Abstract
The 6 high-affinity insulin-like growth factor binding proteins (IGFBPs) are multifunctional proteins that modulate cell signaling through multiple pathways. Their canonical function at the cellular level is to impede access of insulin-like growth factor (IGF)-1 and IGF-2 to their principal receptor IGF1R, but IGFBPs can also inhibit, or sometimes enhance, IGF1R signaling either through their own post-translational modifications, such as phosphorylation or limited proteolysis, or by their interactions with other regulatory proteins. Beyond the regulation of IGF1R activity, IGFBPs have been shown to modulate cell survival, migration, metabolism, and other functions through mechanisms that do not appear to involve the IGF-IGF1R system. This is achieved by interacting directly or functionally with integrins, transforming growth factor β family receptors, and other cell-surface proteins as well as intracellular ligands that are intermediates in a wide range of pathways. Within the nucleus, IGFBPs can regulate the diverse range of functions of class II nuclear hormone receptors and have roles in both cell senescence and DNA damage repair by the nonhomologous end-joining pathway, thus potentially modifying the efficacy of certain cancer therapeutics. They also modulate some immune functions and may have a role in autoimmune conditions such as rheumatoid arthritis. IGFBPs have been proposed as attractive therapeutic targets, but their ubiquity in the circulation and at the cellular level raises many challenges. By understanding the diversity of regulatory pathways with which IGFBPs interact, there may still be therapeutic opportunities based on modulation of IGFBP-dependent signaling.
Keywords: IGF, IGF binding protein, signaling, receptor, cell-surface, nucleus
Graphical Abstract
Graphical Abstract.
Essential Points.
Insulin-like growth factor binding proteins (IGFBPs) are a family of 6 homologous proteins that bind IGF-1 and IGF-2 with high affinity.
IGF-1 and IGF-2 signaling through their principal receptor, IGF1R, is regulated by IGFBPs in both stimulatory and inhibitory ways.
IGFBPs also initiate or modulate signaling cascades from the cell surface through other receptor systems, including integrins, transforming growth factor β family receptors, and other proteins, which may have either high or low specificity for IGFBP binding.
IGFBPs influence intracellular processes through interaction with cytoplasmic proteins and organelles.
Some IGFBPs also enter the nucleus where they interact with nuclear hormone receptors, DNA damage repair proteins, and other key nuclear ligands to influence gene transcription and genomic integrity.
The term “IGF axis” has been used to encompass the insulin-like growth factors (IGF) IGF-1 and IGF-2, and the functionally related families of proteins that mediate or regulate their actions: the insulin/IGF receptors, the IGF-2/mannose 6-phosphate receptor, and the high-affinity IGF binding proteins (IGFBPs), sometimes also including the proteases that cleave IGFBPs. Given the rapidly expanding knowledge of IGFBP actions that do not depend on changes in IGF signaling (as described in the following sections), this definition might be expanded to include other proteins that mediate or regulate IGFBP functions. This review discusses current knowledge of the multiple ways in which IGFBPs can impact a wide variety of cellular functions through their actions on both IGF receptor-mediated and IGF-independent signaling pathways.
The IGFs and Their Receptors
The history, structure, and actions of IGF-1 (1, 2) and IGF-2 (3, 4) have been extensively reviewed (5–9). In brief, they are structurally related peptides of molecular weight 7649 (IGF-1, 70 amino acids) and 7471 (IGF-2, 67 amino acids) with linear sequences related to that of insulin, comprising an internally disulfide-crosslinked B-C-A domain structure plus a short carboxyterminal D-domain not found in insulin. Unlike proinsulin C-peptide, the IGF C-domain is not excised in the mature growth factors. The precursor IGF molecules also contain a further carboxyterminal extension termed the E-domain, which, particularly in the case of IGF-2, is incompletely cleaved in some conditions and may influence IGF-2 interactions (10). IGF-1 and IGF-2 have well-known proliferative, survival, motility, anabolic, and other growth-stimulatory effects in essentially all tissues (7).
IGF1R
The type 1 IGF receptor (IGF1R) is the key signaling molecule for many biological effects stimulated by IGFs and modulated by IGFBPs. It is a transmembrane heterotetrameric tyrosine kinase formed by the dimerization of 2 disulfide-linked αβ dimers and the primary cell surface receptor for both IGF-1 and IGF-2 (11), which bind with comparable high affinity (12) despite some differences in their interactions with the receptor (13). Binding of a single IGF molecule is sufficient to activate dimerized IGF1R (14), initiating a phosphorylation cascade that is primarily transmitted by insulin receptor (InsR) substrate (IRS)-1. IRS-1 also acts to regulate IGF1R endocytosis, thus helping to sustain its signal (15). Once internalized, IGF1R may be degraded, transported to the Golgi or nucleus, or recycled back to the cell surface (16). Nuclear IGF1R interacts with chromatin to regulate transcription and may also modulate the actions of other transcription factors (17, 18). In addition to its high affinity for IGF1R, IGF-2 also binds with high affinity to a form of the InsR termed isoform A (12). The IGF1R αβ dimer can form a hybrid with the corresponding subunits of the structurally-related InsR, with binding properties different from either partner receptor (12, 19). IGF1R is also reported to interact covalently with epidermal growth factor receptor (EGFR), apparently facilitating cross-talk between the 2 receptors (20).
IGF2R
A receptor with high selectivity for IGF-2, the type 2 IGF receptor (IGF2R), was shown in 1987 to be identical to the cation-independent mannose 6-phosphate receptor, a ∼250-kDa monomeric transmembrane glycoprotein with no kinase function or homology to IGF1R (21). IGF2R is found predominantly in the Golgi and endosomal compartments, from where it recycles to and from the cell surface (22), acting as a carrier for mannose 6-phosphate proteins including lysosomal enzymes. IGF2R has an IGF-2 binding site distinct from its mannose 6-phosphate binding site, and its major role in IGF signaling is believed to be its action as an IGF-2 sink, decreasing ambient levels of IGF-2 by binding and internalizing it for lysosomal degradation (23). The degradation of IGF-2 can decrease IGF1R signaling, potentially inhibiting proliferative and other IGF-dependent effects. IGF2R activation of G-protein signaling has also been described, possibly mediated through G-protein-coupled sphingosine 1-phosphate receptors (23).
IGF Binding Proteins
In humans and other mammals, IGF-1 and IGF-2 bind with high affinity to 6 structurally related proteins, IGFBP-1 to IGFBP-6 (encoded by IGFBP1 to IGFBP6) (24–26). In other species, the number may vary; for example, chickens lack IGFBP-4 and -6, whereas fish have up to 4 forms of each IGFBP as a result of 1 or more genome duplication events (26). An evolutionary perspective of the multiple IGFBPs, and discussion of the development of their unique and redundant roles, has been presented by others (26, 27). Notably, a degree of redundancy is suggested by the observation that deletion of individual IGFBP genes in mice caused surprisingly few phenotypic changes (26, 28). Other proteins that have been designated as “IGFBP-related” include IGFBP-7 (also known as mac25 or IGFBP-rP1), CTGF or IGFBP-rP2, and NovH or IGFBP-rP3 (29). Many of these related proteins are now classified as members of the CCN family (named for family members CYR61, CTGF, and NOV) (30). They bind IGFs with, at best, very low affinity, and it is questionable whether any of their actions are dependent on IGF binding.
IGFBP-1 to -6 are secreted, multifunctional proteins with distinct roles in the circulation, the extracellular environment, and the cell (7, 26, 31–34). Structurally, they are considered to comprise 3 major regions of approximately equal size: amino- and carboxy-terminal domains, each constrained by several intradomain disulfide bonds, and a central or linker domain with no disulfides and a less well-defined structure (24–26). Within these domains are various functional motifs, some specific and some shared (such as ligand-binding sites, phosphorylation sites, nuclear localization signals), which together give each IGFBP a unique “identity” that contributes to its functional individuality as described throughout this review. Some of these functional motifs are not yet well characterized structurally.
Each IGFBP can associate with a single molecule of IGF-1 or IGF-2, which interacts with both amino- and carboxy-terminal IGFBP residues (25, 35). There is evidence for cooperative binding between the amino- and carboxyterminal binding sites, each terminal domain enhancing the IGF affinity of the other (36, 37). In the adult human circulation, at least 90% of IGFBP-3 and over half of IGFBP-5 is found in ternary complexes containing the IGFBP bound to either IGF-1 or IGF-2 and a leucine-rich glycoprotein, the acid-labile subunit (ALS; encoded by IGFALS) (38, 39). ALS only binds IGFBP-3 or IGFBP-5 when they are occupied by IGF-1 or IGF-2 (38, 40) and has no known role apart from the transport of IGF complexes, which are cleared from the circulation in minutes unless they are associated with ALS (34, 41). Because IGFBPs typically inhibit the ability of IGFs to bind and activate IGF1R (24), their high binding affinity must be attenuated before IGFs can act at the cell surface, and this it generally believed to occur by limited IGFBP proteolysis, as described later.
IGFBP Modulation of IGF1R Signaling
In addition to transporting IGFs in the circulation, IGFBPs have important roles in the pericellular environment as regulators of intracellular signal transduction by IGF1R. The canonical IGFBP action at the cell surface is the high-affinity binding of IGF-1 or IGF-2, preventing access to the receptor. There are, however, other documented mechanisms by which IGFBPs can modulate IGF1R-dependent pathways.
Inhibition of IGF1R
Phosphorylation
IGF-1 and IGF-2 residues involved in receptor binding (4, 42–45) and IGFBP binding (24, 25, 46, 47) have been extensively documented, potentially explaining how IGFBPs restrict IGF access to IGF1R (25, 46). Inhibition of IGF-dependent IGF1R signaling by IGFBPs is modulated by their interactions with other proteins and by post-translational modifications. In the case of IGFBP-1, hyperphosphorylation of key serine residues including serine (Ser)101, Ser119 (linker domain), and Ser169 (C-terminal domain), dependent on protein kinase Cα and CK2 activity, has been shown to increase IGFBP-1 affinity for IGF-1 leading to decreased IGF1R phosphorylation (Fig. 1) (48). Although all 6 IGFBPs have consensus phosphorylation sites (53), this does not appear to be a general mechanism for modifying IGF affinity, as there are no other examples of IGFBP phosphorylation increasing binding affinity. In contrast, phosphorylation of IGFBP-3 by DNA-dependent protein kinase catalytic subunit (DNA-PKcs) abolishes its ability to bind IGF-1 (54), but this seems unlikely to influence IGF1R signaling from the cell surface.
Figure 1.
