPR-1 is involved in autophagy
The immunoglobulin and proline-rich receptor-1 (IGPR-1) is a ~55 kDa cell adhesion molecule expressed in a variety of cells including epithelial and endothelial cells and mediates cell-cell adhesion [434]. IGPR-1, also known as transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2), is identical to the homologue of CD28 (CD28H), one of the receptors for HHLA2, an immune check point member of the B7 family [435–437]. IGPR-1 harbors a single Ig repeat, a transmembrane domain and a long cytoplasmic tail enriched in Pro residues capable of associating with multiple Src homology 3-containing signaling proteins [434]. Thus, it is not surprising that IGPR-1 is directly involved in regulating homophilic cell aggregation and capillary morphogenesis, thereby implicating this molecule in angiogenesis [434]. It is becoming evident that IGPR-1 is pro-tumorigenic as it promotes multicellular aggregation of cancer cells, increases tumor growth in vitro and in vivo, and increases chemoresistance [438]. Moreover, IGPR-1 is localized at adherens junctions, interacts with several SH3-containing proteins, and is necessary for endothelial cell-cell adhesion and barrier function [439]. Notably, IGPR-1 is activated by flow shear stress with a specific phosphorylation at Ser220 suggesting that IGPR-1 may play a role in endothelial cell mechanosensing [440]. More importantly, shear stress regulates endothelial cell autophagy via a Sirt1-dependent mechanism [441]. More recently, it was found that pro-autophagic stimuli, such nutrient deprivation, rapamycin of lipopolysaccharides, activate IGPR-1 at Ser220 [442]. This in turn evokes AMPK phosphorylation leading to autophagic activation. It would be interesting to test if decorin and/or endorepellin would also cause phosphorylation of IGPR-1 at Ser220 during their respective pro-autophagic activity, and to test whether there is any cross-talk between IGPR-1 and VEGFR2 as the common node for these signaling cascades that lead to activation of AMPK and autophagy. Collectively, IGPR-1 links cell adhesion and energy sensing to autophagy. Thus, IGPR-1 is an additional component of a functional outside-in signaling network connecting matrix molecules and surface receptors to intracellular catabolism via autophagy.
The other side of the coin: Laminin α2, perlecan and lumican inhibit autophagy
In stark contrast to the pro-autophagic effectors discussed in the above sections, the laminin α2 chain and the titanic HSPG vascular basement membrane proteoglycan perlecan shares an exclusive property as they both exert anti-autophagic properties (Fig. 1) [321,443]. Laminin α2, encoded by LAMA2 gene, represents the α2 subunit of laminin 211, a vital basement membrane component [444]. Functionally, akin to collagen VI, several site-specific mutations have been mapped to the α2 subunit as causative for merosin-deficient congenital muscular dystrophy (MDC1A). MDC1A is a progressive muscular dystrophy typified by muscle weakness, peripheral neuropathy, and joint contractures [413,443]. However, in contrast to the loss of collagen VI, loss of LAMA2, triggers the expression of autophagy genes (Fig. 1) [443].
In the case of perlecan, tissue specific ablation of Hspg2 in the Mus musculus soleus muscle results in a significant increase in LC3 puncta and associated signaling apparati such as the PI3K/mTOR pathways at basal levels and following tendonectomy [321,445]. Therefore, basement membranes are composed of functionally opposite members that can fine-tune autophagic induction and may help to terminate aberrant autophagy in a temporal and spatial manner [446]. There might be a link between lack of perlecan and lack of heparan sulfate chains. Indeed, the Drosophila orthologue of perlecan/Hspg2 is a secreted heparan sulfate proteoglycan called Trol (terribly reduced optical lobes) that affects Wg/Wnt signaling at the synapse, regulating both motoneuron terminal outgrowth and the elaboration of a post-synaptic specialization [447]. Trol modulates FGF and Hedgehog signals and the proliferation of neuroblasts [448–450], it regulates bidirectional Wnt signaling at the neuromuscular junction [451], and is involved in mesoderm specification [452] and blood progenitor cell differentiation [453]. Moreover, Trol provides a structural support for the establishment of the ovarian germline niche during larval stages and in maintaining a normal pool of stem cells in the adult ovarian niche [454]. Importantly, heparan sulfate production in Drosophila is required for normal levels of autophagy in the fat body, the central energy storage and nutritional sensing organ [455]. Altering sulfate biosynthesis and thus modifying the fine structure of heparan sulfate affects autophagy and mitophagy [456], indicating that activation of autophagy-mediated removal of mitochondria is potentiated in these mutant animals. Collectively, these findings provide robust genetic evidence that altering the in vivo levels of heparan sulfate synthesis activates autophagy and could provide protection from a variety of cellular stressors (see review by Schultheis et al in this issue).
Another small leucine-rich proteoglycan, lumican, previously shown to be involved in collagen organization and ocular pathophysiology [457–459] as well as cell adhesion and tumorigenesis [460–462], has been recently implicated in suppressing autophagy [463]. With time lumican has been linked to various biological processes and pathologies, including tumor-cell interactions, angiogenesis, inflammatory responses, wound healing and fibrosis, and bacterial phagocytosis and clearance [464–469]. Recently, higher serum levels of lumican have been observed in obese patients with pre-diabetes and in metabolic syndrome patients [470], and it has been proposed that lumican could play a direct role in the development of diet-induced obesity and insulin resistance [471]. Moreover, keratan sulfate degradation of lumican has been found to be one of the urinary markers involved in the early kidney response to hyperglycemia in young patients with type I diabetes [472]. Thus, lumican would provide a link between ECM, glucose homeostasis and features associated with the metabolic syndrome [471]. Notably, a major role for decorin in cardiac physiology has been proposed based on the observation that Dcn−/− mice differ from wild-type mice in cardiac glucose utilization and reduced sensing of nutrient deprivation, thereby preempting functional adjustments of cardiac output linked to metabolic reprogramming [125]. The role of other small leucine-rich proteoglycans in metabolism should be the focus of future studies.
Lumican is a general suppressor of malignant cell growth in pancreatic [473,474], breast [475–477] and prostate [478] cancer, as well as in melanoma [479,480]. However, in lung [481] and gastric [482,483] cancer, lumican expression correlates with a poor prognosis and metastatic spreading suggesting that lumican may act in a tissue-specific context. For example, downregulation of lumican accelerates lung cancer cell invasion via p120 catenin, an intracellular scaffolding protein that stabilizes cell adhesion [484]. Furthermore, lumican is implicated in epithelial-to-mesenchymal transition in breast cancer, especially those expressing estrogen receptor α [476,477]. Notably, the proposed mechanism of the anti-autophagic function of lumican is quite unique as lumican enhances chemotherapeutic activity against pancreatic carcinoma by suppressing chemotherapy-evoked autophagy [485]. Inhibition of AMPK phosphorylation or expression of HIF-1α within hypoxic stellate cells restores lumican expression [486]. The discovery of lumican-derived peptides that inhibit melanoma cell growth and migration [487] provides another example for the presence of an intricate network of outside-in signaling factors controlling intracellular processes. Another recurrent theme is the utilization by matrix constituents of similar receptors with diverse downstream affects, For example, lumican interacts with α2β1 integrin, a receptor also used by endorepellin/perlecan [300,305] and decorin [488–490], to stimulate bone formation and inhibit tumor progression [491,492].
Conclusions and perspectives
We have critically evaluated the role of novel ECM components with intrinsic propensities for autophagic regulation that run both sides of the gamut for either activation or inhibition. Most of these regulatory ECM molecules are soluble proteoglycans or smaller processed forms often derived from their C termini. A new conceptual advance emerges from this rapidly growing literature on the existence of a complex network of matrix signaling molecules closely interconnected with surface receptors. These functional interactions affect intracellular processes such as autophagy relevant to disease prevention, cancer diagnosis, and treatment. This complex network of interacting proteins leads to activation or inhibition of multiple cell surface signaling receptors, predominantly those belonging to the RTK superfamily. This process, often supplemented by the activity of co-receptors, causes sustained signal transduction for protracted and transcriptionally-driven autophagic activation in a variety of cell types and microenvironmental niches. Thus, autophagic regulation further reinforces the idea of matrix-based therapeutics as novel modalities for combating a range of pathologies.
A core commonality shared among all of these intrinsic regulators is Peg3, an intriguing gene product that sits at the intersection of endothelial cell autophagy and angiostasis in cancer development. The trifecta of VEGFR2/AMPK/Peg3 decodes, transduces, and integrates innate pro-autophagic and anti-angiogenic bioinformation encoded within the 3D structure of decorin and ensuing topology of the decorin/VEGFR2 interaction. These same structural and topological considerations most likely govern the downstream signaling of similar matrix/receptor interactions. Despite the breadth of knowledge already gleaned regarding these novel Peg3 neofunctions, much remains to be discovered. Performing an in-depth transcriptomic analysis of Peg3 target genes via ChIP-seq or utilizing cutting-edge techniques that investigate the genomic architecture following autophagic stimulation will provide invaluable insight into the depth of Peg3 as a master transcriptional regulator. Further, conducting a proteomic inventory of Peg3 via proximity-dependent proteomics, such as BioID, would detail the landscape of Peg3 binding partners that may yield therapeutically ideal targets to suppress cancer and angiogenesis. As Peg3 associates with LC3-positive autophagosomes [103], enriching for this autophagosome population [493] would provide functional insight as to the identities of cellular cargo being loaded. This would address whether Peg3 is promoting general, nonspecific (macro) autophagy or is “programmed” to degrade a specific subset of cellular debris, given the non-canonical mode of induction by decorin or related proteoglycans. In the aggregate, Peg3 is a molecular bridge that integrates unorthodox proteoglycan-centric signals resulting in excessive autophagy and sustained angiostasis
Another important conceptual advance is that the matrix control of autophagy occurs via a number of signaling cascades that at times overlap with the stress signaling pathway. Intriguingly, stimuli such as shear stress, LPS, and chemotherapeutic agents are well-known potent inducers of autophagy. In addition, LPS evokes autophagy in primary macrophages via Toll-like receptor 4 (TLR4) [494], thereby linking together two ancient processes, autophagy and innate immunity, via a shared signaling pathway. This concept is further supported by the fact that overexpression of TLR4 affects autophagy and oxidative stress [495] and that AMPK regulates a pro-autophagic TLR4-mediated signaling axis [496]. Thus, it is possible that decorin, which binds to and interacts with TLR4 in macrophages [497,498], could also evoke autophagy by utilizing the innate immunity pathway. Indeed, biglycan, a proteoglycan involved in inflammation, angiogenesis, fibrosis and bone physiology [499–505] evokes autophagy in macrophages via a CD44/TLR4 signaling pathway [99] (see review by Schulz et al in this Special issue). In this context, biglycan could act as a molecular switch by steering signaling toward inflammation via CD14 while triggering autophagy via CD44 [506,507]. Finally, lumican is markedly upregulated in osteoarthritis and increases LPS-induced activation of TLR4 [508], thereby potentially affecting autophagy. Lumican, in this context, would evoke inflammation and could contribute to cartilage degradation and macrophage polarization in osteoarthritic patients [508]. More studies need to be performed using animal models of inflammation and cancer to ascertain the precise roles of these various matrix effectors on regulating pathological autophagy. Perhaps, future therapies will include drugs or small molecules targeting these extracellular effectors.
Another area of potential investigation is the rapidly expanding field of exosomes and vesicle communication where various members of the integrin family and proteases/glycosydases can be transferred intercellularly with modifications of cell behavior including changes in the malignant phenotype and angiogenesis [509–517]. The recent discovery that extracellular vesicles released by hypoxic breast cancer cells affect mitochondrial dynamics [518] together with the role of neutrophil-derived exosomes in proteolytic cleavage of the ECM [519], provide good examples in support of the concept for a functional outside-in network regulating intracellular processes. Finally, there is an emerging body of evidence linking protracted autophagy to inhibition of angiogenesis [326,396]. Thus, the autophagic response appears to be a novel target for boosting the therapeutic efficacy of angiogenesis inhibitors.
Highlights.
Extracellular matrix is emerging as a potent outside-in regulator of intracellular catabolism
Proteoglycans and liberated bioactive fragments constitute the majority of soluble effectors that signal via cell surface receptors to engage a common autophagic core
Conceptually, these molecules possess convergent properties of being simultaneously pro-autophagic and anti-angiogenic
The intrinsic properties of ECM components represent an untapped resource for the design of future protein-based therapeutics to combat disease
Acknowledgments
We thank all the past and present members of the Iozzo’s laboratory for their contribution to the field. This work was supported in part by NIH RO1 CA39481, RO1 CA47282, and RO1 CA245311 to RVI.
Abbreviations used:
- AMP
adenosine monophosphate
- Atg13
Autophagy gene 13
- BafA1
bafilomycin A1
- Bnip3
Bcl-2 interacting protein-3
- CAMKK2
Calcium/calmodulin dependent protein kinase 2
- CARM1
Coactivator associated arginine methyltransferase-1
- CQ
Chloroquine
- FIP200
FAK family kinase-interacting protein of 200 kDa
- FOXO
Forkhead box
- FOXO3a
Forkhead box 3a
- GRP78
glucose regulated protein 78
- GFP
Green fluorescent protein
- KAP1
KRAB-associated protein-1
- IGPR-1
immunoglobulin and proline-receptor-1 (IGPR-1)
- KRAB-A
Krüpple-associated box-A
- LC3
microtubule-associated proteins 1A/1B, light chain 3
- LKB1
Liver kinase B1
- MO25α
Uncharacterized protein MO25 α
- mTORC1
mammalian target of rapamycin complex 1
- ORF
Open reading frame
- PAS
Phagophore assembly site
- PI3K
Phosphatidylinositol 3 kinase
- RAB24
Ras-associated protein 24
- SCAN
SREZBP-Ctfin51-AW1-Number 18
- SCF
Skp1-Cullin-F-box containing complex
- SKP2
S-phase kinase-associated protein 2
- STRAD1
STE20 related adaptor 1
- TFEB
Transcription factor EB
- TLR4
Toll-like receptor 4
- TNF-α
Tumor necrosis factor α
- ULK1/2
Unc51 like autophagy activating kinase 1/2
- VDAC1
voltage-dependent anion channel 1
- VEGFA
Vascular endothelial growth factor A
- Vps34
Vacuolar and protein sorting 34
Footnotes
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Conflict of interest
The authors declare no conflicts of interest.
References
- [1].Iozzo RV, Schaefer L, Proteoglycan form and function: A comprehensive nomenclature of proteoglycans, Matrix Biol. 42 (2015) 11–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Theocharis AD, Skandalis SS, Neill T, Multhaupt HA, Hubo M, Frey H, Gopal S, Gomes A, Afratis N, Lim HC, Couchman JR, Filmus J, Ralph DS, Schaefer L, Iozzo RV, Karamanos NK, Insights into the key roles of proteoglycans in breast cancer biology and translational medicine, Biochim. Biophys. Acta 1855 (2015) 276–300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, Iozzo RV, Karamanos NK, Cell-matrix interactions: focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer, FEBS J. 281 (2014) 5023–5042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Theocharis AD, Karamanos NK, Proteoglycans remodeling in cancer: Underlying molecular mechanisms, Matrix Biol 75–76 (2019) 220–259. [DOI] [PubMed] [Google Scholar]
- [5].Iozzo RV, Cohen I, Altered proteoglycan gene expression and the tumor stroma, Experientia 49 (1993) 447–455. [DOI] [PubMed] [Google Scholar]
- [6].Iozzo RV, Proteoglycans and neoplasia, Cancer Metastasis Rev. 7 (1988) 39–50. [DOI] [PubMed] [Google Scholar]
- [7].Karamanos NK, Piperigkou Z, Theocharis AD, Watanabe H, Franchi M, Baud S, Brezillon S, Gotte M, Passi A, Vigetti D, Ricard-Blum S, Sanderson RD, Neill T, Iozzo RV, Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics, Chem. Rev 118 (2018) 9152–9232. [DOI] [PubMed] [Google Scholar]
- [8].Iozzo RV, Gubbiotti MA, Extracellular matrix: The driving force of mammalian diseases, Matrix Biol 71–72 (2018) 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Bi Y, Stueltens CH, Kilts T, Wadhwa S, Iozzo RV, Robey PG, Chen X-D, Young MF, Extracellular matrix proteoglycans control the fate of bone marrow stromal cells, J. Biol. Chem 280 (2005) 30481–30489. [DOI] [PubMed] [Google Scholar]
- [10].Iozzo RV, Zoeller JJ, Nyström A, Basement membrane proteoglycans: Modulators par excellence of cancer growth and angiogenesis, Mol. Cells 27 (2009) 503–513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Mizushima N, Komatsu M, Autophagy: Renovation of cells and tissues, Cell 147 (2011) 728–741. [DOI] [PubMed] [Google Scholar]
- [12].Karamanos NK, Theocharis AD, Neill T, Iozzo RV, Matrix modeling and remodeling: A biological interplay regulating tissue homeostasis and diseases, Matrix Biol. 75–76 (2019) 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Mongiat M, Buraschi S, Andreuzzi E, Neill T, Iozzo RV, Extracellular matrix: the gatekeeper of tumor angiogenesis, Biochem. Soc. Trans 47 (2019) 1543–1555. [DOI] [PubMed] [Google Scholar]
- [14].Han B, Li Q, Wang C, Patel P, Adams SM, Doyran B, Nia HT, Oftadeh R, Zhou S, Li CY, Liu XS, Lu XL, Enomoto-Iwamoto M, Qin L, Mauck RL, Iozzo RV, Birk DE, Han L, Decorin Regulates the Aggrecan Network Integrity and Biomechanical Functions of Cartilage Extracellular Matrix, ACS Nano. 13 (2019) 11320–11333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Robinson KA, Sun M, Barnum CE, Weiss SN, Huegel J, Shetye SS, Lin L, Saez D, Adams SM, Iozzo RV, Soslowsky LJ, Birk DE, Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons, Matrix Biol 64 (2017) 81–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Walraven M, Hinz B, Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer, Matrix Biol 71–72 (2018) 205–224. [DOI] [PubMed] [Google Scholar]
- [17].Wight TN, A role for proteoglycans in vascular disease, Matrix Biol 71–72 (2018) 396–420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Iozzo RV, Theocharis AD, Neill T, Karamanos NK, Complexity of Matrix Phenotypes, Matrix Biol Plus 6–7 (2020) 100038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Cianfarani F, De DE, Nystrom A, Mastroeni S, Abeni D, Baldini E, Ulisse S, Uva P, Bruckner-Tuderman L, Zambruno G, Castiglia D, Odorisio T, Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa, Matrix Biol 81 (2019) 3–16. [DOI] [PubMed] [Google Scholar]
- [20].Myren M, Kirby DJ, Noonan ML, Maeda A, Owens RT, Ricard-Blum S, Kram V, Kilts TM, Young MF, Biglycan potentially regulates angiogenesis during fracture repair by altering expression and function of endostatin, Matrix Biol. 52–54 (2016) 141–150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Chen F, Lai J, Zhu Y, He M, Hou H, Wang J, Chen C, Wang DW, Tang J, Cardioprotective Effect of Decorin in Type 2 Diabetes, Front Endocrinol. (Lausanne) 11 (2020) 479258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Ricard-Blum S, Baffet G, Théret N, Molecular and tissue alterations of collagens in fibrosis, Matrix Biol 68–69 (2018) 122–149. [DOI] [PubMed] [Google Scholar]
- [23].Tzanakakis G, Giatagana EM, Kuskov A, Berdiaki A, Tsatsakis AM, Neagu M, Nikitovic D, Proteoglycans in the pathogenesis of hormone-dependent cancers: Mediators and effectors, Cancers. (Basel) 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Ojnishi T, Novais EJ, Risbud MV, Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration, Matrix Biol Plus 6–7 (2020) 100036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].VanOpstall C, Perike S, Brechka H, Gillard M, Lamperis S, Zhu B, Brown R, Bhanvadia R, Vander Griend DJ, MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans, Elife. 9 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Folkman J, Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat. Med 1 (1995) 27–31. [DOI] [PubMed] [Google Scholar]
- [27].Folkman J, Role of angiogenesis in tumor growth and metastasis, Semin. Oncol 29 (2002) 15–18. [DOI] [PubMed] [Google Scholar]
- [28].Folkman J, Is angiogenesis an organizing principle in biology and medicine?, J. Pediatr. Surg 42 (2007) 1–11. [DOI] [PubMed] [Google Scholar]
- [29].Iozzo RV, San Antonio JD, Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena, J. Clin. Invest 108 (2001) 349–355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Mongiat M, Andreuzzi E, Tarticchio G, Paulitti A, Extracellular Matrix, a Hard Player in Angiogenesis, Int. J. Mol. Sci 17 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [31].Katoh M, FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review), Int. J. Mol. Med 38 (2016) 3–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].DeLeon-Pennell KY, Barker TH, Lindsey ML, Fibroblasts: The arbiters of extracellular matrix remodeling, Matrix Biol 91–92 (2020) 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Urbanczyk M, Layland SL, Schenke-Layland K, The role of extracellular matrix in biomechanics and its impact on bioengineering of cells and 3D tissues, Matrix Biol 85–86 (2020) 1–14. [DOI] [PubMed] [Google Scholar]
- [34].Eckhard U, Huesgen PF, Schilling O, Bellac CL, Butler GS, Cox JH, Dufour A, Goebeler V, Kappelhoff R, Keller UA, Klein T, Lange PF, Marino G, Morrison CJ, Prudova A, Rodriguez D, Starr AE, Wang Y, Overall CM, Active site specificity profiling of the matrix metalloproteinase family: Proteomic identification of 4300 cleavage sites by nine MMPs explored with structural and synthetic peptide cleavage analyses, Matrix Biol. 49 (2016) 37–60. [DOI] [PubMed] [Google Scholar]
- [35].Panwar P, Butler GS, Jamroz A, Azizi P, Overall CM, Brömme D, Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases, Matrix Biol 65 (2018) 30–44. [DOI] [PubMed] [Google Scholar]
- [36].Daseke MJ, Tenkorang MAA, Chalise U, Konfrst SR, Lindsey ML, Cardiac fibroblast activation during myocardial infarction wound healing: Fibroblast polarization after MI, Matrix Biol 91–92 (2020) 109–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Bradshaw AD, DeLeon-Pennell KY, T-cell regulation of fibroblasts and cardiac fibrosis, Matrix Biol 91–92 (2020) 167–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [38].Alexander J, Cukierman E, Cancer associated fibroblast: Mediators of tumorigenesis, Matrix Biol 91–92 (2020) 19–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [39].Naba A, Clauser KR, Hoersch S, Liu H, Carr SA, Hynes RO, The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices, Mol. Cell Proteomics 11 (2012) M111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Naba A, Clauser KR, Ding H, Whittaker CA, Carr SA, Hynes RO, The extracellular matrix: Tools and insights for the “omics” era, Matrix Biol. 49 (2016) 10–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [41].Teuscher AC, Jongsma E, Davis MN, Gebauer JMNA, Ewald CY, The in-silico characterization of the Caenorhabditis elegans matrisome and proposal of a novel collagen classification, Matrix Biol Plus 1 (2019) 100001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Davis MS, Horne-Badovinac S, Naba A, In-silico definition of Drosophila melanogaster matrisome, Matrix Biol Plus 4 (2019) 100015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [43].Statzer C, Ewald CY, The extracellular matrix phenome across species, Matrix Biol Plus 8 (2020) 100039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [44].Nauroy P, Hughes S, Naba A, Ruggiero F, The in-silico zebrafish matrisome: A new tool to study extracellular matrix gene and protein functions, Matrix Biol 65 (2018) 5–13. [DOI] [PubMed] [Google Scholar]
- [45].Brosseau JP, Sathe AA, Wang Y, Nguyen T, Glass DA, Xing C, Le LQ, Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing, Acta Neuropathol. Commun 9 (2021) 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [46].Brechbuhl HM, Barrett AS, Kopin E, Hagen JC, Han AL, Gillen AE, Finlay-Schultz J, Cittelly DM, Owens P, Horwitz KB, Sartorius CA, Hansen K, Kabos P, Fibroblast subtypes define a metastatic matrisome in breast cancer, JCI. Insight 5 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [47].Tian C, Õhlund D, Rickelt S, Lidstrõm T, Huang Y, Hao L, Zhao RT, Franklin O, Bhatia SN, Tuveson DA, Hynes RO, Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma, Cancer Res. 80 (2020) 1461–1474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [48].Peeney D, Fan Y, Nguyen T, Meerzaman D, Stetler-Stevenson WG, Matrisome-associated gene expression patterns correlating with TIMP2 in cancer, Sci. Rep 9 (2019) 20142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [49].Mitra S, Tiwari K, Podicheti R, Pandhiri T, Rusch DB, Bonetto A, Zhang C, Mitra AK, Transcriptome profiling reveals matrisome alteration as a key feature of ovarian cancer progression, Cancers. (Basel) 11 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [50].Bingham GC, Lee F, Naba A, Barker TH, Spatial-omics: Novel approaches to probe cell heterogeneity and extracellular matrix biology, Matrix Biol 91–92 (2020) 152–166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [51].Naba A, Clauser KR, Mani DR, Carr SA, Hynes RO, Quantitative proteomic profiling of the extracellular matrix of pancreatic islets during the angiogenic switch and insulinoma progression, Sci. Rep 7 (2017) 40495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [52].Izzi V, Lakkala J, Devarajan R, Kääriäinen A, Kolvunen J, Heljasvaara R, Pihlajaniemi T, Pan-Cancer analysis of the expression and regulation of matrisome genes across 32 tumor types, Matrix Biol Plus 1 (2019) 100004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [53].Kääriäinen A, Pesola V, Dittmann A, Kontio J, Koivunen J, Pihlajaniemi T, Izzi V, Machine learning identifies robust matrisome markers and regulatory mechanisms in cancer, Int. J. Mol. Sci 21 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [54].Izzi V, Davis MN, Naba A, Pan-cancer analysis of the genomic alterations and mutations of the matrisome, Cancers. (Basel) 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [55].Honselmann KC, Finetti P, Birnbaum DJ, Monsalve CS, Wellner UF, Begg SKS, Nakagawa A, Hank T, Li A, Goldsworthy MA, Sharma H, Bertucci F, Birnbaum D, Tai E, Ligorio M, Ting DT, Schilling O, Biniossek ML, Bronsert P, Ferrone CR, Keck T, Mino-Kenudson M, Lillemoe KD, Warshaw AL, Fernández-Del CC, Liss AS, Neoplastic-Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer, Mol. Cancer Res 18 (2020) 1889–1902. [DOI] [PubMed] [Google Scholar]
- [56].Li Z, Tremmel DM, Ma F, Yu Q, Ma M, Delafield DG, Shi Y, Wang B, Mitchell SA, Feeney AK, Jain VS, Sackett SD, Odorico JS, Li L, Proteome-wide and matrisome-specific alterations during human pancreas development and maturation, Nat. Commun 12 (2021) 1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [57].Yang Z, Klionsky DJ, Eaten alive: a history of macroautophagy, Nat. Cell Biol 12 (2010) 814–822. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [58].Mizushima N, Levine B, Autophagy in mammalian development and differentiation, Nat. Cell Biol 12 (2010) 823–830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [59].Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G, Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles, Nat. Rev. Drug Discov 16 (2017) 487–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [60].Nussenzweig SC, Verma S, Finkel T, The role of autophagy in vascular biology, Circ. Res 116 (2015) 480–488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [61].Iozzo RV, Perlecan: a gem of a proteoglycan, Matrix Biol. 14 (1994) 203–208. [DOI] [PubMed] [Google Scholar]
- [62].He C, Klionsky DJ, Regulation mechanisms and signaling pathways of autophagy, Annu. Rev. Genet 43 (2009) 67–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [63].Garcia D, Shaw RJ, AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance, Mol. Cell 66 (2017) 789–800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [64].Yang Z, Klionsky DJ, Mammalian autophagy: core molecular machinery and signaling regulation, Curr. Opin. Cell Biol 22 (2010) 124–131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [65].Levine B, Kroemer G, Autophagy in the pathogenesis of disease, Cell 132 (2008) 27–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [66].Mizushima N, Levine B, Cuervo AM, Klionsky DJ, Autophagy fights disease through cellular self-digestion, Nature 451 (2008) 1069–1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [67].Kroemer G, Marino G, Levine B, Autophagy and the integrated stress response, Mol. Cell 40 (2010) 280–293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [68].Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J, Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy, Circ. Res 100 (2007) 914–922. [DOI] [PubMed] [Google Scholar]
- [69].Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, Le V, Levine B, Rothermel BA, Hill JA, Cardiac autophagy is a maladaptive response to hemodynamic stress, J. Clin. Invest 117 (2007) 1782–1793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [70].Levine B, Kroemer G, Biological Functions of Autophagy Genes: A Disease Perspective, Cell 176 (2019) 11–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [71].Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B, Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature 402 (1999) 672–676. [DOI] [PubMed] [Google Scholar]
- [72].Pattingre S, Levine B, Bcl-2 inhibition of autophagy: A new route to cancer?, Cancer Res. 66 (2006) 2885–2888. [DOI] [PubMed] [Google Scholar]
- [73].Xueping Q, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen E-L, Mizushima N, Oshumi Y, Cattoretti G, Levine B, Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene, J. Clin. Inv 112 (2003) 1809–1820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [74].Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B, Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21, Genomics 59 (1999) 59–65. [DOI] [PubMed] [Google Scholar]
- [75].Kondo Y, Kanzawa T, Sawaya R, Kondo S, The role of autophagy in cancer development and response to therapy, Nat. Rev. Cancer 5 (2005) 726–734. [DOI] [PubMed] [Google Scholar]
- [76].Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Kepp O, Scoazec M, Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, diVirgilio F, Zitvogel L, Kroemer G, Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice, Science 334 (2011) 1573–1577. [DOI] [PubMed] [Google Scholar]
- [77].Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, Arfuso F, Yap CT, Goh BC, Sethi G, Huang RY, Shen HM, Manjithaya R, Kumar AP, Dual role of autophagy in hallmarks of cancer, Oncogene 37 (2018) 1142–1158. [DOI] [PubMed] [Google Scholar]
- [78].Li X, He S, Ma B, Autophagy and autophagy-related proteins in cancer, Mol. Cancer 19 (2020) 12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [79].Dikic I, Elazar Z, Mechanism and medical implications of mammalian autophagy, Nat. Rev. Mol. Cell Biol 19 (2018) 349–364. [DOI] [PubMed] [Google Scholar]
- [80].Iozzo RV, Chakrani F, Perrotti D, McQuillan DJ, Skorski T, Calabretta B, Eichstetter I, Cooperative action of germline mutations in decorin and p53 accelerates lymphoma tumorigenesis, Proc. Natl. Acad. Sci. USA 96 (1999) 3092–3097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [81].Iozzo RV, The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins, J. Biol. Chem 274 (1999) 18843–18846. [DOI] [PubMed] [Google Scholar]