IGFBP inhibition of IGF1R signaling. Hyperphosphorylation of key serine residues of IGFBP-1 increases its affinity for IGFs, thus preventing IGF activation of IGF1R (also see Fig. 2) (48). High-affinity IGF binding by IGFBP-4, which blocks IGF action, is greatly decreased by limited proteolysis by the secreted metalloproteinase PAPP-A, which releases bound IGFs. The PAPP-A inhibitors, stanniocalcin 1 and 2, prevent IGFBP-4 proteolysis and inhibit IGF1R activation (49). Like the other IGFBPs, IGFBP-3 can bind IGFs with high affinity to inhibit IGF1R activation. IGFBP-3 can also activate a phosphotyrosine phosphatase that reverses IGF-activated IGF1R signaling (50). IGFBP-3, acting through TGFβ receptor type V (LRP1), also activates the Ser/Thr phosphoprotein phosphatase PP2A (also see Fig. 3) (51). PP2A interaction with IGF1R through the adapter protein RACK1 is associated with signaling inhibition but can be reversed by IGF stimulation and β-integrin ligation (52). Abbreviations: IGF, insulin-like growth factor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; PAPP-A, pregnancy-associated plasma protein; PP2A, phosphoprotein phosphatase 2A; Ser/Thr, serine/threonine; TGFβ, transforming growth factor β.
IGFBP proteolysis
A widespread mechanism for decreasing the affinity of the IGF-IGFBP interaction to allow IGF release and IGF1R signaling is their limited proteolysis, typically at a single cleavage site, which has been observed for all 6 IGFBPs (25, 33, 55, 56). Although several classes of proteolytic enzymes, including serine proteases, metalloproteinases, and cathepsins, have been implicated in IGFBP proteolysis (55), particular interest has been directed in recent years to the zinc-binding endopeptidases known as pappalysins, pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 (57–59). PAPP-A preferentially cleaves IGFBP-4 in the presence of IGF-1 or IGF-2 (Fig. 1), with some activity against IGFBP-2 and IGFBP-5 (57), whereas PAPP-A2 activity is IGF-independent and specific for IGFBP-5 and to a smaller extent, IGFBP-3 (58).
Since IGFBP proteolysis can lower its binding affinity and enhance IGF access to IGF1R, potential roles for IGFBP proteases have been proposed in various disease states including cancer. For example, the prostate cancer marker, prostate-specific antigen, has been shown to have IGFBP-3 proteolytic activity, which could potentially contribute to oncogenic IGF1R activation. There is no direct evidence, however, that prostate-specific antigen actually promotes prostate cancer through this mechanism (60), although it remains a possibility. Similarly, the serine protease cathepsin G enhances IGF1R activation in breast cancer cells through IGFBP-2 proteolysis (61), but the significance of this mechanism in vivo has not been demonstrated. In contrast, the evidence for regulatory systems in many disease states involving pappalysin cleavage of IGFBPs is compelling, supported by studies with protease-resistant IGFBP-4 and considerable cell biology and in vivo experimentation (59, 62–64). In brief, these studies demonstrate the importance of IGFBP (notably IGFBP-4) proteolysis as a mechanism to increase IGF bioavailability, with an additional regulatory layer imposed by the PAPP-A inhibitors, stanniocalcin-1 and −2 (Fig. 1). Thus, for example, transgenic overexpression in mice of stanniocalcin-2, which forms a stable inhibitory complex with PAPP-A, decreases IGFBP proteolytic activity, limiting IGF bioavailability and leading to profound growth reduction. Notably, this cascade of IGF regulation is presumed to occur post-translationally and at the tissue level, without changes in IGF gene expression or circulating levels (59, 65). Similarly, children with PAPP-A2 deficiency and growth retardation have successfully gained height after treatment with recombinant IGF-1, consistent with a role for PAPP-A2 in facilitating IGF bioavailability through IGFBP proteolysis (66).
Cooperative binding
Although proteolysis can clearly act to decrease IGFBP binding affinity, the cooperative nature of IGF binding by the 2 terminal IGFBP domains (25, 36, 37) suggests that if the 2 fragments of a proteolytically cleaved IGFBP remain in proximity, they might still form an IGF binding complex with significant affinity. This can be seen in a study in which an equimolar combination of synthetic amino- and carboxyterminal fragments of IGFBP-3 bound IGF-1 and IGF-2, and inhibited IGF-stimulated DNA synthesis, far more effectively than either fragment alone, although not as well as intact IGFBP-3 (36). Similarly, in human pregnancy serum, in which IGFBP-3 is entirely proteolyzed, IGF-1 and IGF-2 circulate in high molecular weight complexes at equal or higher concentration than in nonpregnancy serum (67, 68). This indicates that IGFs must be bound to IGFBP-3 (fragments) with essentially normal affinity in pregnancy serum, since IGFBP-3 must be occupied by IGF-1 or IGF-2 before it can form a high molecular weight complex with ALS (40).
These findings are not, however, inconsistent with the conclusion that the restriction on IGF bioavailability at the cell surface imposed by IGFBPs is diminished by proteolysis. This might be facilitated by IGFBP interaction with surface proteins including proteoglycans. It has been long understood that several of the IGFBPs have functional glycosaminoglycan interaction domains that facilitate cell-surface binding (69, 70); in the case of IGFBP-2, its affinity for glycosaminoglycan interaction is increased when IGF-2 is bound (71). Many proteases are themselves either membrane-anchored or associated with proteoglycans (56, 59), potentially placing them in proximity to cell-surface IGFBPs.
Other mechanisms
Evidence also exists that IGFBPs may inhibit IGF1R signaling by mechanisms other than blocking receptor binding of IGF-1 or IGF-2. IGFBP-3 has been shown to activate a phosphotyrosine phosphatase in breast cancer cells that inhibits IGF1R signaling (Fig. 1) (50). IGFBP-3 is also reported to activate the Ser/threonine phosphoprotein phosphatase 2A (PP2A) in epithelial cells through a mechanism initiated by binding to the transforming growth factor β (TGFβ) type V receptor, also known as LRP1 (Fig. 1) (51). Among other substrates, PP2A downregulates both Akt (72) and Ras/mitogen-activated protein (MAP) kinase pathways (73), thus inhibiting 2 major mediators of IGF1R signaling. PP2A can associate with IGF1R through the scaffold protein RACK1 (Fig. 1) and is dissociated and deactivated if β1-integrin is recruited to the complex, thus increasing IGF1R signaling (52). Both IGFBP-1 and IGFBP-2 have an integrin-binding arginine-glycine-aspartic acid (RGD) motif in their carboxyterminal domain (26), and there is evidence, at least for IGFBP-1, that interaction with β1-integrin might attenuate its ability to bind and stimulate IGF1R (74).
Potentiation of IGF1R
IGFBP-1, first isolated from human amniotic fluid, was found to have both inhibitory and stimulatory effects on IGF action, the difference proposed to be caused by marked alteration in IGF-binding affinity resulting from changes in IGFBP-1 phosphorylation on specific Ser residues (75, 76). Subsequently it was shown that phosphorylation of IGFBP-1 at Ser residues 101 and 119 markedly increased IGF-1 affinity and inhibited IGF-1 action, as discussed previously, while blocking phosphorylation at these sites stimulated IGF-1-dependent IGF1R activation (Fig. 2) (77). Phosphorylation of these residues is stimulated by protein kinase Cα in response to nutrient deprivation (48), which implies that under conditions of replete nutrition, IGFBP-1 will be relatively hypophosphorylated, consistent with maximal IGF1R activation.
Figure 2.
IGFBP potentiation of IGF1R signaling. Dephosphorylation of IGFBP-1 decreases its IGF affinity, increasing IGF activation of IGF1R (77). IGFBP-3 activates sphingosine kinase, which phosphorylates sphingosine to S1P. S1P activates the G-protein coupled receptors S1P1 and S1P3 leading to IGF1R transactivation, probably mediated by EGFR (78). IGFBP-2 amplifies IGF1R signaling by binding to the protein tyrosine phosphatase RPTPβ, promoting IGF-dependent PKCζ phosphorylation of VIM, which binds to RPTPβ and inactivates it. This inhibits PTEN activity, which enhances IGF-dependent IGF1R signaling [adapted from (79)]. See (79) for further details of the signaling complex. IGFBP-5 and possibly other IGFBPs can enhance IGF1R activation by binding to ECM, which lowers its IGF binding affinity, acting as a reservoir to enhance IGF availability (80). Abbreviations: ECM, extracellular matrix; EGFR, epidermal growth factor receptor; IGF, insulin-like growth factor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; PKCζ, protein kinase C zeta; PTEN, phosphatase and tensin homologue; RPTPβ, receptor protein tyrosine phosphatase beta; VIM, vimentin.
Similar to the hypophosphorylation of IGFBP-1, its polymerization has been reported to decrease IGF affinity leading to an enhancement of IGF-dependent signaling in the placenta. This effect is mediated by tissue transglutaminase, which is located on the trophoblast cell surface (81). IGFBP-1 overexpression has also been reported to stimulate breast cancer cell proliferation, tamoxifen resistance, and phospho-extracellular signal-regulated kinase (ERK), a major mediator of IGF1R activity, but in these cells IGF1R expression was decreased and EGFR was upregulated and activated (82).
Regulation of sphingolipid metabolism
It was reported more than 30 years ago that, whereas IGFBP-3 coincubated with IGF-1inhibited its activity in fibroblasts, preincubation with IGFBP-3 prior to IGF-1 addition potentiated the cell response (83). A possible explanation proposed at that time was that IGFBP-3, by sequestering ambient IGFs in the cell culture medium, might cause IGF1R upregulation and increased responsiveness (83). More recently it has been shown that IGFBP-3 potentiates ligand-dependent activation of both IGF1R and EGFR in breast epithelial cells through a mechanism that depends on the upregulation and activation of sphingosine kinase 1 (SphK1) (78), which phosphorylates sphingosine to generate the pro-survival lipid sphingosine 1-phosphate (84). IGF interaction with IGFBP-3 is not required, since the effect is observed with LR3-IGF-1, which has very low affinity for IGFBP-3. The activating effect of IGFBP-3 on SphK1 had been previously demonstrated in endothelial cells where it was also found that IGFBP-3 could decrease the concentration of the pro-apoptotic sphingosine precursor, ceramide (85)—possibly by inhibiting acid sphingomyelinase, which generates ceramide (86).
The IGFBP-3-dependent increase in IGF1R phosphorylation was prevented by pharmacological inhibition of either SphK1 or the S1P1/S1P3 receptors for sphingosine 1-phosphate (Fig. 2). Interestingly, EGFR tyrosine kinase inhibition also prevented IGFBP-3 activation of IGF1R, suggesting that transactivation of IGF1R by EGFR in response to IGFBP-3 might be involved in this process (78). In vivo studies support this mechanism of IGFBP-3 action, since the growth of xenograft tumors of triple-negative breast cancer (TNBC) cells with high IGFBP-3 expression can be blocked by a combination of EGFR and SphK inhibitors (87). In these tumors IGFBP-3 was predominantly localized in the cell nucleus and had a strong positive correlation with the proliferative (Ki67) index of the tumors (87). SphK1 may also facilitate IGFBP-5-dependent breast cancer cell survival, since SphK inhibition increased cell death in the presence of IGFBP-5 (88). Interestingly, IGFBP-5 is reported to bind to four and a half LIM protein 2 (FHL2) (89), which is inhibitory to S1P-dependent cell survival (90); this suggests that the FHL2-IGFBP-5 interaction may inhibit this pro-apoptotic effect of FHL2. However, although FHL2 inhibition activates Akt (90), it is unknown whether IGFBP-5 acts in this setting by transactivating IGF1R.
Matrix interaction
A more widely proposed mechanism for IGFBP-5 potentiation of IGF1R signaling is by binding to the cell surface or extracellular matrix (ECM) and concentrating IGFs near the receptor (91). This has been particularly observed in studies of bone cells (91, 92) but is also evident in fibroblasts where IGFBP-5 associates with collagen, laminin, and fibronectin in the ECM (Fig. 2) (80). In a contrasting study, fibronectin, which interacts with the carboxyterminal domain of IGFBP-5, was shown to inhibit the ability of IGFBP-5 to enhance IGF-1 activity. In fibronectin-null embryonic mouse cells, IGFBP-5 potentiated IGF-1-dependent cell migration, but this effect was lost when fibronectin was added to the cells or in fibronectin-replete wild-type cells (93). This has been attributed to the increased proteolytic degradation of IGFBP-5 when associated with fibronectin.
A similar mechanism has been attributed to IGFBP-2, which stimulates IGF-2-dependent neurite outgrowth in human neuroblastoma cells (94). In this case the potentiation of IGF1R signaling by IGFBP-2 was mediated by the small leucine-rich proteoglycan osteoglycin. IGFBP-2 is also known to enhance IGF-1-stimulated proliferation of vascular smooth muscle cells, but in this system its interaction with the cell surface does not involve the sequestration of IGFs (95). IGFBP-2 was shown to interact with the cell-surface proteoglycan, receptor protein tyrosine phosphatase β (RPTPβ), leading to RPTPβ inactivation. Loss of this phosphatase activity enhances IGF-1-stimulated tyrosine phosphorylation and inactivation of the phosphoinositide phosphatase, phosphatase and tensin homologue (PTEN), which in turn causes an increase in Akt phosphorylation and stimulation of cell proliferation (95). In a subsequent study, vimentin serine phosphorylation and association with RPTPβ was found to be integral to this mechanism (Fig. 2), and in vivo blockade of the vimentin-RPTPβ interaction in diabetic mice disrupted IGF-1-stimulated Akt activation in aortic extracts (79).
In contrast to IGFBP-1, -2, -3, and -5, it is generally believed that IGFBP-4 and IGFBP-6 have exclusively inhibitory effects on IGF-dependent IGF1R activation and that any positive effects of these IGFBPs on cell survival, proliferation, or migration involve mechanisms that are independent of IGF1R (26, 96).
IGF1R-independent IGFBP Signaling
The concept that IGFBPs exert biological effects entirely independent of the inhibition or potentiation of IGF-dependent IGF1R signaling was initially regarded as controversial, until the demonstration that fibroblasts derived from mice that were genetically null for Igf1r were growth-inhibited by IGFBP-3 overexpression (97). It is now well understood that all 6 high-affinity IGFBPs not only regulate IGF availability to IGF1R but also influence a wide variety of intracellular pathways distinct from IGF1R signal transduction, through their interactions with ligands other than IGF-1 and IGF-2.
IGFBP-1
Integrin signaling
In pregnancy, IGFBP-1 is a major secretory product of the decidualized endometrium, where it is involved in trophoblast invasion (111). During decidualization, IGFBP1 transcription is stimulated by cyclic AMP, acting through transcription factors C/EBPβ and FoxO1 (112). In addition to regulating IGF bioavailability, modulated by its phosphorylation status (see previous discussion), IGFBP-1 signals IGF-independently in trophoblast invasion through an RGD integrin-binding motif located in the carboxy-terminal domain (33). Extravillous trophoblast (EVT) cells express α5β1 integrin, which is essential for their migratory activity, stimulated by the interaction of IGFBP-1 through its RGD domain (Fig. 3). This leads to the phosphorylation of focal adhesion kinase (FAK) and its localization to focal adhesions in the cell lamellipodia, which promotes EVT migration (Table 1) (98). This effect appears to be stimulated by the production of branched-chain amino acids by EVT cells (118).
Figure 3.
IGF1R-independent IGFBP signaling from the cell surface. IGFBP-1 and IGFBP-2 activate α5β1 integrin signaling through their RGD motif. IGFBP-1 can activate FAK-RhoA (100), and IGFBP-2 is reported to signal through both FAK (104) and ILK-NFκB (103). IGFBP-3 can activate apoptosis and other functions through the TMEM219 (113), stimulate SMAD signaling through the TGFβ receptors TβRI/TβRII (114), and inhibit proliferation through TβRV (LRP1) and PP2A activation (also see Fig. 1) (51). IGFBP-4 can block Wnt pathway signaling stimulated by Wnt3A or the receptors LRP6 or Frz8 (115) but in another system promotes Wnt/β-catenin signaling and TCF transcription (116). Despite lacking a recognized integrin-binding motif, IGFBP-5 can signal through α2β1 integrin, upregulating ILK and activating Akt (109). IGFBP-6 can signal from the cell surface through PHB2 and another unknown protein to activate ERK, p38, and JNK MAP kinases (117). See text for other IGF1R-independent IGFBP signaling. Abbreviations: ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; ILK, integrin-linked kinase; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; NF-κB, nuclear factor kappa B; PHB2, prohibitin-2; PP2A, phosphoprotein phosphatase 2A; RGD, arginine-glycine-aspartic acid; RhoA, Ras homolog family member A; TβRV, transforming growth factor β receptor V; TCF, T-cell factor; TGFβ, transforming growth factor β; TMEM219, transmembrane protein 219.
Table 1.
Examples of IGFBP signaling through integrins
IGFBP | Integrin | Cell pathway | Ref. |
---|---|---|---|
IGFBP-1 | α5β1 | FAK activation → migration | (98, 99) |
IGFBP-1 | α5β1, αVβ3 | FAK, RhoA activation → overcome TNF-induced insulin resistance | (100) |
IGFBP-2 | α5β1 | FAK, ERK deactivation → detachment | (101) |
IGFBP-2 | α5 | JNK activation → migration | (102) |
IGFBP-2 | α5β1 | ILK, NFκB → glioma progression | (103) |
IGFBP-2 | α5β1 | FAK activation, PTEN downregulation → inhibition of adipogenesis | (104) |
IGFBP-3 | β1 | FAK, ERK activation → inhibition of apoptosis and proliferation | (105) |
IGFBP-3 | β1 | Akt activation → migration | (106) |
IGFBP-3 | β4 (↓) | FAK deactivation → detachment | (107) |
IGFBP-3/5 | αV | Vitronectin + IGF-1-dependent migration | (108) |
IGFBP-5 | α2β1 | ILK, Akt activation → migration inhibition | (109) |
IGFBP-5 | α6β1 | Laminin-9 induction → migration | (110) |
Abbreviations: ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; ILK, integrin-linked kinase; JNK, c-Jun NH2-terminal kinase; NF-κB, nuclear factor kappa B; PTEN, phosphatase and tensin homologue; RhoA, Ras homolog family member A; TNF, tumor necrosis factor.
Signaling through FAK by IGFBP-1, acting via β1 integrin, is also observed in the kidney and is relevant to declining renal function in type 2 diabetes. As described for trophoblast cells, IGFBP-1 is expressed in glomerular podocytes under the control of FoxO1. In early diabetes, glomerular IGFBP1 expression was found to decrease, consistent with decreased FoxO1 activity. Since IGFBP-1 promotes β1 integrin signaling to activate FAK in podocytes, a loss of IGFBP-1 will lead to impaired podocyte function, a feature of diabetic nephropathy (119). In vascular endothelial cells, IGFBP-1 was shown to increase the expression of integrins, including α5β1 and αVβ3, and to enhance endothelial function. IGFBP-1 also reversed the impairment in migration and proliferation of endothelial cells in which insulin resistance was induced by exposure to TNFα (100). IGFBP-1 effects on proliferation and adhesion were again shown to be mediated by the IGFBP-1 RGD motif and to involve FAK phosphorylation, leading to the activation of the small GTPase Ras homolog family member A (RhoA) (Fig. 3) (100).
Given the functional importance of IGFBP-1 signaling through its RGD motif, a synthetic RGD peptide has been evaluated in vivo as an experimental therapy for insulin resistance (120), a condition in which circulating IGFBP-1 levels are known to be decreased (121, 122). In muscle cells, IGFBP-1 was found to stimulate insulin-dependent Akt and IRS-1 phosphorylation without increasing IGF1R or InsR activation, an effect dependent on the RGD motif. As in the previous examples, IGFBP-1-stimulated FAK phosphorylation was central to the mechanism. Evaluated in mice with diet-induced obesity, infusion of an RGD peptide improved insulin sensitivity and glucose tolerance, leading to the proposal that an RGD- or IGFBP-1-based therapy might have a role in the treatment of type 2 diabetes (120).
Survival signaling
IGFBP-1 has also been identified as a p53-inducible protein (either directly or indirectly) that interacts with the pro-apoptotic protein Bak. In HepG2 hepatoma cells, the induction of apoptosis corresponded with an increase in mitochondrial p53 and its interaction with Bak. This effect could be antagonized by IGFBP-1 overexpression in several cell types, which decreased mitochondrial p53, bound to Bak, and impeded the p53-Bak interaction and Bak oligomerization (123). In vivo evidence of this pro-survival mechanism of IGFBP-1 came from Igfbp1-null mice, which, compared to wildtype controls, showed a chronic low level of hepatic apoptosis with relatively high mitochondrial p53 expression together with p53-Bak complexes, particularly following genotoxic stress (123). This is a novel mitochondrial action of IGFBP-1 that will be of great interest if confirmed in other systems.
IGFBP-2
Integrin signaling
Like IGFBP-1, the carboxyterminal domain of IGFBP-2 contains an RGD motif that allows it to associate with cells through integrin α5β1 binding (Table 1) (101). In contrast to IGFBP-1, however, IGFBP-2 was initially reported to inhibit FAK and ERK phosphorylation associated with a loss of cell adhesion (101). IGFBP-2-stimulated migration of glioma cells, dependent on integrin α5 association, was later shown to require phosphorylation of c-Jun NH2-terminal kinase (JNK) (102). A pathway of glioma progression was proposed to involve IGFBP-2, integrin α5β1, integrin-linked kinase (ILK), and nuclear factor kappa B (NF-κB) (Fig. 3) (103). IGFBP-2 also influences vasculogenesis by tumor cells rather than endothelial cells in glioma, through a pathway involving integrin α5β1 ligation, FAK/ERK activation, and increased expression of vascular-endothelial cadherin (CD144) and MMP2 (124).