- [82].Schaefer L, Iozzo RV, Small leucine-rich proteoglycans, at the crossroad of cancer growth and inflammation, Curr. Opin. Genet. Dev 22 (2012) 56–57. [DOI] [PubMed] [Google Scholar]
- [83].Edwards IJ, Proteoglycans in prostate cancer, Nat. Rev. Urology 9 (2012) 196–206. [DOI] [PubMed] [Google Scholar]
- [84].Skandalis SS, Afratis N, Smirlaki G, Nikitovic D, Theocharis AD, Tzanakakis GN, Karamanos NK, Cross-talk between estradiol receptor and EGFR/IGF-IR signaling pathways in estrogen-responsive breast cancers: focus on the role and impact of proteoglycans, Matrix Biol. 35 (2014) 182–193. [DOI] [PubMed] [Google Scholar]
- [85].Baghy K, Tatrai P, Regos E, Kovalszky I, Proteoglycans in liver cancer, World J. Gastroenterol 22 (2016) 379–393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [86].Suhovskih AV, Aidagulova SV, Kashuba VI, Grigorieva EV, Proteoglycans as potential microenvironmental biomarkers for colon cancer, Cell Tissue Res. 361 (2015) 833–844. [DOI] [PubMed] [Google Scholar]
- [87].Schaefer L, Tredup C, Gubbiotti MA, Iozzo RV, Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology, FEBS J. 284 (2017) 10–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [88].Buraschi S, Neill T, Iozzo RV, Decorin is a devouring proteoglycan: Remodeling of intracellular catabolism via autophagy and mitophagy, Matrix Biol 75–76 (2019) 260–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [89].Hu X, Villodre ES, Larson R, Rahal OM, Wang X, Gong Y, Song J, Krishnamurthy S, Ueno NT, Tripathy D, Woodward WA, Debeb BG, Decorin-mediated suppression of tumorigenesis, invasion, and metastasis in inflammatory breast cancer, Commun. Biol 4 (2021) 72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [90].Mao L, Yang J, Yue J, Chen Y, Zhou H, Fan D, Zhang Q, Buraschi S, Iozzo RV, Bi X, Decorin deficiency promotes epithelial-mesenchymal transition and colon cancer metastasis, Matrix Biol 95 (2021) 1–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [91].Neill T, Torres A, Buraschi S, Owens RT, Hoek J, Baffa R, Iozzo RV, Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitostatin, J. Biol. Chem 289 (2014) 4952–4968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [92].Neill T, Buraschi S, Kapoor A, Iozzo RV, Proteoglycan-driven Autophagy: A Nutrient-independent Mechanism to Control Intracellular Catabolism, J. Histochem. Cytochem 68 (2020) 733–746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [93].Lock R, Debnath J, Extracellular matrix regulation of autophagy, Curr. Opin. Cell Biol 20 (2008) 583–588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [94].Fung C, Lock R, Gao S, Salas E, Debnath J, Induction of autophagy during extracellular matrix detachment promotes cell survival, Mol. Biol Cell 19 (2008) 797–806. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [95].Neill T, Schaefer L, Iozzo RV, Decoding the matrix: Instructive roles of proteoglycan receptors, Biochemistry 54 (2015) 4583–4598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [96].Neill T, Schaefer L, Iozzo RV, Instructive roles of extracellular matrix on autophagy, Am. J. Pathol 184 (2014) 2146–2153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [97].Ricard-Blum S, Vallet SD, Fragments generated upon extracellular matrix remodeling: Biological regulators and potential drugs, Matrix Biol 75–76 (2019) 170–189. [DOI] [PubMed] [Google Scholar]
- [98].de Castro Brás LE, Frangogiannis NG, Extracellular matrix-derived peptides in tissue remodeling and fibrosis, Matrix Biol 91–92 (2020) 176–187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [99].Poluzzi C, Nastase MV, Zeng-Brouwers J, Roedig H, Hsieh LT, Michaelis JB, Buhl EM, Rezende F, Manavski Y, Bleich A, Boor P, Brandes RP, Pfeilschifter J, Stelzer EHK, Munch C, Dikic I, Brandts C, Iozzo RV, Wygrecka M, Schaefer L, Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury, Kidney Int. 95 (2019) 540–562. [DOI] [PubMed] [Google Scholar]
- [100].Iozzo RV, Sanderson RD, Proteoglycans in cancer biology, tumour microenvironment and angiogenesis, J. Cell. Mol. Med 15 (2011) 1013–1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [101].Gubbiotti MA, Vallet SD, Ricard-Blum S, Iozzo RV, Decorin interacting network: A comprehensive analysis of decorin-binding partners and their versatile functions, Matrix Biol 55 (2016) 7–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [102].Neill T, Schaefer L, Iozzo RV, An oncosuppressive role for decorin, Mol. Cell. Oncol 2 (2015) e975645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [103].Buraschi S, Neill T, Goyal A, Poluzzi C, Smythies J, Owens RT, Schaefer L, Torres A, Iozzo RV, Decorin causes autophagy in endothelial cells via Peg3, Proc. Natl. Acad. Sci. U. S. A 110 (2013) E2582–E2591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [104].Neill T, Torres AT, Buraschi S, Iozzo RV, Decorin has an appetite for endothelial cell autophagy, Autophagy 9 (2013) 1626–1628. [DOI] [PubMed] [Google Scholar]
- [105].Gewirtz DA, The four faces of autophagy: Implications for cancer therapy, Cancer Res. 74 (2014) 647–651. [DOI] [PubMed] [Google Scholar]
- [106].Buraschi S, Neill T, Owens RT, Iniguez LA, Purkins G, Vadigepalli R, Evans B, Schaefer L, Peiper SC, Wang Z, Iozzo RV, Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model, PLoS ONE 7 (2012) e45559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [107].Goyal A, Neill T, Owens RT, Schaefer L, Iozzo RV, Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells, Matrix Biol. 34 (2014) 46–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [108].Kim J, Ashworth L, Branscomb E, Stubbs L, The human homolog of a mouse-imprinted gene, Peg3, maps to a zinc finger gene-rich region of human chromosome 19q13.4, Genome Res. 7 (1997) 532–540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [109].Zhou QY, Li CC, Huo JH, Zhao SH, Expression and genomic imprinting of DCN, PON2 and PEG3 genes in porcine placenta, Anim. Reprod. Sci 123 (2011) 70–74. [DOI] [PubMed] [Google Scholar]
- [110].Monk D, Arnaud P, Apostolidou S, Hills FA, Kelsey G, Stanier P, Feil R, Moore GE, Limited evolutionary conservation of imprinting in the human placenta, Proc. Natl. Acad. Sci. U. S. A 103 (2006) 6623–6628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [111].He H, Ye A, Kim H, Kim J, PEG3 Interacts with KAP1 through KRAB-A, PLoS. One 11 (2016) e0167541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [112].Song J, Lu Y, Giang A, Pang S, Chiu R, Promoter analysis of the mouse Peg3 gene, Biochim. Biophys. Acta 1779 (2008) 134–138. [DOI] [PubMed] [Google Scholar]
- [113].Kuroiwa Y, Kaneko-Ishino T, Kagitani F, Kohda T, Li L-L, Tada M, Suzuki R, Yokoyama M, Shiroishi T, Wakana S, Barton SC, Ishino F, Surani MA, Peg3 imprinted gene on proximal chromosome 7 encodes for a zinc finger protein, Nature Genet. 12 (1996) 186–190. [DOI] [PubMed] [Google Scholar]
- [114].Bretz CL, Frey WD, Teruyama R, Kim J, Allele and dosage specificity of the Peg3 imprinted domain, PLoS. One 13 (2018) e0197069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [115].Dang DT, Pevsner J, Yang VW, The biology of the mammalian Krüppel-like family of transcription factors, Int. J. Biochem. Cell Biol 32 (2000) 1103–1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [116].Iuchi S, Three classes of C2H2 zinc finger proteins, Cell Mol. Life Sci 58 (2001) 625–635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [117].Torres A, Gubbiotti MA, Iozzo RV, Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis, J. Biol Chem 292 (2017) 5055–5069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [118].Thiaville MM, Huang JM, Kim H, Ekram MB, Roh T-Y, Kim J, DNA-binding motif and target genes of the imprinted transcription factor PEG3, Gene 512 (2013) 314–320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [119].Lee S, Ye A, Kim J, DNA-Binding Motif of the Imprinted Transcription Factor PEG3, PLoS. One 10 (2015) e0145531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [120].Sander TL, Stringer KF, Maki JL, Szauter P, Stone JR, Collins T, The SCAN domain defines a large family of zinc finger transcription factors, Gene 310 (2003) 29–38. [DOI] [PubMed] [Google Scholar]
- [121].Williams AJ, Blacklow SC, Collins T, The zinc finger-associated SCAN box is a conserved oligomerization domain, Mol. Cell Biol 19 (1999) 8526–8535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [122].Schumacher C, Wang H, Honer C, Ding W, Koehn J, Lawrence Q, Coulis CM, Wang LL, Ballinger D, Bowen BR, Wagner S, The SCAN domain mediates selective oligomerization, J. Biol. Chem 275 (2000) 17173–17179. [DOI] [PubMed] [Google Scholar]
- [123].Rimsa V, Eadsforth TC, Hunter WN, Structure of the SCAN domain of human paternally expressed gene 3 protein, PLoS ONE 8 (2013) e69538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [124].Gubbiotti MA, Neill T, Frey H, Schaefer L, Iozzo RV, Decorin is an autophagy-inducible proteoglycan and is required for proper in vivo autophagy, Matrix Biol. 48 (2015) 14–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [125].Gubbiotti MA, Seifert E, Rodeck U, Hoek JB, Iozzo RV, Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin, J. Biol Chem 293 (2018) 16940–16950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [126].Mammuccari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M, FoxO3 controls autophagy in skeletal muscle in vivo, Cell Metab. 6 (2007) 458–471. [DOI] [PubMed] [Google Scholar]
- [127].Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL, FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells, Cell Metab. 6 (2007) 472–483. [DOI] [PubMed] [Google Scholar]
- [128].Füllgrabe J, Lynch-Day MA, Heldring N, Li W, Struijik RB, Ma Q, Hermanson O, Rosenfeld MG, Klionsky DJ, Joseph B, The histone H4 lysine acetyltransferase hMOF regulates the outcome of autophagy, Nature 500 (2013) 468–471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [129].Fullgrabe J, Klionsky DJ, Joseph B, The return of the nucleus: transcriptional and epigenetic control of autophagy, Nat. Rev. Mol. Cell Biol 15 (2014) 65–74. [DOI] [PubMed] [Google Scholar]
- [130].Frey WD, Kim J, Apeg3: regulation of Peg3 through an evolutionarily conserved ncRNA, Gene 540 (2014) 251–257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [131].Besson V, Smeriglio P, Wegener A, Relaix F, Nait Oumesmar B, Sassoon DA, Marazzi G, PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations, Proc. Natl. Acad. Sci. USA 108 (2011) 11470–11475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [132].Bonfanti C, Rossi G, Tedesco FS, Giannotta M, Benedetti S, Tonlorenzi R, Antonini S, Marazzi G, Dejana E, Sassoon D, Cossu G, Messina G, PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence, Nat. Commun 6 (2015) 6364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [133].Besson V, Kyryachenko S, Janich P, Benitah SA, Marazzi G, Sassoon D, Expression Analysis of the Stem Cell Marker Pw1/Peg3 Reveals a CD34 Negative Progenitor Population in the Hair Follicle, Stem Cells 35 (2017) 1015–1027. [DOI] [PubMed] [Google Scholar]
- [134].Flisikowski K, Venhoranta H, Nowacka-Woszuk J, McKay SD, Flyckt A, Taponen J, Schnabel R, Schwarzenbacher H, Szczerbal I, Lohi H, Fries R, Taylor JF, Switonski M, Andersson M, A novel mutation in the maternally imprinted PEG3 domain results in a loss of MIMT1 expression and causes abortions and stillbirths in cattle (Bos taurus), PLoS ONE 5 (2010) e15116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [135].Li L-L, Keverne EB, Aparicio SA, Ishino F, Barton SC, Surani MA, Regulation of maternal behavior and offspring growth by paternally expressed Peg3, Science 284 (1999) 330–333. [DOI] [PubMed] [Google Scholar]
- [136].Champagne FA, Curley JP, Swaney WT, Hasen NS, Keverne EB, Paternal influence on female behavior: the role of Peg3 in exploration, olfaction, and neuroendocrine regulation of maternal behavior of female mice, Behav. Neurosci 123 (2009) 469–480. [DOI] [PubMed] [Google Scholar]
- [137].Kim J, Frey WD, He H, Kim H, Ekram MB, Bakshi A, Faisal M, Perera BP, Ye A, Teruyama R, Peg3 mutational effects on reproduction and placenta-specific gene families, PLoS. One 8 (2013) e83359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [138].Schwarzkopf M, Coletti D, Sassoon D, Marazzi G, Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway, Genes & Dev. 20 (2006) 3440–3452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [139].Curley JP, Pinnock SB, Dickson SL, Thresher R, Miyoshi N, Surani MA, Keverne EB, Increased body fat in mice with a targeted mutation of the patermally expressed imprinted gene Peg3, FASEB J. 19 (2005) 1302–1322. [DOI] [PubMed] [Google Scholar]
- [140].Relaix F, Wei X, Li W, Pan J, Lin Y, Bowtell DD, Sasoon DA, Wu X, Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis, Proc. Natl. Acad. Sci. USA 97 (2000) 2105–2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [141].Deng Y, Wu X, Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria, Proc. Natl. Acad. Sci. USA 97 (2000) 12050–12055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [142].Johnson MD, Wu X, Aithmitti N, Morrison RS, Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death, J. Biol. Chem 277 (2002) 23000–23007. [DOI] [PubMed] [Google Scholar]
- [143].Yamaguchi A, Taniguchi M, Hori O, Ogawa S, Tojo N, Matsuoka N, Miyake S, Kasai K, Sugimoto H, Tamatani M, Yamashita T, Yamashita T, Tohyama M, Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/hypoxia, J. Biol. Chem 277 (2002) 623–629. [DOI] [PubMed] [Google Scholar]
- [144].Relaix F, Wei X, Wu X, Sassoon DA, Peg3/Pw1 is an imprinted gene involved in the TNF-NFκB signal transduction pathway, Nat. Genet 18 (1998) 287–291. [DOI] [PubMed] [Google Scholar]
- [145].Bouvet M, Claude O, Roux M, Skelly D, Masurkar N, Mougenot N, Nadaud S, Blanc C, Delacroix C, Chardonnet S, Pionneau C, Perret C, Yaniz-Galende E, Rosenthal N, Trégouët DA, Marazzi G, Silvestre JS, Sassoon D, Hulot JS, Anti-integrin α v therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells, Sci. Rep 10 (2020) 11404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [146].Mohan RR, Tovey JCK, Sharma A, Schultz G, Cowden JW, Tandon A, Targeted decorin gene therapy delivered with adeno-associated virus effectively retards corneal neovascularization in vivo, PLoS ONE 6 (2011) e26432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [147].Mohan RR, Tandon A, Sharma A, Cowden JW, Tovey JCK, Significant inhibition of corneal scarring in vivo with tissue-selective, targeted AAV5 decorin gene therapy, Invest. Ophthalmol. Vis. Sci 52 (2011) 4833–4841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [148].Zhang M, Zhang J, PEG3 mutation is associated with elevated tumor mutation burden and poor prognosis in breast cancer, Biosci. Rep 40 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [149].Tapia-Carrillo D, Tovar H, Velazquez-Caldelas TE, Hernandez-Lemus E, Master Regulators of Signaling Pathways: An Application to the Analysis of Gene Regulation in Breast Cancer, Front Genet. 10 (2019) 1180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [150].Denizot AL, Besson V, Correra RM, Mazzola A, Lopes I, Courbard JR, Marazzi G, Sassoon DA, A Novel Mutant Allele of Pw1/Peg3 Does Not Affect Maternal Behavior or Nursing Behavior, PLoS. Genet 12 (2016) e1006053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [151].Ledgerwood EC, O’Rahilly S, Surani MA, The imprinted gene Peg3 is not essential for tumor necrosis factor alpha signaling, Lab Invest 80 (2000) 1509–1511. [DOI] [PubMed] [Google Scholar]
- [152].Yue Z, Jin S, Yang C, Levine AJ, Heintz N, Beclin 1, an authophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor, Proc. Natl. Acad. Sci. USA 100 (2003) 15077–15082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [153].Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N, Autophagy-deficient mice develop multiple liver tumors, Genes Dev. 25 (2011) 795–800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [154].Malinverno M, Corada M, Ferrarini L, Formicola L, Marazzi G, Sassoon D, Dejana E, Peg3/PW1 Is a Marker of a Subset of Vessel Associated Endothelial Progenitors, Stem Cells 35 (2017) 1328–1340. [DOI] [PubMed] [Google Scholar]
- [155].Lu Y-C, Song J, Cho H-Y, Fan G, Yokoyama KK, Chiu R, Cyclophilin A protects Peg3 from hypermethylation and inactive histone modification, J. Biol. Chem 281 (2006) 39081–39087. [DOI] [PubMed] [Google Scholar]
- [156].Nye MDHC, Huang Z, Vidal AC, Wang F, Overcash F, Smith JS, Vasquez B, Hernandez B, Swai B, Oneko O, Mlay P, Obure J, Gammon MD, Bartlett JA, Murphy SK, Association between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer, PLoS ONE 8 (2013) e56325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [157].Dowdy SC, Gostout BS, Shridhar V, Wu X, Smith DI, Podratz KC, Jiang S-W, Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines, Gynecol. Oncol 99 (2005) 126–134. [DOI] [PubMed] [Google Scholar]
- [158].Maegawa S, Yoshioka H, Itaba N, Kubota N, Nishihara S, Shirayoshi Y, Nanba E, Oshimura M, Epigenetic silencing of PEG3 gene expression in human glioma cell lines, Mol. Carcinogenesis 31 (2001) 1–9. [DOI] [PubMed] [Google Scholar]
- [159].Jiang X, Yu Y, Yang HW, Agar NYR, Frado L, Johnson MD, The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth, J. Biol. Chem 285 (2010) 8472–8480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [160].Kohda T, Asai A, Kuroiwa Y, Kobayashi S, Aisaka K, Nagashima G, Yoshida MC, Kondo Y, Kagiyama N, Kirino T, Kaneko-Ishino T, Ishino F, Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line, Genes Cells 6 (2001) 237–247. [DOI] [PubMed] [Google Scholar]
- [161].Feng W, Marquez RT, Lu Z, Liu J, Lu KH, Issa J-PJ, Fishman DM, Yu Y, Bast RC, Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation, Cancer 112 (2008) 1489–1502. [DOI] [PubMed] [Google Scholar]
- [162].Despierre E, Lambrechts D, Neven P, Amant F, Lambrechts S, Vergote I, The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment, Gynecol. Oncol 117 (2010) 358–365. [DOI] [PubMed] [Google Scholar]
- [163].Buraschi S, Pal N, Tyler-Rubinstein N, Owens RT, Neill T, Iozzo RV, Decorin antagonizes Met receptor activity and downregulates β-catenin and Myc levels, J. Biol. Chem 285 (2010) 42075–42085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [164].Alers S, Löffler AS, Wesselborg S, Stork B, Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Crosstalk, shortcuts, and feedbacks, Mol. Cell. Biol 32 (2012) 2–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [165].Liang J, Milson C, AMPK: A contextual oncogene or tumor suppressor?, Cancer Res. 73 (2013) 2929–2935. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [166].Kim J, Kundu M, Viollet B, Guan K-L, AMPK and mTOR regulate autophagy through direct phopshorylation of Ulk1, Nat. Cell Biol 13 (2011) 132–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [167].Herzig S, Shaw RJ, AMPK: guardian of metabolism and mitochondrial homeostasis, Nat. Rev. Mol. Cell Biol 19 (2018) 121–135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [168].Patel S, Santra M, McQuillan DJ, Iozzo RV, Thomas AP, Decorin activates the epidermal growth factor receptor and elevates cytosolic Ca2+ in A431 cells, J. Biol. Chem 273 (1998) 3121–3124. [DOI] [PubMed] [Google Scholar]
- [169].Csordás G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D, Nugent MA, Hajnóczky G, Iozzo RV, Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo, J. Biol. Chem 275 (2000) 32879–32887. [DOI] [PubMed] [Google Scholar]
- [170].Poluzzi C, Casulli J, Goyal A, Mercer TJ, Neill T, Iozzo RV, Endorepellin evokes autophagy in endothelial cells, J. Biol. Chem 289 (2014) 16114–16128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [171].Poluzzi C, Iozzo RV, Schaefer L, Endostatin and endorepellin: A common route of action for similar angiostatic cancer avengers, Adv. Drug Deliv. Rev 97 (2016) 156–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [172].Neill T, Andreuzzi E, Wang Z-X, Peiper SC, Mongiat M, Iozzo RV, Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature, J. Biol. Chem 293 (2018) 12137–12148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [173].Kapoor A, Chen CG, Iozzo RV, Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells, J. Biol Chem 295 (2020) 6344–6356. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [174].Goyal A, Gubbiotti MA, Chery DR, Han L, Iozzo RV, Endorepellin-evoked autophagy contributes to angiostasis, J. Biol. Chem 291 (2016) 19245–19256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [175].Neill T, Schaefer L, Iozzo RV, Decorin as a multivalent therapeutic agent against cancer, Adv. Drug Deliv. Rev 97 (2016) 174–185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [176].Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL, ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase, Nat. Cell Biol 15 (2013) 741–750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [177].Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH, ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery, Mol. Biol Cell 20 (2009) 1992–2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [178].Funderburk SF, Wang QJ, Yue Z, The Beclin 1-VPS34 complex- at the crossroads of autophagy and beyond, Trends Cell Biol. 20 (2010) 355–362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [179].Kang R, Zeh HJ, Lotze MT, Tang D, The beclin 1 network regulates autophagy and apoptosis, Cell Death Differ. 18 (2011) 571–580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [180].Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J, Site specific cleavage mediated by MMPs regulates function of agrin, PLoS ONE 7 (2012) e43669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [181].Morrione A, Neill T, Iozzo RV, Dichotomy of decorin activity on the insulin-like growth factor-I system, FEBS J. 280 (2013) 2138–2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [182].Dodd KM, Yang J, Shen MH, Sampson JR, Tee AR, mTORC1 drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3, Oncogene 34 (2015) 2239–2250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [183].Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N, Nakashima A, Sakurai H, Saito S, Tsukada K, Saiki I, Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells, Eur. J. Cancer 44 (2008) 1022–1029. [DOI] [PubMed] [Google Scholar]
- [184].Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ, Wang S, Ren P, Martin M, Jessen K, Feldman ME, Weissman JS, Shokat KM, Rommel C, Ruggero D, The translational landscape of mTOR signalling steers cancer initiation and metastasis, Nature 485 (2012) 55–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [185].Karali E, Bellou S, Stellas D, Klinakis A, Murphy C, Fotsis T, VEGF signaling, mTOR complexes, and the endoplasmic reticulum: Towards a role of metabolic sensing in the regulation of angiogenesis, Mol. Cell Oncol 1 (2014) e964024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [186].Moschetta M, Reale A, Marasco C, Vacca A, Carratu MR, Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations, Br. J. Pharmacol 171 (2014) 3801–3813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [187].Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ, Termination of autophagy and reformation of lysosomes regulated by mTOR, Nature 465 (2010) 942–946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [188].Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, Kinch L, Koduru P, Christudass CS, Veltri RW, Grishin NV, Peyton M, Minna J, Bhagat G, Levine B, EGFR-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance, Cell 154 (2013) 1269–1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [189].Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, White M, Reichelt J, Levine B, Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation, Science 338 (2012) 956–959. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [190].Lee S-J, Kim HP, Jin Y, Choi AMK, Ryter SW, Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis, Autophagy 7 (2011) 829–839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [191].Li B-X, Li C-Y, Peng R-Q, Wu X-J, Wang H-Y, Wan D-S, Zhu X-F, Zhang X-S, The expression of beclin 1 is associated with favorable prognosis in stage IIIB colon cancers, Autophagy 5 (2009) 303–306. [DOI] [PubMed] [Google Scholar]
- [192].Brayer KJ, Segal DJ, Keep your fingers off my DNA: protein-protein interactions mediated by C2H2 zinc finger domains, Cell Biochem. Biophys 50 (2008) 111–131. [DOI] [PubMed] [Google Scholar]
- [193].Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD, Levine B, Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy, Cell 122 (2005) 927–939. [DOI] [PubMed] [Google Scholar]
- [194].Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y, Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes, Nat. Cell Biol 6 (2004) 1221–1228. [DOI] [PubMed] [Google Scholar]
- [195].Mizushima N, Yoshimori T, Levine B, Methods in mammalian autophagy research, Cell 140 (2010) 313–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [196].Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y, In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker, Mol. Biol. Cell 15 (2004) 1101–1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [197].Lavandero S, Chiong M, Rothermel BA, Hill JA, Autophagy in cardiovascular biology, J. Clin. Invest 125 (2015) 55–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [198].Moore BR, Page-Sharp M, Stoney JR, Ilett KF, Jago JD, Batty KT, Pharmacokinetics, pharmacodynamics, and allometric scaling of chloroquine in a murine malaria model, Antimicrob. Agents Chemother 55 (2011) 3899–3907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [199].Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, Coppes RP, Engedal N, Mari M, Reggiori F, Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion, Autophagy. 14 (2018) 1435–1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [200].Yoshii SR, Kuma A, Mizushima N, Transgenic rescue of Atg5-null mice from neonatal lethality with neuron-specific expression of ATG5: Systemic analysis of adult Atg5-deficient mice, Autophagy. 13 (2017) 763–764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [201].Mizushima N, Methods for monitoring autophagy using GFP-LC3 transgenic mice, Methods Enzymol. 452 (2009) 13–23. [DOI] [PubMed] [Google Scholar]
- [202].Tanida I, Mimematsu-Ikeguchi N, Ueno T, Kominami E, Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker of autophagy, Autophagy 1 (2005) 84–91. [DOI] [PubMed] [Google Scholar]
- [203].Iwai-Kanai E, Yuan H, Huang C, Sayen MR, Perry-Garza CN, Kim L, Gottlieb RA, A method to measure cardiac autophagic flux in vivo, Autophagy. 4 (2008) 322–329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [204].Mizushima N, Yoshimori T, How to interpret LC3 immunoblotting, Autophagy. 3 (2007) 542–545. [DOI] [PubMed] [Google Scholar]
- [205].Gurney MA, Huang C, Ramil JM, Ravindran N, Andres AM, Sin J, Linton PJ, Gottlieb RA, Measuring cardiac autophagic flux in vitro and in vivo, Methods Mol. Biol 1219 (2015) 187–197. [DOI] [PubMed] [Google Scholar]
- [206].Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T, LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing, EMBO J. 19 (2000) 5720–5728. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [207].Fu MM, Nirschl JJ, Holzbaur ELF, LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes, Dev. Cell 29 (2014) 577–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [208].Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A, A lysosome-to-lysosome signaling mechanism senses and regulates the lysosome via mTOR and TFEB, EMBO J. 31 (2012) 1095–1108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [209].Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A, A gene network regulating lysosomal biogenesis and function, Science 325 (2009) 473–477. [DOI] [PubMed] [Google Scholar]
- [210].Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A, TFEB links autophagy to lysosomal biogenesis, Science 332 (2011) 1429–1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [211].Settembre C, Ballabio A, TFEB regulates autophagy: an integrated coordination of cellular degradation and recycling processes, Autophagy. 7 (2011) 1379–1381. [DOI] [PubMed] [Google Scholar]
- [212].Settembre C, Fraldi A, Medina DL, Ballabio A, Signals from the lysosome: a control centre for cellular clearance and energy metabolism, Nat. Rev. Mol. Cell Biol 14 (2013) 283–296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [213].Palmieri M, Impey S, Kang H, di RA, Pelz C, Sardiello M, Ballabio A, Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways, Hum. Mol. Genet 20 (2011) 3852–3866. [DOI] [PubMed] [Google Scholar]
- [214].Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, Di Bernardo D, Chan L, Irazoqui JE, Ballabio A, TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop, Nat. Cell Biol 15 (2013) 647–658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [215].Neill T, Sharpe C, Owens RT, Iozzo RV, Decorin-Evoked Paternally Expressed Gene 3 (PEG3) is an Upstream Regulator of the Transcription Factor EB (TFEB) in Endothelial Cell Autophagy, J. Biol Chem 292 (2017) 16211–16220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [216].Moskot M, Montefusco S, Jakóbliewicz-Banecka J, Mozolewski P, Wegrzyn A, Di Bernardo D, Wegrzyn G, Medina DL, Ballabio A, Gabig-Ciminska M, The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation, J. Biol. Chem 289 (2014) 17054–17069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [217].Baskin KK, Taegtmeyer H, AMP-activated protein kinase regulates E3 ligases in rodent heart, Circ. Res 109 (2011) 1153–1161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [218].Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, Kweon MN, Won KJ, Baek SH, AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy, Nature 534 (2016) 553–557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [219].Iozzo RV, Bolender RP, Wight TN, Proteoglycan changes in the intercellular matrix of human colon carcinoma, Lab. Invest 47 (1982) 124–138. [PubMed] [Google Scholar]
- [220].Robinson PS, Lin TW, Reynolds PR, Derwin KA, Iozzo RV, Soslowsky LJ, Strain-rate sensitive mechanical properties of tendon fascicles from mice with genetically engineered alterations in collagen and decorin, J. Biomech. Eng 126 (2004) 252–257. [DOI] [PubMed] [Google Scholar]
- [221].Häkkinen L, Strassburger S, Kahari VM, Scott PG, Eichstetter I, Iozzo RV, Larjava H, A role for decorin in the structural organization of periodontal ligament, Lab. Invest 80 (2000) 1869–1880. [DOI] [PubMed] [Google Scholar]
- [222].Weis SM, Zimmerman SD, Shah M, Covell JW, Omens JH, Ross J Jr., Dalton N, Jones Y, Reed CC, Iozzo RV, McCulloch AD, A role for decorin in the remodeling of myocardial infarction, Matrix Biol. 24 (2005) 313–324. [DOI] [PubMed] [Google Scholar]
- [223].Dunkman AA, Buckley MR, Mienaltowski MJ, Adams SM, Thomas SJ, Satchell L, Kumar A, Pathmanathan L, Beason DP, Iozzo RV, Birk DE, Soslowsky LJ, Decorin expression is important for age-related changes in tendon structure and mechanical properties, Matrix Biol. 32 (2013) 3–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [224].Dunkman AA, Buckley MR, Mienaltowski MJ, Adams SM, Thomas SJ, Kumar A, Beason DP, Iozzo RV, Birk DE, Soslowsky LJ, The injury response of aged tendons in the absence of biglycan and decorin, Matrix Biol. 35 (2014) 232–238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [225].Schönherr E, Sunderkotter C, Schaefer L, Thanos S, Grässel S, Oldberg Å, Iozzo RV, Young MF, Kresse H, Decorin deficiency leads to impaired angiogenesis in injured mouse cornea, J. Vasc. Res 41 (2004) 499–508. [DOI] [PubMed] [Google Scholar]
- [226].Goldoni S, Iozzo RV, Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs, Int. J. Cancer 123 (2008) 2473–2479. [DOI] [PubMed] [Google Scholar]
- [227].Robinson PS, Lin TW, Jawad AF, Iozzo RV, Soslowsky LJ, Investigating tendon fascicle structure-function relationship in a transgenic age mouse model using multiple regression models, Ann. Biomed. Eng 32 (2004) 924–931. [DOI] [PubMed] [Google Scholar]
- [228].Robinson PS, Huang TF, Kazam E, Iozzo RV, Birk DE, Soslowsky LJ, Influence of decorin and biglycan on mechanical properties of multiple tendons in knockout mice, J. Biomechanical Eng 127 (2005) 181–185. [DOI] [PubMed] [Google Scholar]
- [229].Fetting JL, Guay JA, Karolak MJ, Iozzo RV, Adams DC, Maridas DE, Brown AC, Oxburgh L, FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney, Development 141 (2014) 17–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [230].Schönherr E, Sunderkötter C, Iozzo RV, Schaefer L, Decorin, a novel player in the insulin-like growth factor system, J. Biol. Chem 280 (2005) 15767–15772. [DOI] [PubMed] [Google Scholar]
- [231].Merline R, Lazaroski S, Babelova A, Tsalastra-Greul W, Pfeilschifter J, Schluter KD, Gunther A, Iozzo RV, Schaefer RM, Schaefer L, Decorin deficiency in diabetic mice: aggravation of nephropathy due to overexpression of profibrotic factors, enhanced apoptosis and mononuclear cell infiltration, J. Physiol. Pharmacol 60 (suppl 4) (2009) 5–13. [PMC free article] [PubMed] [Google Scholar]
- [232].Goldoni S, Owens RT, McQuillan DJ, Shriver Z, Sasisekharan R, Birk DE, Campbell S, Iozzo RV, Biologically active decorin is a monomer in solution, J. Biol. Chem 279 (2004) 6606–6612. [DOI] [PubMed] [Google Scholar]