PTEN
Loss of PTEN function is characterized by a marked upregulation of IGFBP-2 expression, and PTEN is associated with IGFBP-2 downregulation in cell culture (125), consistent with regulation of IGFBP-2 by PI3K/Akt/mTOR signaling (126). Circulating IGFBP-2 levels have been used clinically as a biomarker of mTOR inhibition by rapamycin in a case of germline PTEN mutation (127). In prostate cancer cells, IGFBP-2 promotes PTEN phosphorylation and inactivation through a mechanism involving integrin β1 ligation (128). Similarly, in adipocytes from visceral fat, IGFBP-2 was found to stimulate FAK phosphorylation and downregulate PTEN, in parallel with the inhibition of adipogenesis. These effects depended at least in part on integrin binding by IGFBP-2, since they were prevented by the disintegrin, echistatin (104). However, mutation of the linker-region heparin-binding domain of IGFBP-2 (which corresponds to its nuclear localization signal, described later) also abolished FAK phosphorylation and PTEN downregulation, suggesting that membrane binding through the heparin-binding domain was necessary in addition to interaction with β1 integrin (104).
In patients with type 2 diabetes, circulating IGFBP-2 levels are decreased (129), and in a transgenic mouse model of IGFBP-2 overexpression, insulin sensitivity and glucose clearance were improved compared to wild-type mice (130). However, a more recent study of IGFBP-2-transgenic mice showed impaired clearance of an oral glucose load, and muscle GLUT4 levels were decreased; these effects were lost if the IGFBP-2 had a mutated RGD motif (131). Muscle levels of both FAK and ILK were higher in IGFBP-2-transgenic mice than either controls or mutant-RGD mice. The latter study appears inconsistent with the clinical findings that IGFBP-2 is positively associated with insulin sensitivity (129) and patients with high circulating IGFBP-2 are protected from type 2 diabetes (132). A possible explanation for the discrepancy is that local IGFBP-2 overexpression in this transgenic model may inhibit IGF signaling to impair insulin secretion or sensitivity.
Wnt signaling
Circulating IGFBP-2 levels rise significantly with increasing age (133). Wnt signaling is known to increase during aging, and IGFBP-2 gene expression is upregulated in arteries of old, compared to middle-aged, patients (134). IGFBP-2 is inducible by the Wnt/β-catenin/T-cell factor (TCF) pathway, with Wnt1 or Wnt3a treatment of vascular smooth muscle cells causing β-catenin phosphorylation and IGFBP-2 upregulation (134). Conversely, in glioblastoma cells, IGFBP-2 upregulates β-catenin post-translationally, stabilizing it through a process involving GSK3β phosphorylation and inactivation (135), apparently mediated by induction of the E3-ubiquitin ligase TRIM33 (136). This pathway depends on IGFBP-2 activation of FAK following integrin ligation and is associated with increased glioblastoma growth in preclinical models and poor prognosis in patients (135).
Nuclear localization
IGFBP-2 has a functional monopartite nuclear localization signal (NLS) with consensus sequence K-(K/R)-X-(K/R) (137) within its linker domain, through which it may translocate to the nucleus in neuroblastoma cells, mediated by importin-α (138). Within the nucleus, IGFBP-2 interacts with the VEGF promoter to upregulate VEGF transcription (Fig. 4), stimulating angiogenesis in an in vitro model (138). IGFBP-2 has transactivation activity in vitro (153), but it is not known if direct DNA binding is involved. Notably, IGFBP-2 and vascular endothelial growth factor (VEGF) are described as 2 master regulators driving poor survival in glioblastoma patients, with VEGF induction by IGFBP-2 regulated by the transcription factor FRA-1 (154). IGFBP-2 also stimulates telomerase activity and induces TERT transcription in prostate cancer cells (155), and, in patients with glioblastoma, a combination of high tumor IGFBP-2 expression and TERT promoter mutation predicted very poor patient survival (156). There is also evidence that transcriptional regulation by IGFBP-2 involves activation of EGFR and the transcription factor STAT3. In glioma cells, exogenous IGFBP-2 caused a marked phosphorylation of STAT3, in parallel with increases in phospho- and total EGFR, the survival protein Bcl-xL, and the cell cycle stimulator cyclin D1 (157). STAT3 activation was dependent on EGFR, and the 2 proteins were shown to coprecipitate and colocalize, mainly extra-nuclearly, although nuclear IGFBP-2, EGFR, and phospho-STAT3 were evident in patient glioma samples. An NLS-deficient IGFBP-2 mutant failed to translocate to the nucleus or to increase nuclear EGFR or phospho-STAT3 (157). This study provides a mechanism for oncogenic stimulation by IGFBP-2 in glioma, although it remains to be clarified how IGFBP-2 promotes the nuclear translocation of EGFR. IGFBP-2-dependent activation of nuclear EGFR-STAT3 signaling has also been described in melanoma, where it induced the immune checkpoint regulator PD-L1 (158).
Figure 4.
IGF1R-independent IGFBP signaling in the nucleus. (A) IGFBP-3 promotes DNA damage repair by NHEJ after translocating with EGFR from the cell surface to the nucleus (139). In a complex with the RNA-binding proteins SFPQ and NONO, it is required for DNA-PKcs activation in response to DNA double-strand breaks. The involvement of long noncoding RNA(s) in this process has also been proposed (140). Similarly, IGFBP-2 enhances the nuclear translocation of EGFR and promotes both EGFR and DNA-PKcs phosphorylation (141). IGFBP-6 can also modulate DNA repair through interaction with the NHEJ complex proteins, Ku70/Ku80, but appears to inhibitory to NHEJ (142). (B) IGFBP-3 interacts with, and modulates the transcriptional effects of, the nuclear receptor RXRα as well as its heterodimerization partners Nur77, RARα, PPARγ, VDR, and TRα1. In similar mechanisms, IGFBP-5 binds and modulates RXRα and VDR and IGFBP-6 interacts with VDR and TRα1 (see Table 2). (C). IGFBP-2, -3 and -5 have defined transactivation domains in their N-terminal regions (153) potentially enabling DNA interactions that may also involve other DNA-binding factors; for example, IGFBP-2 interacts with the VEGF promoter to induce VEGF (138), possibly involving the transcription factor FRA-1 (154). See text for other examples. Abbreviations: EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; NHEJ, nonhomologous end-joining; PKcs, protein kinase catalytic subunit; PPARγ, peroxisome proliferator activated receptor-γ; RARα, retinoic acid receptor-α; RXRα, retinoid X receptor-α; TRα1, thyroid hormone receptor-α; VEGF, vascular endothelial growth factor; VDR, vitamin D receptor.
IGFBP-3
Autophagy
Among the many documented intracellular effects of IGFBP-3 is its increasingly recognized role in mediating cellular responses to metabolic stress. The discovery that IGFBP-3 binds GRP78 (heat shock 70 kDa protein 5) (159, 160) led to evidence that it could contribute to the survival of breast cancer cells deprived of nutrients and oxygen through the induction of autophagy (159). IGFBP-3 has 3 N-linked glycosylation sites (161), and the observation that hypoglycosylation of IGFBP-3, under conditions of glucose and oxygen deprivation enhances its interaction with GRP78 suggests that IGFBP-3 glycosylation may serve as a metabolic stress sensor (159). IGFBP-3 interacts with a single-span transmembrane protein of ∼26 kDa, transmembrane protein 219 (TMEM219), which mediates some of its intracellular effects and has been termed an IGFBP-3 receptor (Fig. 3; discussed further later) (113). TMEM219 forms a complex with calmodulin in the presence of IGFBP-3 and calcium, which also involves association with calcium/calmodulin dependent protein kinase II (162). The induction of autophagy by IGFBP-3 in Vero (kidney epithelial) cells was found to be dependent on this complex (162). Autophagy induced by interleukin (IL)-33 in the myocardium of diabetic mice, in association with decreased cardiomyopathy, has also been shown to be dependent on IGFBP-3 (163), and, in human bronchial epithelial cells, IGFBP-3 was found to mediate IL-13-induced autophagy (164). In contrast to these findings, in corneal epithelial cells exogenous IGFBP-3 was reported to suppress mitochondrial degradation (mitophagy), resulting in sustained mitochondrial function (165).
Apoptosis
In addition to autophagy, IGFBP-3 also induces stress-induced apoptosis in mammary epithelial cells (166), an observation that follows many earlier studies on the role of IGFBP-3 in promoting apoptosis in cancer cells (167–169). IGFBP-3 has a bipartite NLS in its carboxyterminal domain, which mediates its nuclear import through binding to importin-β (170, 171). The abundance of nuclear IGFBP-3 is regulated by its polyubiquitination and proteasome-dependent degradation and has been proposed to determine its pro-apoptotic activity (172). The interaction of IGFBP-3 with importin-β is inhibited by the mitochondrial-derived peptide humanin (173), which was previously shown to bind to IGFBP-3 and inhibit apoptosis in some, but not all, cell lines (174). In primary cortical neurons, IGFBP-3 actually potentiated the protective effect of humanin against cell death induced by amyloid-β (174), but in a contrasting study, in which acetylcholinesterase was used to induce amyloid-β aggregation and cytotoxicity, IGFBP-3 binding was found to oppose the inhibitory effect of humanin on this process (175). These studies highlight the complex nature of humanin action and IGFBP-3-induced apoptosis.
Notably, the concept that IGFBP-3 in the nucleus leads to apoptosis is contradicted by some preclinical and clinical studies showing anti-apoptotic or tumor survival effects of nuclear IGFBP-3. In 2 TNBC xenograft tumor models, IGFBP-3 was found to be predominantly nuclear, and there was a strong negative association between tumor nuclear IGFBP-3 abundance and cleaved caspase-3, a marker of apoptosis, with high nuclear IGFBP-3 significantly predictive of shorter mouse survival (87). As discussed earlier, in these models mouse survival was prolonged by treatment with a combination of SphK1 and EGFR inhibitors, consistent with a role for IGFBP-3-driven SphK1 activity as a driver of tumorigenesis (87). Similarly, in patients with prostate cancer, high nuclear IGFBP-3 significantly predicted tumor recurrence (176, 177). However, there is considerable variability in the subcellular localization of IGFBP-3 in tumors and its predictive or prognostic value, as previously reviewed (34).