- [233].Yamaguchi Y, Ruoslahti E, Expression of human proteoglycan in Chinese hamster ovary cells inhibits cell proliferation, Nature 336 (1988) 244–246. [DOI] [PubMed] [Google Scholar]
- [234].Hildebrand A, Romaris M, Rasmussen LM, Heinegård D, Twardzik DR, Border WA, Ruoslahti E, Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor β, Biochem. J 302 (1994) 527–534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [235].Yamaguchi Y, Mann DM, Ruoslahti E, Negative regulation of transforming growth factor-β by the proteoglycan decorin, Nature 346 (1990) 281–284. [DOI] [PubMed] [Google Scholar]
- [236].Baghy K, Iozzo RV, Kovalszky I, Decorin-TGFβ axis in hepatic fibrosis and cirrhosis, J. Histochem. Cytochem 60 (2012) 262–268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [237].Ferdous Z, Wei VM, Iozzo RV, Höök M, Grande-Allen KJ, Decorin-transforming growth factor-ß interaction regulates matrix organization and mechanical characteristics of three-dimensional collagen matrices, J. Biol. Chem 282 (2007) 35887–35898. [DOI] [PubMed] [Google Scholar]
- [238].Bi X, Xia X, Fan D, Mu T, Zhang Q, Iozzo RV, Yang W, Oncogenic activin C interacts with decorin in colorectal cancer in vivo and in vitro, Mol. Carcinog 55 (2015) 1786–1795. [DOI] [PubMed] [Google Scholar]
- [239].Santra M, Skorski T, Calabretta B, Lattime EC, Iozzo RV, De novo decorin gene expression suppresses the malignant phenotype in human colon cancer cells, Proc. Natl. Acad. Sci. USA 92 (1995) 7016–7020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [240].Santra M, Mann DM, Mercer EW, Skorski T, Calabretta B, Iozzo RV, Ectopic expression of decorin protein core causes a generalized growth suppression in neoplastic cells of various histogenetic origin and requires endogenous p21, an inhibitor of cyclin-dependent kinases, J. Clin. Invest 100 (1997) 149–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [241].Moscatello DK, Santra M, Mann DM, McQuillan DJ, Wong AJ, Iozzo RV, Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor, J. Clin. Invest 101 (1998) 406–412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [242].Reed CC, Gauldie J, Iozzo RV, Suppression of tumorigenicity by adenovirus-mediated gene transfer of decorin, Oncogene 21 (2002) 3688–3695. [DOI] [PubMed] [Google Scholar]
- [243].Reed CC, Waterhouse A, Kirby S, Kay P, Owens RA, McQuillan DJ, Iozzo RV, Decorin prevents metastatic spreading of breast cancer, Oncogene 24 (2005) 1104–1110. [DOI] [PubMed] [Google Scholar]
- [244].Seidler DG, Goldoni S, Agnew C, Cardi C, Thakur ML, Owens RA, McQuillan DJ, Iozzo RV, Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation, J. Biol. Chem 281 (2006) 26408–26418. [DOI] [PubMed] [Google Scholar]
- [245].Järveläinen H, Puolakkainen P, Pakkanen S, Brown EL, Höök M, Iozzo RV, Sage H, Wight TN, A role for decorin in cutaneous wound healing and angiogenesis, Wound Rep. Reg 14 (2006) 443–452. [DOI] [PubMed] [Google Scholar]
- [246].Goldoni S, Seidler DG, Heath J, Fassan M, Baffa R, Thakur ML, Owens RA, McQuillan DJ, Iozzo RV, An anti-metastatic role for decorin in breast cancer, Am. J. Pathol 173 (2008) 844–855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [247].Bi X, Tong C, Dokendorff A, Banroft L, Gallagher L, Guzman-Hartman G, Iozzo RV, Augenlicht LH, Yang W, Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation, Carcinogenesis 29 (2008) 1435–1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [248].Iozzo RV, Buraschi S, Genua M, Xu S-Q, Solomides CC, Peiper SC, Gomella LG, Owens RT, Morrione A, Decorin antagonizes IGF receptor I (IGF-IR) function by interfering with IGF-IR activity and attenuating downstream signaling, J. Biol. Chem 286 (2011) 34712–34721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [249].Bi X, Pohl NM, Yang GR, Gou Y, Guzman G, Kajdacsy-Balla A, Iozzo RV, Yang W, Decorin-mediated inhibition of colorectal cancer growth and migration is associated with E-cadherin in vitro and in mice, Carcinogenesis 33 (2012) 326–330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [250].Santra M, Eichstetter I, Iozzo RV, An anti-oncogenic role for decorin: downregulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells, J. Biol. Chem 275 (2000) 35153–35161. [DOI] [PubMed] [Google Scholar]
- [251].Grant DS, Yenisey C, Rose RW, Tootell M, Santra M, Iozzo RV, Decorin suppresses tumor cell-mediated angiogenesis, Oncogene 21 (2002) 4765–4777. [DOI] [PubMed] [Google Scholar]
- [252].Tralhão JG, Schaefer L, Micegova M, Evaristo C, Schönherr E, Kayal S, Veiga-Fernandes H, Danel C, Iozzo RV, Kresse H, Lemarchand P, In vivo selective and distant killing of cancer cells using adenovirus-mediated decorin gene transfer, FASEB J. 17 (2003) 464–466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [253].Neill T, Painter H, Buraschi S, Owens RT, Lisanti MP, Schaefer L, Iozzo RV, Decorin antagonizes the angiogenic network. Concurrent inhibition of Met, hypoxia inducible factor-1α and vascular endothelial growth factor A and induction of thrombospondin-1 and TIMP3, J. Biol. Chem 287 (2012) 5492–5506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [254].Nikitovic D, Aggelidakis J, Young MF, Iozzo RV, Karamanos NK, Tzanakakis GN, The biology of small leucine-rich proteoglycans in bone pathophysiology, J. Biol. Chem 287 (2012) 33926–33933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [255].Neill T, Jones HR, Crane-Smith Z, Owens RT, Schaefer L, Iozzo RV, Decorin induces rapid secretion of thrombospondin-1 in basal breast carcinoma cells via inhibition of Ras homolog gene family, member A/Rho-associated coiled-coil containing protein kinase 1, FEBS J. 280 (2013) 2353–2368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [256].Xu W, Neill T, Yang Y, Hu Z, Cleveland E, Wu Y, Hutten R, Xiao X, Stock SR, Shevrin D, Kaul K, Brendler C, Iozzo RV, Seth P, The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer, Gene Therapy 22 (2015) 31–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [257].Järveläinen H, Sainio A, Wight TN, Pivotal role for decorin in angiogenesis, Matrix Biol. 43 (2015) 15–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [258].Lee H, Lim J, Oh JH, Cho S, Chung JH, IGF-1 upregulates biglycan and decorin by Increasing translation and reducing ADAMTS5 expression, Int. J. Mol. Sci 22 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [259].Brown EL, Wooten RM, Johnson BJB, Iozzo RV, Smith A, Dolan MC, Guo BP, Weis JJ, Höök M, Resistance to Lyme disease in decorin-deficient mice, J. Clin. Invest 107 (2001) 845–852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [260].Liang FT, Wang T, Brown EL, Iozzo RV, Fikrig E, Protective niche for Borrelia burgdorferi to evade humoral immunity, Am. J. Pathol 165 (2004) 977–985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [261].Gubbiotti MA, Buraschi S, Kapoor A, Iozzo RV, Proteoglycan signaling in tumor angiogenesis and endothelial cell autophagy, Semin. Cancer Biol 68 (2020) 1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [262].Chen L, Lin G, Chen K, Wan F, Liang R, Sun Y, Chen X, Zhu X, VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway, Sci. Rep 10 (2020) 16328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [263].Spengler K, Kryeziu N, Große S, Mosig AS, Heller R, VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1, Cells 9 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [264].Li X, Hu Z, Shi H, Wang C, Lei J, Cheng Y, Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy, Onco. Targets. Ther 13 (2020) 8161–8171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [265].Neill T, Chen CG, Buraschi S, Iozzo RV, Catabolic degradation of endothelial VEGFA via autophagy, J. Biol Chem 295 (2020) 6064–6079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [266].Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase, J. Neurosci 24 (2004) 479–487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [267].Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS, mTOR Mediated Anti-Cancer Drug Discovery, Drug Discov. Today Ther. Strateg 6 (2009) 47–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [268].Munafo DB, Colombo MI, Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24, Traffic. 3 (2002) 472–482. [DOI] [PubMed] [Google Scholar]
- [269].Yla-Anttila P, Eskelinen EL, Roles for RAB24 in autophagy and disease, Small GTPases. 9 (2018) 57–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [270].Yla-Anttila P, Mikkonen E, Happonen KE, Holland P, Ueno T, Simonsen A, Eskelinen EL, RAB24 facilitates clearance of autophagic compartments during basal conditions, Autophagy. 11 (2015) 1833–1848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [271].Zhang Y-W, Su Y, Volpert OV, Vande Woude GF, Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation, Proc. Natl. Acad. Sci. USA 100 (2003) 12718–12723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [272].Murphy-Ullrich JE, Sage EH, Revisiting the matricellular concept, Matrix Biol. 37 (2014) 1–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [273].Resovi A, Pinessi D, Chiorino G, Taraboletti G, Current understanding of the thrombospondin-1 interactome, Matrix Biol. 37 (2014) 83–91. [DOI] [PubMed] [Google Scholar]
- [274].Taraboletti G, Rusnati M, Ragona L, Colombo G, Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors, Oncotarget. 1 (2010) 662–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [275].Torisu T, Torisu K, Lee IH, Liu J, Malide D, Combs CA, Wu XS, Rovira II, Fergusson MM, Weigert R, Connelly PS, Daniels MP, Komatsu M, Cao L, Finkel T, Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor, Nat. Med 19 (2013) 1281–1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [276].Mongiat M, Sweeney S, San Antonio JD, Fu J, Iozzo RV, Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan, J. Biol. Chem 278 (2003) 4238–4249. [DOI] [PubMed] [Google Scholar]
- [277].Cohen IR, Grässel S, Murdoch AD, Iozzo RV, Structural characterization of the complete human perlecan gene and its promoter, Proc. Natl. Acad. Sci. U. S. A 90 (1993) 10404–10408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [278].Iozzo RV, Pillarisetti J, Sharma B, Murdoch AD, Danielson KG, Uitto J, Mauviel A, Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming factor-β via a nuclear factor 1-binding element, J. Biol. Chem 272 (1997) 5219–5228. [DOI] [PubMed] [Google Scholar]
- [279].Sharma B, Iozzo RV, Transcriptional silencing of perlecan gene expression by interferon-γ, J. Biol. Chem 273 (1998) 4642–4646. [DOI] [PubMed] [Google Scholar]
- [280].Iozzo RV, Basement membrane proteoglycans: from cellar to ceiling, Nat. Rev. Mol. Cell Biol 6 (2005) 646–656. [DOI] [PubMed] [Google Scholar]
- [281].Lord MS, Chuang CY, Melrose J, Davies MJ, Iozzo RV, Whitelock JM, The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling, Matrix Biol 35 (2014) 112–122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [282].Martinez JR, Dhawan A, Farach-Carson MC, Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions, Genes (Basel) 9 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [283].Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV, BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan, J. Biol. Chem 280 (2005) 7080–7087. [DOI] [PubMed] [Google Scholar]
- [284].Cailhier J-F, Sirois I, Raymond M-A, Lepage S, Laplante P, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hebért M-J, Caspase-3 activation triggers extracellular release of cathepsin L and endorepellin proteolysis, J. Biol. Chem 283 (2008) 27220–27229. [DOI] [PubMed] [Google Scholar]
- [285].Handler M, Yurchenco PD, Iozzo RV, Developmental expression of perlecan during murine embryogenesis, Dev. Dyn 210 (1997) 130–145. [DOI] [PubMed] [Google Scholar]
- [286].Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV, Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization, J. Histochem. Cytochem 42 (1994) 239–249. [DOI] [PubMed] [Google Scholar]
- [287].Pozzi A, Yurchenco PD, Iozzo RV, The nature and biology of basement membranes, Matrix Biol 57–58 (2017) 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [288].Moerman DG, Hutter H, Mullen GP, Schnabel R, Cell autonomous expression of perlecan and plasticity of cell shape in embryonic muscle of Caenorhabditis elegans, Dev. Biol 173 (1996) 228–242. [DOI] [PubMed] [Google Scholar]
- [289].Farach-Carson MC, Carson DD, Perlecan - a multifunctional extracellular proteoglycan scaffold, Glycobiology 17 (2007) 897–905. [DOI] [PubMed] [Google Scholar]
- [290].Pastor-Pareja JC, Xu T, Shaping cells and organs in Drosophila by opposing roles of fat body-secreted collagen IV and perlecan, Dev. Cell 21 (2011) 245–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [291].Farach-Carson MC, Warren CR, Harrington DA, Carson DD, Border patrol:Insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders, Matrix Biol. 34 (2014) 64–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [292].Bonche R, Chessel A, Boisivon S, Smolen P, Thérond P, Pizette S, Two different sources of Perlecan cooperate for its function in the basement membrane of the Drosophila wing imaginal disc, Dev. Dyn 2020). [DOI] [PubMed] [Google Scholar]
- [293].Mongiat M, Otto J, Oldershaw R, Ferrer F, Sato JD, Iozzo RV, Fibroblast growth factor-binding protein is a novel partner for perlecan protein core, J. Biol. Chem 276 (2001) 10263–10271. [DOI] [PubMed] [Google Scholar]
- [294].Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown A, Iozzo RV, Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis, J. Biol. Chem 278 (2003) 17491–17499. [DOI] [PubMed] [Google Scholar]
- [295].Gonzalez EM, Mongiat M, Slater SJ, Baffa R, Iozzo RV, A novel interaction between perlecan protein core and progranulin: Potential effects on tumor growth, J. Biol. Chem 278 (2003) 38113–38116. [DOI] [PubMed] [Google Scholar]
- [296].Chuang CY, Lord MS, Melrose J, Rees MD, Knox SM, Freeman C, Iozzo RV, Whitelock J, Heparan sulfate-dependent signaling of fibroblast growth growth factor 18 by chondrocyte-derived perlecan, Biochemistry 49 (2010) 5524–5532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [297].Tanimoto R, Palladino C, Xu SQ, Buraschi S, Neill T, Gomella LG, Peiper SC, Belfiore A, Iozzo RV, Morrione A, The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin, Matrix Biol. 64 (2017) 27–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [298].Zoeller JJ, McQuillan A, Whitelock J, Ho S-Y, Iozzo RV, A central function for perlecan in skeletal muscle and cardiovascular development, J. Cell Biol 181 (2008) 381–394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [299].Zoeller JJ, Whitelock J, Iozzo RV, Perlecan regulates developmental angiogenesis by modulating the VEGF-VEGFR2 axis, Matrix Biol. 28 (2009) 284–291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [300].San Antonio JD, Zoeller JJ, Habursky K, Turner K, Pimtong W, Burrows M, Choi S, Basra S, Bennett JS, DeGrado WF, Iozzo RV, A key role for the integrin α2β1 in experimental and developmental angiogenesis, Am. J. Pathol 175 (2009) 1338–1347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [301].Cohen IR, Murdoch AD, Naso MF, Marchetti D, Berd D, Iozzo RV, Abnormal expression of perlecan proteoglycan in metastatic melanomas, Cancer Res. 54 (1994) 5771–5774. [PubMed] [Google Scholar]
- [302].Aviezer D, Iozzo RV, Noonan DM, Yayon A, Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA, Mol. Cell. Biol 17 (1997) 1938–1946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [303].Mathiak M, Yenisey C, Grant DS, Sharma B, Iozzo RV, A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells, Cancer Res. 57 (1997) 2130–2136. [PubMed] [Google Scholar]
- [304].Sharma B, Handler M, Eichstetter I, Whitelock J, Nugent MA, Iozzo RV, Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo, J. Clin. Invest 102 (1998) 1599–1608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [305].Woodall BP, Nyström A, Iozzo RA, Eble JA, Niland S, Krieg T, Eckes B, Pozzi A, Iozzo RV, Integrin α2β1 is the required receptor for endorepellin angiostatic activity, J. Biol. Chem 283 (2008) 2335–2343. [DOI] [PubMed] [Google Scholar]
- [306].Elgundi Z, Papanicolaou M, Major G, Cox TR, Melrose J, Whitelock JM, Farrugia BL, Cancer metastasis: The role of the extracellular matrix and the heparan sulfate proteoglycan perlecan, Front Oncol. 9 (2019) 1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [307].Fuki I, Iozzo RV, Williams KJ, Perlecan heparan sulfate proteoglycan. A novel receptor that mediates a distinct pathway for ligand catabolism, J. Biol. Chem 275 (2000) 25742–25750. [DOI] [PubMed] [Google Scholar]