Nuclear receptor interactions
Apoptosis induction by IGFBP-3 has been reported to involve its association with the nuclear receptor nuclear receptor subfamily 4 group A member 1 (Nur77) (147). The interactions of IGFBP-3 with the retinoid X receptor (RXR), and other type II nuclear receptors with which RXR interacts, are responsible for some notable IGF-independent actions (Table 2) (178). Nur77 is one such RXR binding partner, and in response to IGFBP-3 it is phosphorylated and exported from the nucleus, resulting in cytochrome c release from the mitochondria and caspase 3/7 activation (147, 148). This apoptotic effect of IGFBP-3 through Nur77 has been proposed to contribute to osteoarthritis by causing chondrocyte death (179).
Table 2.
IGFBP signaling through class II nuclear hormone receptors
IGFBP | Receptor | Cell pathway | Ref. |
---|---|---|---|
IGFBP-3 | RXRα | Promotes apoptosis | (143) |
IGFBP-3 | RARα | Inhibits RAR growth-inhibitory signaling | (143, 144) |
IGFBP-3 | PPARγ | Inhibits preadipocyte differentiation | (145) |
IGFBP-3 | VDR | Inhibits osteoblast differentiation | (146) |
IGFBP-3 | Nur77 | Promotes apoptosis | (147, 148) |
IGFBP-3 | TRα1 | Inhibits T3-dependent transcription | (149) |
IGFBP-5 | VDR | Inhibits VDR signaling and cell cycle | (150) |
IGFBP-6 | VDR | Inhibits osteoblast differentiation | (151) |
IGFBP-6 | TRα1 | Inhibits TR-dependent osteoblast differentiation | (152) |
Abbreviations: IGFBP, insulin-like growth factor binding protein; Nur77, nuclear receptor subfamily 4 group A member 1 (NR4A1); PPARγ, peroxisome proliferator activated receptor-γ (NR1C3); RARα, retinoic acid receptor-α (NR1B1); RXRα, retinoid X receptor-α (NR2B1); TRα1, thyroid hormone receptor-α (NR1A1); VDR, vitamin D receptor (NR1I1).
Although a specific interaction between IGFBP-3 and Nur77 was not demonstrated in these studies, there are several examples of direct IGFBP-3 binding to other type II nuclear receptors. The primary discovery in this area was the demonstration that IGFBP-3 binds RXRα (Fig. 4) to promote RXR-specific transcription and that RXRα was essential for IGFBP-3-dependent apoptosis (143). IGFBP-3 also binds to the RXRα binding partner retinoic acid receptor (RAR) (144) and inhibits RAR signaling (143, 144). In IGFBP-3-expressing TNBC cells, RAR signaling is growth inhibitory, so its inhibition by IGFBP-3 is permissive for cell growth, and depletion of IGFBP-3 by immunoneutralization causes RAR-dependent growth inhibition (144). Other RXRα-binding nuclear receptors that also interact with, and are inhibited by, IGFBP-3 include peroxisome proliferator activated receptor-γ (PPARγ) (145), thyroid hormone receptor-α (TRα1) (149), and the vitamin D receptor (VDR) (146, 150). IGFBP-3 was shown to inhibit osteoblast differentiation, preventing vitamin D-dependent transcription of osteocalcin and CYP24a1 and decreasing alkaline phosphatase activity (146). Interestingly, IGFBP3 gene expression is induced by the transcriptional activity of each of these nuclear receptors (180–182), potentially leading to regulatory loops in which IGFBP-3 is transcriptionally upregulated by nuclear receptor signaling and then has the ability to modulate that signaling.
TMEM219
The transmembrane IGFBP-3-interacting protein TMEM219, discussed previously in the context of autophagy, is believed to mediate some of the antiproliferative effects of IGFBP-3 (113). TMEM219 was first identified as an IGFBP-3 ligand by yeast 2-hybrid screening. Its overexpression in IGFBP-3-producing breast cancer cells was shown to induce caspase-dependent apoptosis, while its silencing by small interfering RNA prevented the apoptotic effect of IGFBP-3 overexpression (Fig. 3) (183). Independent yeast 2-hybrid screening has also identified another TMEM219-interacting protein, the interleukin-13 receptor α2 (IL13Rα2). In contrast to the IGFBP-3–TMEM219 system, which promotes apoptosis in breast cancer cells, the IL13Rα2–TMEM219 system was shown to exert a protective effect against H2O2-induced apoptosis in human airway epithelial cells (184). In fact, IGFBP-3-dependent TMEM219 activity is also protective against airway inflammation, apparently acting through caspase activation (185). These studies indicate a complex relationship between TMEM219 and its ligands in the regulation of airway disease.
In chemotherapy-resistant pancreatic ductal adenocarcinoma cells, TMEM219 is upregulated compared to control cells, and the reversal of chemoresistance by IGFBP-3 was lost when TMEM219 was silenced by small interfering RNA (186), suggesting that the IGFBP-3–TMEM219 system could regulate chemosensitivity in pancreatic cancer. In normal pancreatic β-cells, TMEM219 expression was abundant and mediated IGFBP-3-dependent β-cell loss (187). Pharmacological blockade of the IGFBP-3–TMEM219 interaction in newly hyperglycemic nonobese diabetic mice, using a recombinant TMEM219 ectodomain polypeptide, was found to strongly protect against the onset of hyperglycemia, raising the possibility that this interaction might be exploited as a therapeutic target in diabetes (187).
TGFβ receptor-related pathways
The TGFβ type V receptor (TβRV), identical to the low-density lipoprotein receptor-related protein 1 (LRP1), is a multifunctional endocytic receptor with diverse roles in inflammation and disease (188). LRP1 has also been designated as an IGFBP-3 receptor, based on its ability to mediate growth inhibition by IGFBP-3 in mink lung epithelial cells (51, 189). Both IGFBP-4 and IGFBP-5 are also ligands for LRP1 (190), and an IGFBP-5-derived peptide stimulates cell migration and proliferation through LRP1-mediated activation of ERK, JNK, and p38 MAP kinases (191). IGFBP-3 and TGFβ have distinct binding sites on LRP1, and their growth inhibition involves the LRP1-dependent stimulation of different protein phosphatases: PP2A for IGFBP-3 and PP1 for TGFβ (51). IGFBP-3-stimulated growth inhibition is reported to involve IRS-2 activation and nuclear translocation of PP2A, dephosphorylation of the retinoblastoma protein-related proteins p130 or p107, and subsequent growth inhibition (Fig. 3) (51). A role for LRP1 in IGFBP-3 signaling has also been demonstrated in retinal endothelial cells under hyperglycemic conditions, but, paradoxically, in this system IGFBP-3 acted to inhibit TNFα receptor-2 signaling, thus attenuating apoptosis (192). In another study of the protective action of IGFBP-3 on retinal endothelial cells, its effect was shown to be mediated by scavenger receptor-B1 (193), a receptor that has been functionally linked with LRP1 (194). Whether these effects of IGFBP-3 also involve TGFβ signaling is unknown.
In an alternative mechanism in breast cancer cells, the canonical TGFβ receptor (TβRI/TβRII) system was shown to be required for IGFBP-3-dependent growth inhibition. In MCF-7 cells, IGFBP-3 overexpression inhibited cell growth and sensitized the cells to further inhibition by TGFβ1, but in wild-type T47D cell that lack TβRII, growth was unaffected by either TGFβ1 or IGFBP-3; in contrast, T47D cells transfected to express TβRII were dose-dependently growth-inhibited by IGFBP-3 in the presence of TGFβ1 (195). This effect was shown to be mediated by IGFBP-3-dependent phosphorylation of TβRI and its effectors Smad2/Smad3 (Fig. 3) and was unaffected by mutation of the IGFBP-3 NLS motif (114). IGFBP-3 signaling through TβRI/TβRII and Smad activation has also been observed in human placental cytotrophoblast cells (196), 3T3L1 preadipocytes (197), and intestinal smooth muscle cells (198), but direct binding of IGFBP-3 to TGFβ was not demonstrated in any study. In contrast to these stimulatory effects of IGFBP-3 on Smad signaling, in zebrafish embryos IGFBP-3 bound to bone morphogenetic protein-2 (BMP2) and inhibited BMP2-stimulated Smad phosphorylation (199).
Modulation of other growth factor activity
A biochemical (surface plasmon resonance) study has characterized high-affinity IGFBP-3 binding to growth factors other than IGF-1 and IGF-2, including basic fibroblast growth factor, hepatocyte growth factor, neuregulin-1, and platelet-derived growth factor. IGFBP-2 was similarly shown to bind to VEGF-B (200). In some cases, engineered IGFBP-3 derivatives inhibited the proliferative effects of these growth factors, presumably independently of IGF1R involvement. These recent findings recall much older studies in which a murine IGFBP-3 preparation was shown to inhibit basic fibroblast growth factor-stimulated, but not platelet-derived growth factor-stimulated, DNA synthesis (201), but the biological significance of these effects remains to be further explored.
Integrin-dependent effects
Despite no recognized integrin-binding domain having been described for IGFBP-3, there have been several reports of its integrin-linked actions (Table 1). A basic sequence in the IGFBP-3 carboxyterminal domain was shown to interact directly with integrin subunits αV and β1 (202), and a β1 blocking antibody partially reversed apoptosis caused by IGFBP-3 plus ceramide in TNBC cells, while preventing IGFBP-3-induced proliferation in nontransformed breast epithelial cells (105). IGFBP-3 enhanced the association between β1 integrin and FAK, leading to increased ERK phosphorylation, which was abolished by the cholesterol-binding drug nystatin (105). Since nystatin disrupts cholesterol-rich lipid rafts, these data support the concept of IGFBP-3 signaling from the cell surface through integrins and FAK activation. A facilitating role for β1 integrin in IGFBP-3 signaling has also been demonstrated in the migration of hepatic stellate cells, mediated through Akt (106), and oral squamous cell carcinoma cells, mediated by ERK (203). Integrin αV has also been shown to facilitate vitronectin- and IGFBP-3-dependent migration of keratinocytes (108). Surprisingly, in a different oral squamous cell carcinoma cell line, IGFBP-3 silencing induced the expression of several integrin subunits including α1, α3, β1, and β4, and the observed downregulation of β4 caused by IGFBP-3 overexpression was accompanied by a loss of FAK activation, apparently accounting for an inhibitory effect of IGFBP-3 on cell adhesion (107). The contrasting actions of IGFBP-3 in different experimental systems again highlights the cell context dependency of this pleiotropic protein.