- [308].Nakamura K, Ikeuchi T, Nara K, Rhodes CS, Zhang P, Chiba Y, Kazuno S, Miura Y, Ago T, Arikawa-Hirasawa E, Mukouyama YS, Yamada Y, Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier, J. Cell Biol 218 (2019) 3506–3525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [309].Ocken AR, Ku MM, Kinzer-Ursem TL, Calve S, Perlecan Knockdown Significantly Alters Extracellular Matrix Composition and Organization During Cartilage Development, Mol. Cell Proteomics 19 (2020) 1220–1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [310].Castellanos BS, Reyes-Nava NG, Quintana AM, Knockdown of hspg2 is associated with abnormal mandibular joint formation and neural crest cell dysfunction in zebrafish, BMC. Dev. Biol 21 (2021) 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [311].Vennin C, Mélénec P, Rouet R, Nobis M, Cazet AS, Murphy KJ, Herrmann D, Reed DA, Lucas MC, Warren SC, Elgundi Z, Pinese M, Kalna G, Roden D, Samuel M, Zaratzian A, Grey ST, Da SA, Leung W, Mathivanan S, Wang Y, Braithwaite AW, Christ D, Benda A, Parkin A, Phillips PA, Whitelock JM, Gill AJ, Sansom OJ, Croucher DR, Parker BL, Pajic M, Morton JP, Cox TR, Timpson P, CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan, Nat. Commun 10 (2019) 3637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [312].Nugent MA, Nugent HM, Iozzo RV, Sanchack K, Edelman ER, Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia, Proc. Natl. Acad. Sci. U. S. A 97 (2000) 6722–6727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [313].Zhou X, Liang S, Zhan Q, Yang L, Chi J, Wang L, HSPG2 overexpression independently predicts poor survival in patients with acute myeloid leukemia, Cell Death. Dis 11 (2020) 492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [314].Murdoch AD, Dodge GR, Cohen I, Tuan RS, Iozzo RV, Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor, J. Biol. Chem 267 (1992) 8544–8557. [PubMed] [Google Scholar]
- [315].Gubbiotti MA, Neill T, Iozzo RV, A current view of perlecan in physiology and pathology: A mosaic of functions, Matrix Biol 57–58 (2017) 285–298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [316].Bix G, Fu J, Gonzalez E, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M, Reed CC, Iozzo RV, Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through the α2β1 integrin, J. Cell Biol 166 (2004) 97–109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [317].Bix G, Castello R, Burrows M, Zoeller JJ, Weech M, Iozzo RA, Cardi C, Thakur MT, Barker CA, Camphausen KC, Iozzo RV, Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism, J. Natl. Cancer Inst 98 (2006) 1634–1646. [DOI] [PubMed] [Google Scholar]
- [318].Bix G, Iozzo RV, Matrix revolutions: “tails” of basement-membrane components with angiostatic functions, Trends Cell Biol. 15 (2005) 52–60. [DOI] [PubMed] [Google Scholar]
- [319].Willis CD, Poluzzi C, Mongiat M, Iozzo RV, Endorepellin laminin-like globular repeat 1/2 domains bind Ig3–5 of vascular endothelial growth factor(VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells, FEBS J. 280 (2013) 2271–2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [320].Nyström A, Shaik ZP, Gullberg D, Krieg T, Eckes B, Zent R, Pozzi A, Iozzo RV, Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity, Blood 114 (2009) 4897–4906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [321].Ning L, Xu Z, Furuya N, Nonaka R, Yamada Y, Arikawa-Hirasawa E, Perlecan inhibits autophagy to maintain muscle homeostasis in mouse soleus muscle, Matrix Biol. 48 (2015) 26–35. [DOI] [PubMed] [Google Scholar]
- [322].Bolger AM, Lohse M, Usadel B, Trimmomatic: a flexible trimmer for Illumina sequence data, Bioinformatics. 30 (2014) 2114–2120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [323].Parzych KR, Klionsky DJ, An overview of autophagy: morphology, mechanism, and regulation, Antioxid. Redox. Signal 20 (2014) 460–473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [324].Choi AMK, Ryter SW, Levine B, Autophagy in human health and disease, New Engl. J. Med 368 (2013) 651–662. [DOI] [PubMed] [Google Scholar]
- [325].Goyal A, Pal N, Concannon M, Paulk M, Doran M, Poluzzi C, Sekiguchi K, Whitelock JM, Neill T, Iozzo RV, Endorepellin, the angiostatic module of perlecan, interacts with both the α2β1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2), J. Biol. Chem 286 (2011) 25947–25962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [326].Chen CG, Iozzo RV, Angiostatic cues from the matrix: endothelial cell autophagy meets hyaluronan biology, J. Biol Chem 295 (2020) 16797–16812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [327].Goyal A, Poluzzi C, Willis AC, Smythies J, Shellard A, Neill T, Iozzo RV, Endorepellin affects angiogenesis by antagonizing diverse VEGFR2- evoked signaling pathways: transcriptional repression of HIF-1α and VEGFA and concurrent inhibition of NFAT1 activation, J. Biol. Chem 287 (2012) 43543–43556. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [328].Hohenester E, Tisi D, Talts JF, Timpl R, The crystal structure of a laminin G-like module reveals the molecular basis of α-dystroglycan binding to laminins, perlecan, and agrin, Mol. Cell 4 (1999) 783–792. [DOI] [PubMed] [Google Scholar]
- [329].Hohenester E, Engel J, Domain structure and organisation in extracellular matrix proteins, Matrix Biol. 21 (2002) 115–128. [DOI] [PubMed] [Google Scholar]
- [330].Bix G, Iozzo RA, Woodall B, Burrows M, McQuillan A, Campbell S, Fields GB, Iozzo RV, Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the α2β1 integrin receptor, Blood 109 (2007) 3745–3748. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [331].Bhattacharya R, Kwon J, Wang E, Mukherjee P, Mukhopadhyay D, Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF receptor-2 and attenuates endothelial DNA synthesis, but not migration, J. Mol. Signal 3 (2008) 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [332].Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L, Signal transduction by vascular endothelial growth factor receptors, Biochem. J 437 (2011) 169–183. [DOI] [PubMed] [Google Scholar]
- [333].Holmes K, Roberts OL, Thomas AM, Cross MJ, Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition, Cell. Signalling 19 (2007) 2003–2012. [DOI] [PubMed] [Google Scholar]
- [334].Olsson A-K, Dimberg A, Kreuger J, Claesson-Welsh L, VEGF receptor signalling - in control of vascular function, Nat. Rev. Mol. Cell Biol 7 (2006) 359–371. [DOI] [PubMed] [Google Scholar]
- [335].Karali E, Bellou S, Stellas D, Klinakis A, Murphy C, Fotsis T, VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress, Mol. Cell 54 (2014) 559–572. [DOI] [PubMed] [Google Scholar]
- [336].Kapoor A, Chen CG, Iozzo RV, A simplified aortic ring assay: A useful ex vivo method to assess biochemical and functional parameters of angiogenesis, Matrix Biol Plus 6–7 (2020) 100025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [337].Yang F, Zhang W, Li D, Zhan Q, Gadd45α suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway, J. Biol. Chem 288 (2013) 6552–6560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [338].Heldin P, Lin CY, Kolliopoulos C, Chen YH, Skandalis SS, Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production, Matrix Biol 78–79 (2019) 100–117. [DOI] [PubMed] [Google Scholar]
- [339].Karalis TT, Heldin P, Vynios DH, Neill T, Buraschi S, Iozzo RV, Karamanos NK, Skandalis SS, Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status: Regulation of hyaluronan/HAS2/CD44 and specific matrix effectors, Matrix Biol 78–79 (2019) 118–138. [DOI] [PubMed] [Google Scholar]
- [340].Passi A, Vigetti D, Hyaluronan as tunable drug delivery system, Adv. Drug Deliv. Rev 146 (2019) 83–96. [DOI] [PubMed] [Google Scholar]
- [341].Vigetti D, Karousou E, Viola M, Deleonibus S, De LG, Passi A, Hyaluronan: biosynthesis and signaling, Biochim. Biophys. Acta 1840 (2014) 2452–2459. [DOI] [PubMed] [Google Scholar]
- [342].Passi A, Vigetti D, Buraschi S, Iozzo RV, Dissecting the role of hyaluronan synthases in the tumor microenvironment, FEBS J. 286 (2019) 2937–2949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [343].Caon I, Bartolini B, Parnigoni A, Carava E, Moretto P, Viola M, Karousou E, Vigetti D, Passi A, Revisiting the hallmarks of cancer: The role of hyaluronan, Semin. Cancer Biol 62 (2020) 9–19. [DOI] [PubMed] [Google Scholar]
- [344].Knudson W, Ishizuka S, Terabe K, Askew EB, Knudson CB, The pericellular hyaluronan of articular chondrocytes, Matrix Biol 78–79 (2019) 32–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [345].Tighe RM, Garantziotis S, Hyaluronan interactions with innate immunity in lung biology, Matrix Biol 78–79 (2019) 84–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [346].Tammi MI, Oikari S, Pasonen-Seppanen S, Rilla K, Auvinen P, Tammi RH, Activated hyaluronan metabolism in the tumor matrix - Causes and consequences, Matrix Biol 78–79 (2019) 147–164. [DOI] [PubMed] [Google Scholar]
- [347].Caon I, Parnigoni A, Viola M, Karousou E, Passi A, Vigetti D, Cell energy metabolism and hyaluronan synthesis, J. Histochem. Cytochem 69 (2021) 35–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [348].Petz A, Grandoch M, Gorski DJ, Abrams M, Piroth M, Schneckmann R, Homann S, Müller J, Hartwig S, Lehr S, Yamaguchi Y, Wight TN, Gorressen S, Ding Z, Kötter S, Krüger M, Heinen A, Kelm M, Gõdecke A, Flögel U, Fischer JW, Cardiac hyaluronan synthesis Is critically involved in the cardiac macrophage response and promotes healing after ischemia reperfusion injury, Circ. Res 124 (2019) 1433–1447. [DOI] [PubMed] [Google Scholar]
- [349].Fischer JW, Role of hyaluronan in atherosclerosis: Current knowledge and open questions, Matrix Biol 78–79 (2019) 324–336. [DOI] [PubMed] [Google Scholar]
- [350].Karalis TT, Chatzopoulos A, Kondyli A, Aletras AJ, Karamanos NK, Heldin P, Skandalis SS, Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells, Matrix Biol Plus 6–7 (2020) 100031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [351].Tavianatou AG, Piperigkou Z, Barbera C, Beninatto R, Masola V, Caon I, Franchi M, Galesso D, Karamanos NK, Molecular-size dependent specificity of hyaluronan on functional properties, morphology and matrix composition of mammary cancer cells, Matrix Biol 3 (2019) 100008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [352].Kobayashi T, Chanmee T, Itano N, Hyaluronan: Metabolism and Function, Biomolecules. 10 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [353].Leng Y, Abdullah A, Wendt MK, Calve S, Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during embryogenesis, Matrix Biol 78–79 (2019) 236–254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [354].Queisser KA, Mellema RA, Petrey AC, Hyaluronan and its receptors as regulatory molecules of the endothelial interface, J. Histochem. Cytochem 69 (2021) 25–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [355].Wang G, Kostidis S, Tiemeier GL, Sol WMPJ, de Vries MR, Giera M, Carmeliet P, van den Berg BM, Rabelink TJ, Shear Stress Regulation of Endothelial Glycocalyx Structure Is Determined by Glucobiosynthesis, Arterioscler. Thromb. Vasc. Biol 40 (2020) 350–364. [DOI] [PubMed] [Google Scholar]
- [356].Wang G, Tiemeier GL, van den Berg BM, Rabelink TJ, Endothelial glycocalyx hyaluronan: Regulation and role in prevention of diabetic complications, Am. J. Pathol 190 (2020) 781–790. [DOI] [PubMed] [Google Scholar]
- [357].Wang G, de Vries MR, Sol WMPJ, van Oeveren-Rietdijk AM, de Boer HC, van Zonneveld AJ, Quax PHA, Rabelink TJ, van den Berg BM, Loss of endothelial glycocalyx hyaluronan impairs endothelial stability and adaptive vascular remodeling after arterial ischemia, Cells 9 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [358].Potter DR, van TJ, Vink H, van den Berg BM, Perturbed mechanotransduction by endothelial surface glycocalyx modification greatly impairs the arteriogenic process, Am. J. Physiol Heart Circ. Physiol 309 (2015) H711–H717. [DOI] [PubMed] [Google Scholar]
- [359].Garantziotis S, Savani RC, Hyaluronan biology: A complex balancing act of structure, function, location and context, Matrix Biol 78–79 (2019) 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [360].Chen CG, Gubbiotti MA, Kapoor A, Han X, Yu Y, Linhardt RJ, Iozzo RV, Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis, Matrix Biol 90 (2020) 1–19. [DOI] [PubMed] [Google Scholar]
- [361].Karousou E, Kamiryo M, Skandalis SS, Ruusala A, Asteriou T, Passi A, Yamashita H, Hellman U, Heldin CH, Heldin P, The activity of hyaluronan synthase 2 is regulated by dimerization and ubiquitination, J. Biol Chem 285 (2010) 23647–23654. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [362].Nguyen TMB, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S, Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and β-catenin levels, J. Cell. Mol. Med 13 (2009) 3687–3698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [363].Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, Fornace AJ Jr., Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53, Cancer Res. 62 (2002) 7305–7315. [PubMed] [Google Scholar]
- [364].Ebert SM, Dyle MC, Kunkel SD, Bullard SA, Bongers KS, Fox DK, Dierdorff JM, Foster ED, Adams CM, Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy, J. Biol. Chem 287 (2012) 27290–27301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [365].Zhang D, Zhang W, Li D, Fu M, Chen R, Zhan Q, GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3, Autophagy. 11 (2015) 2247–2258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [366].Karousou E, Misra S, Ghatak S, Dobra K, Gotte M, Vigetti D, Passi A, Karamanos NK, Skandalis SS, Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer, Matrix Biol 59 (2017) 3–22. [DOI] [PubMed] [Google Scholar]
- [367].Vigetti D, Viola M, Karousou E, De LG, Passi A, Metabolic control of hyaluronan synthases, Matrix Biol. 35 (2014) 8–13. [DOI] [PubMed] [Google Scholar]
- [368].Kobayashi N, Miyoshi S, Mikami T, Koyama H, Kitazawa M, Takeoka M, Sano K, Amano J, Isogai Z, Niida S, Oguri K, Okayama M, McDonald JA, Kimata K, Taniguchi S, Itano N, Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization, Cancer Res. 70 (2010) 7073–7083. [DOI] [PubMed] [Google Scholar]
- [369].Delpech B, Girard N, Bertrand P, Courel MN, Chauzy C, Delpech A, Hyaluronan: fundamental principles and applications in cancer, J. Intern. Med 242 (1997) 41–48. [DOI] [PubMed] [Google Scholar]
- [370].Evanko SP, Tammi MI, Tammi RH, Wight TN, Hyaluronan-dependent pericellular matrix, Adv. Drug Deliv. Rev 59 (2007) 1351–1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [371].Sainio A, Takabe P, Oikari S, Salomaki-Myftari H, Koulu M, Soderstrom M, Pasonen-Seppanen S, Jarvelainen H, Metformin decreases hyaluronan synthesis by vascular smooth muscle cells, J. Investig. Med 68 (2020) 383–391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [372].Mattera R, Park SY, De PR, Guardia CM, Bonifacino JS, AP-4 mediates export of ATG9A from the trans-Golgi network to promote autophagosome formation, Proc. Natl. Acad. Sci. U. S. A 114 (2017) E10697–E10706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [373].Zhuang X, Chung KP, Cui Y, Lin W, Gao C, Kang BH, Jiang L, ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis, Proc. Natl. Acad. Sci. U. S. A 114 (2017) E426–E435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [374].Ivankovic D, Drew J, Lesept F, White IJ, Lopez DG, Tooze SA, Kittler JT, Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome, Autophagy. 16 (2020) 391–407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [375].Ungermann C, Reggiori F, Atg9 proteins, not so different after all, Autophagy. 14 (2018) 1456–1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [376].Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA, Maiolica A, Hansmann I, Pfaffenwimmer T, Kijanska M, Stoffel I, Lee SS, Brezovich A, Lou JH, Turk BE, Aebersold R, Ammerer G, Peter M, Kraft C, Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase, Mol Cell 53 (2014) 471–483. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [377].Felbor U, Dreier L, Bryant RAR, Ploegh HL, Olsen BR, Mothes W, Secreted cathepsin L generates endostatin from collagen XVIII, EMBO J. 19 (2000) 1187–1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [378].Abdollahi A, Hahnfeldt P, Maercker C, Gröne H-J, Debus J, Ansorge W, Folkman J, Hlatky L, Huber PE, Endostatin’s antioangiogenic signaling network, Mol. Cell 13 (2004) 649–663. [DOI] [PubMed] [Google Scholar]
- [379].Folkman J, Antiangiogenesis in cancer therapy - endostatin and its mechanisms of action, Exp. Cell Res 312 (2006) 594–607. [DOI] [PubMed] [Google Scholar]
- [380].Delaney CE, Weagant BT, Addison CL, The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix, Exp. Cell Res 312 (2006) 2476–2849. [DOI] [PubMed] [Google Scholar]
- [381].Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M, Sukhatme VP, Endostatin induces endothelial cell apoptosis, J. Biol. Chem 274 (1999) 11721–11726. [DOI] [PubMed] [Google Scholar]