IGFBP-4
Wnt signaling
Although IGFBP-4 is believed to act predominantly as an inhibitor of IGF1R signaling, there is evidence that it has IGF-independent activity. In a model of murine cardiomyocyte differentiation, IGFBP-4 was highly stimulatory, independent of any effect on IGF signaling; indeed, addition of IGF-1 attenuated the effect (115). Canonical Wnt signaling through β-catenin is inhibitory to at least some stages of cardiogenesis (204), and IGFBP-4 was shown to promote cardiomyocyte differentiation by blocking Wnt pathway signaling stimulated by Wnt3A or the receptors LRP6 or Frz8, with the ability to bind directly to both receptor proteins (Fig. 3) (115). IGFBP-4 appears to inhibit β-catenin activation through LRP6 only when the LDLR domain of LRP6 is exposed in the presence of Wnt ligands, and this inhibition leads to cardioprotection by IGFBP-4 in an in vivo model of ischemic injury (205). Interestingly, in a contrasting study, IGFBP-4 was found to promote Wnt/β-catenin signaling in a renal cell carcinoma cell line. In this model, stable IGFBP-4 expression stimulated cell proliferation and invasion, increased β-catenin signaling and TCF transcription, and enhanced the growth of xenograft tumors (116). There is currently no explanation for the differing effect of IGFBP-4 on Wnt pathway signaling in different biological systems, but it is clear that the discrepancy needs be taken into account when interpreting IGFBP-4 actions.
In breast cancer cells, IGFBP-4 was induced by estradiol (E2) treatment, but IGFBP-4 inhibited E2-stimulated phosphorylation of ERα, the Wnt mediator GSK3β, and Akt (206). There was no evidence of IGF1R involvement in E2 activation of Akt or its inhibition by IGFBP-4. This study was interpreted as showing that IGFBP-4 could inhibit E2-stimulated growth of breast cancer cells in an IGF-dependent manner (206); however, it should be noted that IGFBP-5, which may have a different IGF-independent mechanism of action from IGFBP-4, acted similarly to IGFBP-4 in this system.
Angiogenesis
IGFBP-4 has antiangiogenic activity that in some circumstances may be independent of IGF1R modulation. In a chick embryo chorioallantoic membrane assay for angiogenesis, IGFBP-4 inhibited angiogenesis induced by IGF-1 but also when induced by FGF-2, although not when induced by VEGF (207). The inhibitory effects were accompanied by attenuation of endothelial cell proliferation. The failure of IGFBP-4 to inhibit VEGF-induced activity was reversed in the presence of a p38 MAPK inhibitor, which had no effect alone. These results suggest that the inhibitory effect of IGFBP-4 on new vessel growth may be antagonized by p38 MAPK activity, although no further mechanistic details were presented (207). IGFBP-4 appears to act through its carboxyterminal domain in blocking angiogenesis, since a C-terminal peptide showed inhibitory activity in brain endothelial cells and blocked the growth of xenograft glioblastoma tumors in mice (208). IGFBP-4 contains a C-terminal thyroglobulin type 1 (Tg1) subdomain, and it was proposed that the decrease in angiogenesis by C-terminal IGFBP-4 was attributable to the inhibitory effect of the Tg1 region on the lysosomal cysteine protease, cathepsin B, which has an important role in angiogenesis (208). The Tg1 subdomain is in fact present in IGFBP-1, -2, -4, and -6 (25), so if this proposal is correct, these IGFBPs might all inhibit cathepsin B and angiogenesis by this mechanism, but there is no current evidence to support this.
IGFBP-5
Integrins and cell migration
Although IGFBP-5 has no recognized integrin-binding motif, it appears capable of modulating some integrin-mediated functions (Table 1). In breast cancer cells, IGFBP-5 increased cell attachment to various ECM proteins including collagen and fibronectin (but not laminin), the effect being inhibited by blocking α2 and β1 integrins (109). IGFBP-5 was shown to bind directly to α2β1 integrin, an effect that required the IGFBP-5 carboxy-terminal heparin-binding domain, and to upregulate ILK and activate Akt (Fig. 3). IGFBP-5 also inhibited cell migration in this system. A dominant-negative form of Cdc42 blocked the stimulation of cell adhesion by IGFBP-5, suggesting a role for this small Rho-GTPase in IGFBP-5 signaling in these cells (109). In an earlier study, IGFBP-5 was similarly shown to promote cell adhesion to ECM in a different breast cancer line, the effect inhibited by an RGD peptide (209). Since α2β1 integrin signaling can be blocked by RGD peptides (210), this result is consistent with IGFBP-5 acting through α2β1. In contrast to the inhibition of cell migration by IGFBP-5 in breast cancer cells, it has a potentiating effect on migration in mesangial cells (110, 211). This involves the induction of laminin-9 by IGFBP-5 and was inhibited by antibodies that block α6 and β1 integrins, which were induced by laminin-9 (110). There was no evidence from this study of direct IGFBP-5 binding to α6β1 integrin. Impairment of IGFBP-5-dependent mesangial cell migration by high glucose was attributed to downregulation of laminin subunit β2 and may be relevant to the defect in mesangial function in diabetic nephropathy (211).
Nuclear actions
IGFBP-5 shares with IGFBP-3 a carboxy-terminal domain NLS, which is believed to mediate its nuclear import in a complex with importin α/β (171, 212). Some nuclear import studies have used detergent-permeabilized nuclei (171), raising the question whether IGFBP-5 can enter intact nuclei, since in 1 study fluorescently labeled exogenous IGFBP-5 was only detected in extra-nuclear vesicles (213). Supporting the existence of nuclear IGFBP-5 is the immunocytochemical visualization of endogenous IGFBP-5 in cell nuclei (150, 214), and the functional evidence that IGFBP-5 has strong IGF-independent transactivation activity that is conserved between the zebrafish and human proteins (214). Interaction with the nuclear protein nucleolin may be required for IGFBP-5 nuclear retention since IGFBP-5 uptake was inhibited by nucleolin downregulation (215). Like IGFBP-3, IGFBP-5 binds to the nuclear receptors RXRα and VDR (Fig. 4) and inhibits their heterodimerization, which blocks vitamin D-dependent transcriptional activity in osteoblast-like cells (Table 2) (150).
TNF and NF-κB
IGFBP-5-induced apoptosis in MDA-MB-231 breast cancer cells involves the activation of both caspase-8 and caspase-9 (216). An investigation of the role of IGFBP-5 in caspase-8 dependent (extrinsic), death receptor-mediated apoptosis showed that, whereas wild-type cells were unresponsive to TNF in proliferation or survival assays, IGFBP-5-expressing cells showed inhibition of growth and survival in the presence of TNF. TNF treatment induces a survival response by stimulating an increase in NF-κB p65 (relA), but this response was lost in IGFBP-5-expressing cells, concomitant with activation of pro-apoptotic Bid (216). Although IGFBP-5 did not affect levels of the TNF receptor TNFR1 in this study, a more recent study using 293 embryonic kidney cells showed upregulation of TNFR1 expression by IGFBP-5 (217). IGFBP-5 was shown to interact directly with TNFR1 through the central or linker-domain, and IGFBP-5 appeared to bind in competition with TNF binding. IGFBP-5, presumably by competing with TNF, inhibited TNF-dependent nuclear localization of p65 (217). Although the carboxy-terminal domain of IGFBP-5 does not interact with TNFR1 (217), it may also inhibit NF-κB signaling since it was shown to downregulate activity in a NF-κB reporter assay, as well as the expression of TNF, IL-6, and VEGF-A (218), key mediators in NF-κB-dependent pathways (219).
Metabolic regulation
In differentiated murine C2C12 myoblast cells, increased lipid deposition resulting from treatment with oleate was accompanied by downregulation of IGFBP-5. Addition of recombinant IGFBP-5 together with oleate partially reversed the triglyceride accumulation and was accompanied by a decline in adipogenic mediators including PPARγ and aP2 (220). IGFBP-5 also improved the cellular insulin resistance caused by oleate. Comparable findings have been reported in HepG2 liver-derived cells treated with a free fatty acid mixture (221). These results point to IGFBP-5 downregulation as a contributor to the metabolic defects caused by free fatty acids. Consistent with an insulin-sensitizing role for IGFBP-5, Igfbp5-null mice become more hyperglycemic and more insulin-resistant after high-fat diet (HFD) feeding than their wild-type controls (222). Similarly, in mice with nonalcoholic fatty liver disease, hepatic IGFBP-5 was decreased, and IGFBP-5 overexpression using an AAV-IGFBP-5 construct reversed the lipid-dependent insulin resistance (221). Hepatic abundance of pAMPK, which fell after HFD feeding, was increased by IGFBP-5 overexpression, suggesting that AMPK signaling might mediate the IGFBP-5 effect (221).
AMPK activation is known to prevent the accumulation of hepatic lipid after excess nutrient intake, in association with a reduction in endoplasmic reticulum (ER) stress (223). Consistent with an AMPK-mediated decrease in ER stress contributing to the actions of IGFBP-5, tonsil-derived mesenchymal stem cells (T-MSCs)—which express high levels of IGFBP-5—or their culture medium, improved the impairment in glucose tolerance seen in HFD mice, and this effect was lost when T-MSC IGFBP-5 was silenced. In isolated pancreatic islets T-MSCs reversed HFD-dependent insulin hypersecretion and normalized HFD-induced upregulation of the ER stress proteins Chop and BiP (GRP78), all effects being dependent on T-MSC-derived IGFBP-5 (224). Together these results suggest a pathway of IGFBP-5 action through AMPK phosphorylation and ER stress suppression, but the primary link between IGFBP-5 and AMPK remains unknown.
IGFBP-6
Migration and prohibitin-2
In rhabdomyosarcoma cells IGFBP-6 signals transiently through ERK1/2 and JNK to stimulate chemotactic cell migration (225). Migration was inhibited by ERK1/2, JNK, and p38 MAPK blockade, with p38 apparently required for ERK activation and evidence of crosstalk among all three kinases. Although it is unknown exactly how IGFBP-6 initiates signaling to these pathways, the multifunctional protein prohibitin-2 (PHB2) appears to act as an essential mediator since silencing PHB2 blocks the effect of IGFBP-6 on migration (117). PHB2 has a wide variety of ligands and functions that depend on its localization within the cell (226). It was found to colocalize with, and bind directly to, IGFBP-6 on cell membranes, resulting in its tyrosine phosphorylation and in a cell-free system bound with high affinity to the IGFBP-6 C-domain (117). However, PHB2 downregulation did not prevent the activation of MAP kinases by IGFBP-6 (which are also involved in migration), suggesting that IGFBP-6 interacts with both PHB2 and another unidentified signaling system to effect the stimulation of cell migration (Fig. 3) (117). IGFBP-6 also induces the migration of peripheral blood mononuclear cells from patients with rheumatoid arthritis (mostly CD3+ T cells) but not healthy subjects, but the mechanism is unknown (227).
Hedgehog signaling
IGFBP-6 promotes the transition of bone marrow stromal cells to a more cancer-associated fibroblast-like phenotype. This effect of IGFBP-6 was mimicked by purmorphamine, a stimulator of hedgehog signaling via the activation of the hedgehog receptor Smoothened (228). IGFBP-6 is known to be induced by sonic hedgehog (SHH) signaling via the transcription factor GLI1 (229) and appears to act as an intermediary in the SHH pathway. In the bone marrow system IGFBP-6 induced a variety of proteins regulating proliferation and migration including TGF-β, MMP-2 and -9, TIMP2, and BMP2 (228). The toll-like receptor TLR4 was also induced by IGFBP-6, suggesting a role in inflammation. Notably, however, TLR4 upregulation by IGFBP-6 was blocked by the Smoothened antagonist cyclopamine (228), which implies that SHH responses additional to IGFBP-6 induction are required to activate TLR4-dependent signaling.
Angiogenesis
Under hypoxic conditions IGFBP-6 is induced in endothelial and other cells (230)—an effect that requires the unfolded protein response mediator, inositol-requiring enzyme 1 (231)—and IGFBP-6 expression is increased in specific brain regions following hypoxic-ischemic injury (232). Both basal and VEGF-stimulated angiogenesis are inhibited by IGFBP-6 in zebrafish and mammalian models, including rhabdomyosarcoma xenograft tumors, in a mechanism shown to be IGF-independent by the use of a non-IGF-binding IGFBP-6 mutant (233). Given that tumor angiogenesis is in part driven by hypoxia, the parallel induction of IGFBP-6 acting as an angiogenesis inhibitor seems paradoxical but may represent a feedback mechanism to balance the rate of tumor growth to oxygen availability.
Nuclear actions
Like IGFBP-3 and IGFBP-5 (170), IGFBP-6 has a functional NLS in its C-terminal domain (234). Similar to the interactions with type II (nonsteroid) nuclear receptors demonstrated for IGFBP-3 and -5 (178), IGFBP-6 binds to RXR dimerization partners (Fig. 4) including the VDR and the thyroid hormone receptor TRα1 (Table 2). The interaction of IGFBP-6 and VDR in cell-free systems was inhibited by IGF-2, the preferred IGF ligand for IGFBP-6, and IGFBP-6 appeared to competitively inhibit the interaction between VDR and RXR (151). In 293 T and HeLa cells, IGFBP-6 and VDR colocalized in the nucleus. IGFBP-6 attenuated VDR-dependent transcriptional activity, and, in osteosarcoma-derived MG-63 cells, it inhibited VDR-dependent osteoblast differentiation (151). In a parallel study, IGFBP-6 was shown to bind TRα1 in a cell-free system, predominantly through the IGFBP-6 carboxyterminal domain, and to block TRα1-RXRα heterodimerization (152). The interaction was also seen by FRET in 293 cell nuclei, where it was enhanced by the TRα1 ligand, triiodothyronine (T3). IGFBP-6 overexpression partly suppressed T3-dependent transcription of osteocalcin in murine MC3T3-E1 cells, and alkaline phosphatase in human U2-OS cells (152). These studies demonstrate that IGFBP-6 shares with IGFBP-3 and -5 the ability to modulate nuclear receptor signaling, with the potential to modify the activity of other RXRα binding partners such as PPARγ. A remaining challenge is to identify whether distinct nuclear factors can distinguish the transcriptional regulation by these 3 IGFBPs.
Focus on Selected Cellular Functions
IGFBPs and Cell Senescence
The arrest of replication in aged or stressed cells is important in maintaining organismal integrity and is associated with the upregulation of p53 signaling (235, 236), which in turn induces IGFBP-3 (237). Although circulating levels of IGFBP-3 show a slow decline as adults age, with only a modest effect of body mass index (238), IGFBP-3 secretion by dermal fibroblasts rises with increasing donor age (239). The age-related decline in circulating IGFBP-3 reflects the marked post-pubertal decline in IGF-1 and slower decline in ALS (240), proteins which bind and stabilize IGFBP-3 in the circulation (34). In cell culture, late passage cells, associated with replicative senescence, show increased IGFBP-3 expression compared to early passage in many studies, in parallel with senescence markers such as β-galactosidase (SA-β-gal) (241–243). IGFBP-3 secretion by senescent endometrial mesenchymal stem cells (MSCs) is decreased by PI3K/Akt inhibition, and exogenous IGFBP-3 promotes a senescent phenotype in young MSCs (243); conversely, in senescent endothelial cells, IGFBP-3 silencing partially reverses markers of senescence (242). In a mouse model of atherosclerosis, senescent cells impaired vascular smooth muscle repair functions through the secretion of IGFBP-3, which appeared to act by blocking IGF-1 signaling (244). IGFBP-3 also mediates the ability of PAI-1 to promote senescence, since PAI-1 inhibits the IGFBP-3 protease tPA, thus increasing bioactive IGFBP-3, which, in turn, inhibits IGF-1 (245). Interestingly, whereas acute treatment with IGF-1 promotes cell proliferation, opposed by p53 and IGFBP-3, prolonged exposure to IGF-1 can induce premature cell senescence by inhibiting SIRT1 deacetylase, which increases p53 acetylation (235), thus stabilizing p53 and enhancing its transcriptional activity.
Since IGFBP-3 promotes cell senescence at least in part through IGF-1 blockade, other IGFBPs might be expected to show similar effects. In a study of retinal pigment epithelial cells grown to replicative exhaustion, IGFBP-2 messenger RNA was found to be upregulated over 100-fold, although protein levels were not measured (246). Similarly, in senescent keratinocytes from psoriatic skin, IGFBP-2, but not IGFBP-3, was strongly overexpressed compared to normal keratinocytes, in parallel with upregulation of the cell cycle inhibitors p16 and p21 (247). Transfection with p16 caused upregulation of IGFBP-2, which interacted with p21 in the nucleus and protected it from proteasomal degradation. IGFBP-2 also inhibited IGF-1-dependent cell proliferation, leading to a proposed model of senescence progression in keratinocytes in which IGFBP-2 upregulation contributes to p21-mediated cell cycle arrest, p16 upregulation, and further IGFBP-2 induction (247).
In late-passage MSCs, IGFBP-4 was identified as an important secreted senescence factor, inducing characteristic phenotypic changes, including increased SA-β-gal and histone H3 Lys9 trimethylation, when applied to young MSCs (248), although no mechanism was proposed. Similarly, in bone marrow MSCs, IGFBP-4 abundance increased with cell passage number, and IGFBP-4 immunoneutralization significantly increased cell proliferation, but senescence markers were not measured (249). A more mechanistic study in MSCs showed that IGFBP-4 induction followed the release of PGE2 in stressed cells but that the associated increase in senescence did not absolutely depend on IGFBP-4 induction, even though exogenous IGFBP-4 is capable of promoting a senescent phenotype (250). Surprisingly, IGF-2, but not IGF-1, was found to increase the number of SA-β-gal-positive cells, and this effect was blocked by the addition of anti-IGF2R antibodies. Further, IGFBP-4 potentiated the ability of IGF-2 to induce senescence and enhanced the IGF-2-dependent loss of proliferative (Ki67+) cells, increasing p53 and the cell cycle inhibitor p27 (250). IGFBP-4 was proposed to act by protecting IGF-2 from proteolytic degradation, and senescence induction by IGF-2 was shown to require the activation of phospholipase-C-β, protein kinase C-β, and MEK/ERK signaling, potentially acting through ELK1 and p53 activation (250). This is a novel and detailed mechanism of IGFBP-4 enhancing IGF-2 signaling through IGF2R in cell senescence that will be important to confirm in other cell models.
IGFBP-5 has been extensively studied as a promotor of cell senescence. In endothelial cells and fibroblasts, IGFBP-5 is more highly expressed in late-passage cells than early-passage, in parallel with increased SA-β-gal staining, and IGFBP-5 downregulation reverses the senescent phenotype (251). IGFBP-5 was found to induce p53 and p21 in young fibroblasts, contributing to a decrease in proliferation. Its high expression in atherosclerotic arteries was interpreted as indicating a role for IGFBP-5 in vascular aging (251). A increase in IGFBP-5 also appears to mediate prostaglandin E2-dependent senescence (252), and senescence induced by IL-6 and soluble IL-6 receptor in lung fibroblasts similarly depends on IGFBP-5 upregulation, mediated by STAT3, and leading to increased reactive oxygen species and activated p53 signaling (253). Several other studies have also implicated IGFBP-5 upregulation in cell senescence induced by both endogenous and external agents (254–256). These reports present a unified picture of the important intermediary role of IGFBP-5, but more detailed mechanistic studies will be needed to fully elucidate the precise signaling pathways involved.
Contrasting with findings for the other IGFBPs are studies on the suppression of senescence by IGFBP-1 and IGFBP-6. In human coronary artery endothelial cells, IGFBP-1 was found to reverse H2O2-induced cell senescence, in parallel with stimulating cell replication (257). IGFBP-1 was induced by the Notch ligand Jagged1, which is involved in arterial wall thickening in aging mice. IGFBP-1 alleviated the increase in SA-β-gal seen in late-passage cells, the effect being mediated in part by IGFBP-1-dependent Akt activation (257). As noted earlier, hypophosphorylated IGFBP-1 can potentiate IGF action, which might explain its protective effect in this system. Alternatively, through its interaction with α5β1 integrin, IGFBP-1 might activate Akt in an IGF-independent manner (258). Similar to IGFBP-3 in some other studies, IGFBP-6 has been identified as a senescence-upregulated protein in colon cancer cells, but this effect was seen even in p53- and p21-null cells (259). IGFBP-6 is also increased in senescent skin fibroblast medium, but in contrast to IGFBP-3, stable downregulation of IGFBP-6 in young fibroblasts decreased the subsequent replication rate and increased SA-β-gal-positive cells and p21 expression (260). Conversely, IGFBP-6 overexpression delayed the onset of senescence, allowing several further population doublings in cells approaching the end of lifespan, accompanied by a decrease in p21. This protective role of IGFP-6 upregulation in delaying senescence has been interpreted as an adaptive response that might protect against the growth-arrest effects of other senescence inducers (260), but notably in this study IGFBP-3 was not recorded as a senescence-induced fibroblast protein as observed by others, highlighting the difficulty in interpreting disparate findings in different cell models.