- [382].Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engström Å, Timpl R, Welsh M, Claesson-Welsh L, Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis, Blood 95 (2000) 3403–3411. [PubMed] [Google Scholar]
- [383].Dixelius J, Cross M, Matsumoto T, Sasaki T, Timpl R, Claesson-Welsh L, Endostatin regulates endothelial cell adhesion and cytoskeletal organization, Cancer Res. 62 (2002) 1944–1947. [PubMed] [Google Scholar]
- [384].Chang Z, Choon A, Friedl A, Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding, Am. J. Pathol 155 (2000) 71–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [385].Chen J, Yao Q, Huang M, Wang B, Zhang J, Wang T, Ming Y, Zhou X, Jia Q, Huan Y, Wang J, Wang L, A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01), Int. J. Cancer 142 (2018) 2130–2138. [DOI] [PubMed] [Google Scholar]
- [386].Herbst RS, Hess KR, Tran HT, Tseng JE, Mullani NA, Charnsangavej C, Madden T, Davis DW, McConkey DJ, O’Reilly MS, Ellis LM, Pluda J, Hong WK, Abbruzzese JL, Phase I study of recombinant human endostatin in patients with advanced solid tumors, J. Clin. Oncol 20 (2002) 3792–3803. [DOI] [PubMed] [Google Scholar]
- [387].Cheng YJ, Meng CT, Ying HY, Zhou JF, Yan XY, Gao X, Zhou N, Bai CM, Effect of Endostar combined with chemotherapy in advanced well-differentiated pancreatic neuroendocrine tumors, Medicine (Baltimore) 97 (2018) e12750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [388].An J, Lv W, Endostar (rh-endostatin) versus placebo in combination with vinorelbine plus cisplatin chemotherapy regimen in treatment of advanced non-small cell lung cancer: A meta-analysis, Thorac. Cancer 9 (2018) 606–612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [389].Wu J, Zhao X, Sun Q, Jiang Y, Zhang W, Luo J, Li Y, Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model, Biomed. Pharmacother 125 (2020) 109746. [DOI] [PubMed] [Google Scholar]
- [390].Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, Zampetaki A, Zhang Z, Wang W, Jiang Z, Gao C, Ma B, Chen YG, Cockerill G, Hu Y, Xu Q, Zeng L, XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation, J. Biol Chem 288 (2013) 859–872. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [391].Wu G, Zhang R, Ren J, Sun Y, Autophagic cell death of human hepatoma cells induced by endostar, a recombinant human endostatin, Cancer Biother. Radiopharm 23 (2008) 735–740. [DOI] [PubMed] [Google Scholar]
- [392].Wickström SA, Alitalo K, Keski-Oja J, Endostatin associates with integrin α5β1 and caveolin-1, and activates src via a tyrosyl phosphatase-dependent pathway in human endothelial cells, Cancer Res. 62 (2002) 5580–5589. [PubMed] [Google Scholar]
- [393].Chau Y-P, Lin J-Y, Chen JH-C, Tai M-H, Endostatin induces autophagic cell death in EAhy926 human endothelial cells, Histol. Histopathol 18 (2003) 715–726. [DOI] [PubMed] [Google Scholar]
- [394].Kim Y-M, Hwang S, Kim Y-M, Pyun B-J, Kim T-Y, Lee S-T, Gho YS, Kwon Y-G, Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1, J. Biol. Chem 277 (2002) 27872–27879. [DOI] [PubMed] [Google Scholar]
- [395].Miosge N, Simniok T, Sprysch P, Herken R, The collagen type XVIII endostatin domain is co-localized with perlecan in basement membranes in vivo, J. Histochem. Cytochem 51 (2003) 285–296. [DOI] [PubMed] [Google Scholar]
- [396].Ramakrishnan S, Nguygen TMB, Subramanian IV, Kelekar A, Autophagy and angiogenesis inhibition, Autophagy 3 (2007) 512–515. [DOI] [PubMed] [Google Scholar]
- [397].Nguygen TMB, Subramanian IV, Kelekar A, Ramakrishnan S, Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells, Blood 109 (2007) 4793–4802. [DOI] [PubMed] [Google Scholar]
- [398].Perri SR, Martineau D, François M, Lejeune L, Bisson L, Durocher Y, Galipeau J, Plasminogen Kringle 5 blocks tumor progression by antiangiogenic and proinflammatory pathways, Mol. Cancer Ther 6 (2007) 441–449. [DOI] [PubMed] [Google Scholar]
- [399].Chen C, Kapoor A, Iozzo RV, Methods for monitoring matrix-induced autophagy, Methods Mol. Biol 1952 (2019) 157–191. [DOI] [PubMed] [Google Scholar]
- [400].Cao Y, Chen A, An SS, Ji RW, Davidson D, Llinás M, Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth, J. Biol Chem 272 (1997) 22924–22928. [DOI] [PubMed] [Google Scholar]
- [401].Lu H, Dhanabal M, Volk R, Waterman MJ, Ramchandran R, Knebelmann B, Segal M, Sukhatme VP, Kringle 5 causes cell cycle arrest and apoptosis of endothelial cells, Biochem. Biophys. Res. Commun 258 (1999) 668–673. [DOI] [PubMed] [Google Scholar]
- [402].Gonzalez-Gronow M, Selim MA, Papalas J, Pizzo SV, GRP78: a multifunctional receptor on the cell surface, Antioxid. Redox. Signal 11 (2009) 2299–2306. [DOI] [PubMed] [Google Scholar]
- [403].Davidson DJ, Haskell C, Majest S, Kherzai A, Egan DA, Walter KA, Schneider A, Gubbins EF, Solomon L, Chen Z, Lesniewski R, Henkin J, Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78, Cancer Res. 65 (2005) 4663–4672. [DOI] [PubMed] [Google Scholar]
- [404].McFarland BC, Stewart J Jr., Hamza A, Nordal R, Davidson DJ, Henkin J, Gladson CL, Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1, Cancer Res. 69 (2009) 5537–5545. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [405].Li L, Yao YC, Gu XQ, Che D, Ma CQ, Dai ZY, Li C, Zhou T, Cai WB, Yang ZH, Yang X, Gao GQ, Plasminogen kringle 5 induces endothelial cell apoptosis by triggering a voltage-dependent anion channel 1 (VDAC1) positive feedback loop, J. Biol Chem 289 (2014) 32628–32638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [406].Gonzalez-Gronow M, Kalfa T, Johnson CE, Gawdi G, Pizzo SV, The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells, J. Biol Chem 278 (2003) 27312–27318. [DOI] [PubMed] [Google Scholar]
- [407].Gu X, Yao Y, Cheng R, Zhang Y, Dai Z, Wan G, Yang Z, Cai W, Gao G, Yang X, Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-x(L) subcellular distribution, Apoptosis. 16 (2011) 846–855. [DOI] [PubMed] [Google Scholar]
- [408].Fang S, Hong H, Li L, He D, Xu Z, Zuo S, Han J, Wu Q, Dai Z, Cai W, Ma J, Shao C, Gao G, Yang X, Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78, Cell Death. Dis 8 (2017) e3144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [409].Kim HK, Choi JS, Lee SW, Joo CK, Joe YA, A novel peptide derived from tissue-type plasminogen activator potently inhibits angiogenesis and corneal neovascularization, J. Cell Biochem 118 (2017) 1132–1143. [DOI] [PubMed] [Google Scholar]
- [410].Zhang Y, Zhang R, Bai J, Liu W, Yang J, Bian L, Human laminin α3 chain G1 domain is a receptor for plasminogen Kringle 5 on human endothelial cells by biological specificity technologies and molecular dynamic, J. Chromatogr. A 1620 (2020) 460986. [DOI] [PubMed] [Google Scholar]
- [411].Urciuolo A, Quarta A, Morbidoni V, gattazzo F, Molon S, Grumati P, Montemurro F, Tedesco FS, Blaauw B, Cossu G, Vozzi G, Rando TA, Bonaldo P, Collagen VI regulates satellite cell self-renewal and muscle regeneration, Nat. Commun 4 (2013) 1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [412].Chen P, Cescon M, Bonaldo P, Collagen VI in cancer and its biological mechanisms, Trends Mol. Med 19 (2013) 410–417. [DOI] [PubMed] [Google Scholar]
- [413].Bonaldo P, Sandri M, Cellular and molecular mechanisms of muscle atrophy, Disease Models Mechan. 6 (2013) 25–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [414].Lamande SR, Bateman JF, Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond, Matrix Biol 71–72 (2018) 348–367. [DOI] [PubMed] [Google Scholar]
- [415].Mohassel P, Foley AR, Bönnemann CG, Extracellular matrix-driven congenital muscular dystrophies, Matrix Biol 71–72 (2018) 188–204. [DOI] [PubMed] [Google Scholar]
- [416].Capitanio D, Moriggi M, De PS, Bizzotto D, Molon S, Torretta E, Fania C, Bonaldo P, Gelfi C, Braghetta P, Collagen VI Null Mice as a Model for Early Onset Muscle Decline in Aging, Front Mol. Neurosci 10 (2017) 337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [417].Grumati P, Bonaldo P, Autophagy in skeletal muscle homeostasis and in muscular dystrophies, Cells 1 (2012) 325–345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [418].Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P, Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration, Nat. Med 16 (2011) 1313–1320. [DOI] [PubMed] [Google Scholar]
- [419].Castagnaro S, Chrisam M, Cescon M, Braghetta P, Grumati P, Bonaldo P, Extracellular Collagen VI Has Prosurvival and Autophagy Instructive Properties in Mouse Fibroblasts, Front Physiol 9 (2018) 1129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [420].Irwin WA, Bergamin N, Sabatelli P, Reggiani C, Megighian A, Merlini L, Braghetta P, Columbaro M, Volpin D, Bressan GM, Bernardi P, Bonaldo P, Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency, Nat. Genet 35 (2003) 367–371. [DOI] [PubMed] [Google Scholar]
- [421].Cescon M, Chen P, Castagnaro S, Gregorio I, Bonaldo P, Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging, Aging (Albany. NY) 8 (2016) 1083–1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [422].Metti S, Gambarotto L, Chrisam M, Baraldo M, Braghetta P, Blaauw B, Bonaldo P, The polyphenol pterostilbene ameliorates the myopathic phenotype of collagen VI deficient mice via autophagy induction, Front Cell Dev. Biol 8 (2020) 580933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [423].Settembre C, Cinque L, Bartolomeo R, Di MC, De LC, Forrester A, Defective collagen proteostasis and matrix formation in the pathogenesis of lysosomal storage disorders, Matrix Biol 71–72 (2018) 283–293. [DOI] [PubMed] [Google Scholar]
- [424].Rudnicka L, Varga J, Christiano AM, Iozzo RV, Jimenez SA, Uitto J, Elevated expression of type VII collagen in the skin of patients with systemic sclerosis, J. Clin. Invest 93 (1994) 1709–1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [425].Nyström A, Velati D, Mittapalli VR, Fritsch A, Kern JS, Bruckner-Tuderman L, Collagen VII plays a dual role in wound healing, J. Clin. Invest 123 (2013) 3498–3509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [426].Ryynänen M, Ryynänen J, Solberg S, Iozzo RV, Knowlton RG, Uitto J, Genetic linkage of Type VII collagen (COL7A1) to dominant dystrophic epidermolysis bullosa in families with abnormal anchoring fibrils, J. Clin. Invest 89 (1992) 974–980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [427].Nystrom A, Bruckner-Tuderman L, Injury- and inflammation-driven skin fibrosis: The paradigm of epidermolysis bullosa, Matrix Biol 68–69 (2018) 547–560. [DOI] [PubMed] [Google Scholar]
- [428].Nystrom A, Bornert O, Kuhl T, Cell therapy for basement membrane-linked diseases, Matrix Biol 57–58 (2017) 124–139. [DOI] [PubMed] [Google Scholar]
- [429].Küttner V, Mack C, Gretzmeier C, Bruckner-Tuderman L, Dengjel J, Loss of collagen VII is associated with reduced transglutaminase 2 abundance and activity, J. Invest Dermatol 134 (2014) 2381–2389. [DOI] [PubMed] [Google Scholar]
- [430].Weber IT, Evaluation of homology modeling of HIV protease, Proteins 7 (1990) 172–184. [DOI] [PubMed] [Google Scholar]
- [431].Guerra L, Odorisio T, Zambruno G, Castiglia D, Stromal microenvironment in type VII collagen-deficient skin: The ground for squamous cell carcinoma development, Matrix Biol 63 (2017) 1–10. [DOI] [PubMed] [Google Scholar]
- [432].Besio R, Garibaldi N, Leoni L, Cipolla L, Sabbioneda S, Biggiogera M, Mottes M, Aglan M, Otaify GA, Temtamy SA, Rossi A, Forlino A, Cellular stress due to impairment of collagen prolyl hydroxylation complex is rescued by the chaperone 4-phenylbutyrate, Dis. Model. Mech 12 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [433].Nakamura T, Yamashita M, Ikegami K, Suzuki M, Yanagita M, Kitagaki J, Kitamura M, Murakami S, Autophagy facilitates type I collagen synthesis in periodontal ligament cells, Sci. Rep 11 (2021) 1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [434].Rahimi N, Rezazadeh K, Mahoney JE, Hartsough E, Meyer RD, Identification of IGPR-1 as a novel adhesion molecule involved in angiogenesis, Mol. Biol Cell 23 (2012) 1646–1656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [435].Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, Phennicie RT, Flies SJ, Broadwater M, Ruff W, Taube JM, Zheng L, Luo L, Zhu G, Chen J, Chen L, B7-H5 costimulates human T cells via CD28H, Nat. Commun 4 (2013) 2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [436].Janakiram M, Chinai JM, Zhao A, Sparano JA, Zang X, HHLA2 and TMIGD2: new immunotherapeutic targets of the B7 and CD28 families, Oncoimmunology. 4 (2015) e1026534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [437].Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X, The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3, Immunol. Rev 276 (2017) 26–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [438].Woolf N, Pearson BE, Bondzie PA, Meyer RD, Lavaei M, Belkina AC, Chitalia V, Rahimi N, Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy, Oncogenesis. 6 (2017) e378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [439].Wang YHW, Meyer RD, Bondzie PA, Jiang Y, Rahimi I, Rezazadeh K, Mehta M, Laver NMV, Costello CE, Rahimi N, IGPR-1 Is Required for Endothelial Cell-Cell Adhesion and Barrier Function, J. Mol. Biol 428 (2016) 5019–5033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [440].Ho RX, Tahboub R, Amraei R, Meyer RD, Varongchayakul N, Grinstaff M, Rahimi N, The cell adhesion molecule IGPR-1 is activated by and regulates responses of endothelial cells to shear stress, J. Biol Chem 294 (2019) 13671–13680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [441].Liu J, Bi X, Chen T, Zhang Q, Wang SX, Chiu JJ, Liu GS, Zhang Y, Bu P, Jiang F, Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression, Cell Death. Dis 6 (2015) e1827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [442].Amraei R, Alwani T, Ho RX, Aryan Z, Wang S, Rahimi N, Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to autophagy, J. Biol Chem 295 (2020) 16691–16699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [443].Carmignac V, Svensson M, Körner Z, Elowsson L, Matsumura C, Gawlik KI, Allamand V, Durbeej M, Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A, Human Mol. Gen 20 (2011) 4891–4902. [DOI] [PubMed] [Google Scholar]
- [444].Colognato H, MacCarrick M, O’Rear JJ, Yurchenco PD, The laminin α2-chain short arm mediates cell adhesion through both the α1β1 and α2β1 integrins, J. Biol. Chem 272 (1997) 29330–29336. [DOI] [PubMed] [Google Scholar]
- [445].Douglass S, Goyal A, Iozzo RV, The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy, Connect. Tissue Res 19 (2015) 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [446].Gubbiotti MA, Iozzo RV, Proteoglycans regulate autophagy via outside-in signaling: An emerging new concept, Matrix Biol. 48 (2015) 6–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [447].Kamimura K, Ueno K, Nakagawa J, Hamada R, Saitoe M, Maeda N, Perlecan regulates bidirectional Wnt signaling at the Drosophila neuromuscular junction, J. Cell Biol 200 (2013) 219–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [448].Voigt A, Pflanz R, Schafer U, Jackle H, Perlecan participates in proliferation activation of quiescent Drosophila neuroblasts, Dev. Dyn 224 (2002) 403–412. [DOI] [PubMed] [Google Scholar]
- [449].Park Y, Rangel C, Reynolds MM, Caldwell MC, Johns M, Nayak M, Welsh CJR, McDermott S, Datta S, Drosophila perlecan modulates FGF and Hedgehog signals to activate neural stem cell division, Dev. Biol 253 (2003) 247–257. [DOI] [PubMed] [Google Scholar]
- [450].Lindner JR, Hillman PR, Barrett AL, Jackson MC, Perry TL, Park Y, Datta S, The Drosophila perlecan gene trol regulates multiple signaling pathways in different developmental contexts, BMC Dev. Biol 7 (2007) 121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [451].Kamimura K, Ueno K, Nakagawa J, Hamada R, Saitoe M, Maeda N, Perlecan regulates bidirectional Wnt signaling at the Drosophila neuromuscular junction, J. Cell Biol 200 (2013) 219–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [452].Trisnadi N, Stathopoulos A, Ectopic expression screen identifies genes affecting Drosophila mesoderm development including the HSPG Trol, G3. (Bethesda.) 5 (2014) 301–313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [453].Grigorian M, Liu T, Banerjee U, Hartenstein V, The proteoglycan Trol controls the architecture of the extracellular matrix and balances proliferation and differentiation of blood progenitors in the Drosophila lymph gland, Dev. Biol 384 (2013) 301–312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [454].Díaz-Torres A, Rosales-Nieves AE, Pearson JR, Santa-Cruz MC, Marín-Menguiano M, Marshall OJ, Brand AH, González-Reyes A, Stem cell niche organization in the Drosophila ovary requires the ECM component Perlecan, Curr. Biol 2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [455].Reynolds-Peterson CE, Zhao N, Xu J, Serman TM, Xu J, Selleck SB, Heparan sulfate proteoglycans regulate autophagy in Drosophila, Autophagy.2017) 1–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [456].Reynolds-Peterson C, Xu J, Zhao N, Cruse C, Yonel B, Trasorras C, Toyoda H, Kinoshita-Toyoda A, Dobson J, Schultheis N, Jiang M, Selleck S, Heparan Sulfate Structure Affects Autophagy, Lifespan, Responses to Oxidative Stress, and Cell Degeneration inDrosophila parkin Mutants, G3. (Bethesda.) 2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [457].Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H, Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican, J. Cell Biol 141 (1998) 1277–1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [458].Chakravarti S, Paul J, Roberts L, Chervoneva I, Oldberg A, Birk DE, Ocular and scleral alterations in gene-targeted lumican-fibromodulin double-null mice, Invest. Ophthalmol. Vis. Sci 44 (2003) 2422–2432. [DOI] [PubMed] [Google Scholar]
- [459].Chen D, Smith LR, Khandekar G, Patel P, Yu CK, Zhang K, Chen CS, Han L, Wells RG, Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization, Sci. Rep 10 (2020) 19065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [460].Nikitovic D, Berdiaki A, Zafiropoulos A, Katonis P, Tsatsakis A, Karamanos N, Tzanakakis GN, Lumican expression is positively correlated with the differentiation and negatively with the growth of human osteosarcoma cells, FEBS J. 275 (2008) 350–361. [DOI] [PubMed] [Google Scholar]
- [461].Nikitovic D, Chalkiadaki G, Berdiaki A, Aggelidakis J, Katonis P, Karamanos NK, Tzanakakis GN, Lumican regulates osteosarcoma cell adhesion by modulating TGFbeta2 activity, Int. J. Biochem. Cell Biol 43 (2011) 928–935. [DOI] [PubMed] [Google Scholar]
- [462].Nikitovic D, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN, Lumican, a small leucine-rich proteoglycan, IUBMB. Life 60 (2008) 818–823. [DOI] [PubMed] [Google Scholar]
- [463].Li X, Roife D, Kang Y, Dai B, Pratt M, Fleming JB, Extracellular lumican augments cytotoxicity of chemotherapy in pancreatic ductal adenocarcinoma cells via autophagy inhibition, Oncogene 35 (2016) 4881–4890. [DOI] [PubMed] [Google Scholar]
- [464].Nikitovic D, Papoutsidakis A, Karamanos N, Tzanakasis GN, Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response, Matrix Biol. 35 (2014) 206–214. [DOI] [PubMed] [Google Scholar]
- [465].Karamanou K, Perrot G, Maquart FX, Brézillon S, Lumican as a multivalent effector in wound healing, Adv. Drug Deliv. Rev 129 (2018) 344–351. [DOI] [PubMed] [Google Scholar]
- [466].Huang Y, Kyriakides TR, The role of extracellular matrix in the pathophysiology of diabetic wounds, Matrix Biol. Plus 6–7 (2020) 100037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [467].Xiao D, Liang T, Zhuang Z, He R, Ren J, Jiang S, Zhu L, Wang K, Shi D, Lumican promotes joint fibrosis through TGF-β signaling, FEBS Open. Bio 10 (2020) 2478–2488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [468].Shao H, Lee S, Gae-Scott S, Nakata C, Chen S, Hamad AR, Chakravarti S, Extracellular matrix lumican promotes bacterial phagocytosis, and Lum−/− mice show increased Pseudomonas aeruginosa lung infection severity, J. Biol. Chem 287 (2012) 35860–35872. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [469].Shao H, Scott SG, Nakata C, Hamad AR, Chakravarti S, Extracellular matrix protein lumican promotes clearance and resolution of Pseudomonas aeruginosa keratitis in a mouse model, PLoS. One 8 (2013) e54765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [470].Karamfilova V, Gateva A, Assyov Y, Nedeva I, Velikova T, Cherkezov N, Mateva L, Kamenov Z, Lumican in obese patients with nonalcoholic fatty liver disease with or without prediabetes, Metab Syndr. Relat Disord 18 (2020) 443–448. [DOI] [PubMed] [Google Scholar]
- [471].Wolff G, Taranko AE, Meln I, Weinmann J, Sijmonsma T, Lerch S, Heide D, Billeter AT, Tews D, Krunic D, Fischer-Posovszky P, Müller-Stich BP, Herzig S, Grimm D, Heikenwälder M, Kao WW, Vegiopoulos A, Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis, Mol. Metab 19 (2019) 97–106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [472].Van JAD, Clotet-Freixas S, Hauschild AC, Batruch I, Jurisica I, Elia Y, Mahmud FH, Sochett E, Diamandis EP, Scholey JW, Konvalinka A, Urinary proteomics links keratan sulfate degradation and lysosomal enzymes to early type 1 diabetes, PLoS. One 15 (2020) e0233639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [473].Li X, Truty MA, Kang Y, Chopin-Laly X, Zhang R, Roife D, Chatterjee D, Lin E, Thomas RM, Wang H, Katz MH, Fleming JB, Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery, Clin. Cancer Res 20 (2014) 6529–6540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [474].Li X, Kang Y, Roife D, Lee Y, Pratt M, Perez MR, Dai B, Koay EJ, Fleming JB, Prolonged exposure to extracellular lumican restrains pancreatic adenocarcinoma growth, Oncogene 36 (2017) 5432–5438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [475].Karamanou K, Franchi M, Onisto M, Passi A, Vynios DH, Brézillon S, Evaluation of lumican effects on morphology of invading breast cancer cells, expression of integrins and downstream signaling, FEBS J. 287 (2020) 4862–4880. [DOI] [PubMed] [Google Scholar]
- [476].Karamanou K, Franchi M, Piperigkou Z, Perreau C, Maquart FX, Vynios DH, Brézillon S, Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition, Sci. Rep 7 (2017) 45138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [477].Karamanou K, Franchi M, Vynios D, Brézillon S, Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator, Semin. Cancer Biol 62 (2020) 125–133. [DOI] [PubMed] [Google Scholar]
- [478].Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Andrade de Paula CA, Carneiro CR, Ortiz V, Toma L, Kao WW, Nader HB, Lumican expression, localization and antitumor activity in prostate cancer, Exp. Cell Res 319 (2013) 967–981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [479].Brézillon S, Zeltz C, Schneider L, Terryn C, Vuillermoz B, Ramont L, Perreau C, Pluot M, Diebold MD, Radwanska A, Malicka-Blaszkiewicz M, Maquart F-X, Wegrowski Y, Lumican Inhibits B16F1 melanoma cell lung metastasis, J. Physiol. Pharmacol 60 (suppl. 4) (2009) 15–22. [PubMed] [Google Scholar]
- [480].Brézillon S, Radwanska A, Zeltz C, Malkowski A, Ploton D, Bobichon H, Perreau C, Malicka-Blaszkiewicz M, Maquart F-X, Wegrowski Y, Lumican core protein inhibits melanoma cell migration via alterations of focal adhesion compleses, Cancer Lett. 283 (2009) 92–100. [DOI] [PubMed] [Google Scholar]
- [481].Hsiao KC, Chu PY, Chang GC, Liu KJ, Elevated expression of lumican in lung cancer cells promotes bone metastasis through an autocrine regulatory mechanism, Cancers. (Basel) 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [482].Chen X, Li X, Hu X, Jiang F, Shen Y, Xu R, Wu L, Wei P, Shen X, LUM Expression and Its Prognostic Significance in Gastric Cancer, Front Oncol. 10 (2020) 605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [483].Mao W, Luo M, Huang X, Wang Q, Fan J, Gao L, Zhang Y, Geng J, Knockdown of Lumican Inhibits Proliferation and Migration of Bladder Cancer, Transl. Oncol 12 (2019) 1072–1078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [484].Yang CT, Li JM, Chu WK, Chow SE, Downregulation of lumican accelerates lung cancer cell invasion through p120 catenin, Cell Death. Dis 9 (2018) 414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [485].Galluzzi L, Kepp O, Kroemer G, Mitochondria: master regulators of danger signalling, Nat. Rev. Mol. Cell Biol 13 (2012) 780–788. [DOI] [PubMed] [Google Scholar]
- [486].Li X, Lee Y, Kang Y, Dai B, Perez MR, Pratt M, Koay EJ, Kim M, Brekken RA, Fleming JB, Hypoxia-induced autophagy of stellate cells inhibits expression and secretion of lumican into microenvironment of pancreatic ductal adenocarcinoma, Cell Death. Differ 26 (2019) 382–393. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- [487].Pietraszek K, Brézillon S, Perreau C, Malicka-Blsaszkiewicz M, Maquart FX, Wegrowski Y, Lumican-derived peptides inhibit melanoma cell growth and migration, PLoS. One 8 (2013) e76232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [488].Guidetti G, Bertoni A, Viola M, Tira E, Balduini C, Torti M, The small proteoglycan decorin supports adhesion and activation of human platelets, Blood 100 (2002) 1707–1714. [PubMed] [Google Scholar]
- [489].Fiedler LR, Schönherr E, Waddington R, Niland S, Seidler DG, Aeschlimann D, Eble JA, Decorin regulates endothelial cell motility on collagen I through activation of Insulin-like growth factor I receptor and modulation of α2β1 integrin activity, J. Biol. Chem 283 (2008) 17406–17415. [DOI] [PubMed] [Google Scholar]
- [490].Jungmann O, Nikolovska K, Stock C, Schulz J-N, Eckes B, Riethmüller C, Owens RT, Iozzo RV, Seidler DG, The dermatan sulfate proteoglycan decorin modulates α2β1 integrin and vimentin intermediate filament system during collagen synthesis, PLoS ONE 7 (2012) e50809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [491].Lee JY, Park SJ, Kim DA, Lee SH, Koh JM, Kim BJ, Muscle-Derived Lumican Stimulates Bone Formation via Integrin α2β1 and the Downstream ERK Signal, Front Cell Dev. Biol 8 (2020) 565826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [492].Sarcar B, Li X, Fleming JB, Hypoxia-Induced Autophagy Degrades Stromal Lumican into Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma: A Mini-Review, J. Cancer Treatment. Diagn 3 (2019) 22–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [493].Le GF, Eck F, Jung J, Starzetz T, Mittelbronn M, Kaulich M, Behrends C, Autophagosomal Content Profiling Reveals an LC3C-Dependent Piecemeal Mitophagy Pathway, Mol. Cell 68 (2017) 786–796. [DOI] [PubMed] [Google Scholar]
- [494].Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT, Toll-like receptor 4 is a sensor for autophagy associated with innate immunity, Immunity. 27 (2007) 135–144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [495].Wang S, Song X, Zhang K, Deng S, Jiao P, Qi M, Lian Z, Yao Y, Overexpression of Toll-Like Receptor 4 Affects Autophagy, Oxidative Stress, and Inflammatory Responses in Monocytes of Transgenic Sheep, Front Cell Dev. Biol 8 (2020) 248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [496].Kim MJ, Min Y, Son J, Kim JY, Lee JS, Kim DH, Lee KY, AMPKα1 regulates lung and breast cancer progression by regulating TLR4-mediated TRAF6-BECN1 signaling axis, Cancers. (Basel) 12 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [497].Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhão JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L, Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and microRNA-21, Sci. Signal 4 (2011) ra75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [498].Moreth K, Frey H, Hubo M, Zeng-Brouwers J, Nastase MV, Hsieh LT, Haceni R, Pfeilschifter J, Iozzo RV, Schaefer L, Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury, Matrix Biol. 35 (2014) 143–151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [499].Schaefer L, Babelova A, Kiss E, Hausser H-J, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Götte M, Malle E, Schaefer RM, Gröne H-J, The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages, J. Clin. Invest 115 (2005) 2223–2233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [500].Schaefer L, Iozzo RV, Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction, J. Biol. Chem 283 (2008) 21305–21309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [501].Schaefer L, Small leucine-rich proteoglycans in kidney disease, J. Am. Soc. Nephrol 22 (2011) 1200–1207. [DOI] [PubMed] [Google Scholar]
- [502].Berendsen AD, Pinnow EL, Maeda A, Brown AC, McCartney-Francis N, Kram V, Owens RT, Robey PG, Holmbeck K, de Castro LF, Kilts TM, Young MF, Biglycan modulates angiogenesis and bone formation during fracture healing, Matrix Biol. 35 (2014) 223–231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [503].Schaefer L, Decoding fibrosis: Mechanisms and translational aspects, Matrix Biol 68–69 (2018) 1–7. [DOI] [PubMed] [Google Scholar]
- [504].Nastase MV, Zeng-Brouwers J, Beckmann J, Tredup C, Christen U, Radeke HH, Wygrecka M, Schaefer L, Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney, Matrix Biol. 68–69 (2018) 293–317. [DOI] [PubMed] [Google Scholar]
- [505].Chen Y, Keskin D, Sugimoto H, Kanasaki K, Phillips PE, Bizarro L, Sharpe A, LeBleu VS, Kalluri R, Podoplanin+ tumor lymphatics are rate limiting for breast cancer metastasis, PLoS. Biol 16 (2018) e2005907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [506].Roedig H, Nastase MV, Wygrecka M, Schaefer L, Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy, FEBS J. 286 (2019) 2965–2979. [DOI] [PubMed] [Google Scholar]
- [507].Zeng-Brouwers J, Pandey S, Trebicka J, Wygrecka M, Schaefer L, Communications via the Small Leucine-rich Proteoglycans: Molecular Specificity in Inflammation and Autoimmune Diseases, J. Histochem. Cytochem 68 (2020) 887–906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [508].Barreto G, Senturk B, Colombo L, Brück O, Neidenbach P, Salzmann G, Zenobi-Wong M, Rottmar M, Lumican is upregulated in osteoarthritis and contributes to TLR4-induced proinflammatory activation of cartilage degradation and macrophage polarization, Osteoarthritis. Cartilage 28 (2020) 92–101. [DOI] [PubMed] [Google Scholar]
- [509].Fedele C, Singh A, Zerlanko BJ, Iozzo RV, Languino LR, The αVβ6 integrin is transferred intercellularly via exosomes, J. Biol Chem 290 (2015) 4545–4551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [510].Bandari SK, Purushothaman A, Ramani VC, Brinkley GJ, Chandrashekar DS, Varambally S, Mobley JA, Zhang Y, Brown EE, Vlodavsky I, Sanderson RD, Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior, Matrix Biol 65 (2018) 104–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [511].Krishn SR, Singh A, Bowler N, Duffy AN, Friedman A, Fedele C, Kurtoglu S, Tripathi SK, Wang K, Hawkins A, Sayeed A, Goswami CP, Thakur ML, Iozzo RV, Peiper SC, Kelly WK, Languino LR, Prostate cancer sheds the αvβ3 integrin in vivo through exosomes, Matrix Biol 77 (2019) 41–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [512].Lu H, Bowler N, Harshyne LA, Craig HD, Krishn SR, Kurtoglu S, Fedele C, Liu Q, Tang HY, Kossenkov AV, Kelly WK, Wang K, Kean RB, Weinreb PH, Yu L, Dutta A, Fortina P, Ertel A, Stanczak M, Forsberg F, Gabrilovich DI, Speicher DW, Altieri DC, Languino LR, Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer, Matrix Biol 70 (2018) 20–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [513].Krishn SR, Salem I, Quaglia F, Naranjo NM, Agarwal E, Liu Q, Sarker S, Kopenhaver J, McCue PA, Weinreb PH, Violette SM, Altieri DC, Languino LR, The αvβ6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis, J. Extracell. Vesicles 9 (2020) 1763594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [514].Quaglia F, Krishn SR, Daaboul GG, Sarker S, Pippa R, Domingo-Domenech J, Kumar G, Fortina P, McCue P, Kelly WK, Beltran H, Liu Q, Languino LR, Small extracellular vesicles modulated by αVβ3 integrin induce neuroendocrine differentiation in recipient cancer cells, J. Extracell. Vesicles 9 (2020) 1761072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [515].DeRita RM, Sayeed A, Garcia V, Krishn SR, Shields CD, Sarker S, Friedman A, McCue P, Molugu SK, Rodeck U, Dicker AP, Languino LR, Tumor-derived extracellular vesicles require β1 integrins to promote anchorage-independent growth, iScience. 14 (2019) 199–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [516].McAtee CO, Booth C, Elowsky C, Zhao L, Payne J, Fangman T, Caplan S, Henry MD, Simpson MA, Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling, Matrix Biol 78–79 (2019) 165–179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [517].Sanderson RD, Bandari SK, Vlodavsky I, Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling, Matrix Biol 75–76 (2019) 160–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [518].Bertolini I, Ghosh JC, Kossenkov AV, Mulugu S, Krishn SR, Vaira V, Qin J, Plow EF, Languino LR, Altieri DC, Small extracellular vesicle regulation of mitochondrial dynamics reprograms a hypoxic tumor microenvironment, Dev. Cell 55 (2020) 163–177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [519].Genschmer KR, Russell DW, Lal C, Szul T, Bratcher PE, Noerager BD, Abdul RM, Xu X, Rezonzew G, Viera L, Dobosh BS, Margaroli C, Abdalla TH, King RW, McNicholas CM, Wells JM, Dransfield MT, Tirouvanziam R, Gaggar A, Blalock JE, Activated PMN exosomes: Pathogenic entities causing matrix destruction and disease in the lung, Cell 176 (2019) 113–126. [DOI] [PMC free article] [PubMed] [Google Scholar]