IGFBPs and DNA Repair
DNA double-strand break (DSB) damage that evokes the DNA damage response can induce either cell senescence, apoptotic cell death, or DNA repair (236, 261). The repair of DNA damaged by endogenous or external impacts can follow several alternative pathways depending on the nature of the damage (262) and is of great interest in the context of the repair of DNA targeted by radiotherapy or chemotherapeutic drugs, since effective cellular DNA repair can negate the effect of these treatments. A primary sensor of DNA damage is p53, which typically responds by post-translational upregulation owing to the inactivation of the E3 ubiquitin ligase MDM2, which otherwise targets p53 for proteasomal degradation (263). In recent years the participation of several IGFBPs in DNA repair pathways has been described (18). Each of the 6 human IGFBP genes includes putative p53 response elements (264) which appear to be functional and lead to IGFBP induction at least for IGFBP-1 (123), IGFBP-2 (265), IGFBP-6 (266), and IGFBP-3 (237, 267, 268). IGFBP-2 secretion is specifically noted to be upregulated in response to mutant p53, although this effect occurs post-transcriptionally (269). In the case of IGFBP-3, a truncated form of p53 is reported to be more effective than full-length p53 in inducing IGFBP-3 (268). Another study showed that the presence of wild-type p53 in breast cell lines such as MCF-10A is associated with IGFBP-3 upregulation in response to chemotoxic stress, whereas cell lines with gain-of-function p53 mutations, such as MDA-MB-468 breast cancer cells, downregulate IGFBP-3 (267, 270). The significance of this complex pattern of regulation for DNA damage repair requires further investigation.
DNA DSB repair by nonhomologous end-joining (NHEJ) is regarded as the prevalent pathway for repair of damage cause by chemotherapy drugs such as anthracyclines and other topoisomerase II inhibitors (271). Briefly, NHEJ involves the binding of the Ku70-Ku80 heterodimer to the broken DNA ends, recruitment, autophosphorylation, and dissociation of DNA-PKcs, DNA end-processing by Artemis endonuclease, and direct ligation of the broken strands by DNA ligase IV (272). Several other proteins are also involved in the NHEJ repair complex, and the EGF receptor, translocated from the cell surface to the nucleus, also plays a critical role, interacting directly with DNA-PKcs (273). IGFBP-2, DNA-PKcs, and EGFR have been found to be highly expressed in high-grade astrocytomas, and treatment of glioblastoma-derived cell lines with exogenous IGFBP-2 caused a marked upregulation of DNA-PKcs (274), suggesting a possible role for IGFBP-2 in DNA repair. Acidic bile salts cause DNA damage in esophageal adenocarcinoma cells, in parallel with a strong upregulation of IGFBP-2 (141). IGFBP-2 was found to have a protective effect against DNA DSBs and mediated the activity of bile salts in enhancing nuclear accumulation of EGFR and phosphorylation of both EGFR and DNA-PKcs (Fig. 4). IGFBP-2 also promoted nuclear EGFR accumulation in malignant melanoma (158). Coimmunoprecipitation studies indicated that IGFBP-2, EGFR, and DNA-PKcs interacted in a common protein complex in response to DNA damage (141). Since IGFBP-2 silencing led to a prolonged elevation of γH2AX, a marker of DSBs, it may be concluded that IGFBP-2 acts in the nucleus to promote DSB repair by NHEJ.
As discussed earlier, IGFBP-6 is known to have actions within the nucleus, where it can translocate mediated by its carboxyterminal NLS (234). IGFBP-6 is upregulated in a p53-dependent manner in both the cytoplasm and nucleus of neurons treated with copper, which is genotoxic in these cells (266). IGFBP-6 induction appeared to be associated with increased neuronal apoptosis, with no evidence for its involvement in DNA damage repair. In contrast, a study of IGFBP-6-associated proteins in HEK-293 cells revealed the heterodimerization partners Ku70 and Ku80 as binding to IGFBP-6 (Fig. 4) through the interaction of Ku80 with residues in the IGFBP-6 NLS (142). In a DNA end-joining assay using nuclear extracts, IGFBP-6 was found to impair activity, suggesting that by binding to Ku80, IGFBP-6 might be inhibitory to DNA DSB repair by NHEJ (142).
IGFBP-3 can be phosphorylated by nuclear extracts or purified DNA-PKcs, resulting in decreased IGF binding and enhanced nuclear uptake and retention (54, 275), suggesting that phospho-IGFBP-3 might interact with nuclear components. IGFBP-3 Ser-156 was shown to be the critical DNA-PK-phosphorylated residue, and, in the absence of its phosphorylation, IGFBP-3 was unable to induce apoptosis in prostate cancer cells (275). Intriguingly, in retinal epithelial cells grown in high glucose, phosphorylation of the same IGFBP-3 residue appeared to prevent apoptosis (276), suggesting a possible protective effect of phospho-IGFBP-3 against diabetic retinopathy. The explanation of these seemingly contradictory findings is unknown. Nevertheless, the observations that IGFBP-3 could transactivate EGFR (78) and was preferentially retained in the nucleus after DNA-PK phosphorylation led to the discovery in breast cancer cells of a nuclear interaction between IGFBP-3, EGFR, and DNA-PKcs (Fig. 4) in response to DNA damage by the topoisomerase II inhibitors doxorubicin or etoposide (139). In response to these chemotherapy drugs, IGFBP-3 complexed with EGFR in the cytoplasm and nucleus, and with phosphorylated DNA-PKcs within the nucleus, and these interactions were blocked by EGFR tyrosine kinase inhibition. IGFBP-3 silencing inhibited DNA-PKcs autophosphorylation in response to etoposide, prevented the EGFR-DNA-PKcs interaction, and decreased activity in a DNA end-joining assay (139). These findings point to a role for IGFBP-3 in facilitating the nuclear interaction between EGFR and DNA-PKcs, which is important in DSB repair by NHEJ.
Supporting a role for IGFBP-3 in DNA damage repair, IGFBP-3 silencing in glioma cells caused an accumulation of γH2AX foci, indicating persistent DNA DSBs (277). Similarly, in oral squamous cell carcinoma cells, IGFBP-3 coprecipitated with both EGFR and phospho-DNA-PKcs in response to irradiation, and DNA-PKcs autophosphorylation was decreased by IGFBP-3 silencing, consistent with earlier findings in breast cancer cells. The resolution of γH2AX foci, 24 hours after irradiation, was also significantly inhibited by IGFBP-3 knockdown (278). A search for IGFBP-3-interacting proteins in breast cancer cells revealed that, after exposure to chemotherapy, the heterodimerizing RNA-binding proteins NONO and SFPQ also interacted with IGFBP-3, EGFR, and DNA-PKcs in the DNA repair complex (Fig. 4) (140). The involvement of NONO and SFPQ in NHEJ, which had been shown previously (279, 280), required both EGFR and DNA-PKcs phosphorylation, and NONO-SFPQ binding to IGFBP-3 in response to chemotherapy was blocked by poly (ADP-ribose) polymerase inhibition, which concomitantly inhibited in vitro DNA end-joining activity and delayed the resolution of γH2AX foci (140). The significance of RNA binding by NONO-SFPQ was possibly explained by the observation that the long noncoding RNA, LINP1, appeared to have a facilitating role in NONO-SFPQ interaction with IGFBP-3, which was blocked by LINP1 silencing (140). LINP1 has been shown to bind Ku70-Ku80 (281) and to act as a scaffold between Ku80 and DNA-PKcs (282).
These studies indicate the perhaps unexpected involvement of IGFBP-2, IGFBP-3, and IGFBP-6 in DNA damage repair by NHEJ: IGFBP-2 and -3 with facilitating roles and IGFBP-6 potentially inhibitory. To date there is no evidence that IGFBPs influence the other major pathway of DNA DSB repair, homologous recombination (HR). However, IGFBPs might regulate this pathway indirectly since it is promoted by IGF1R activation, which influences the interaction between IRS-1 and Rad51, a key HR intermediate (283). Since IGFBPs can both inhibit and potentiate IGF1R signaling under different conditions, the possibility exists that they might modulate HR signaling and perhaps even influence the cell choice between HR and NHEJ repair.
IGFBPs and Immune Function
The importance of IGF-dependent IGF1R signaling in regulating immune function is well recognized, ranging from effects on immune cell lineages and immune coordination to autoimmunity (284). As positive and negative regulators of IGF1R signaling, IGFBPs have the potential to modulate these functions at many levels. For example, IGFBP-1 has been proposed to mediate the inhibition of bone marrow B lymphocyte generation that is characteristic of old age. Peripheral B cells were found to upregulate TNFα, which led to increased circulating IGFBP-1. This in turn was proposed to inhibit bone marrow IGF-1 signaling, which is essential for B cell lymphopoiesis (285). IGF-1 administration to aging mice, or TNFα blockade in aging humans, restored B-cell generation, the proposed mechanism being the reversal of IGF-1 blockade by IGFBP-1. This interesting proposed pathway requires further investigation since reported IGF-1 levels were implausibly low and the induction of IGFBP-1 was not directly demonstrated, highlighting the difficulty of assessing cellular IGF-IGFBP activity based on peripheral levels.
The inhibitory effect of IGFBPs was confirmed in a study of B-cell precursor acute lymphoblastic leukemia cell lines, in which IGF-1 was found to enhance proliferation and was inhibited by IGFBP-1, -3, and -4 but not the other IGFBPs. This was interpreted as simple blockade of IGF-1 stimulation of IGF1R (286), although the selective effectiveness of these 3 IGFBPs is unexplained. IGF-1 was also shown to be necessary for pro-B-cell development from CD34+ bone marrow cells (287). Among the 6 IGFBPs, only IGFBP-3 was inhibitory after 4 weeks of treatment. In contrast, a neutralizing antibody against IGFBP-6 inhibited pro-B-cell development, and this was reversible by exogenous IGFBP-6, consistent with a permissive effect of IGFBP-6 (287). These studies indicate a complex interplay between IGF-1 signaling and IGFBPs in early B-cell development.
T cell regulation
The population of naïve (CD28+ CD95−) CD8+ T cells declines with increasing age. In groups of young, elderly, or very old subjects, the proportion of naïve CD8+ T cells was found to correlate positively with circulating IGFBP-3 but not IGF-1, and it was suggested that IGFBP-3 may have a role independent from IGF-1 in the development and maintenance of naïve CD8+ T cells (288). Again, caution is needed when extrapolating from circulating IGFBP-3 levels (which decline with age) to cellular effects of IGFBP-3 (which is more highly expressed in aging cells). Tumor infiltration by CD8+ (cytotoxic) T lymphocytes is regarded as a key component of the host antitumor response (289). The relationship between IGFBP-3 and CD8+ T cells was further explored in a model of wild-type and Igfbp3-null mice bearing syngeneic EO771 mammary tumors (290). In mice lacking IGFBP-3, tumor growth was inhibited by about 50%, in parallel with a significant increase in tumor T cell (CD3+) infiltration (290) and tumor weight was positively associated with (tumor-derived) Igfbp3 expression (291). The percentage of CD8+ T cells was strongly increased in Igfbp3-null mouse tumors whereas CD4+ cells were unchanged between wild-type and null mice. Gene expression of Cd8a and Cd8b1 were inversely associated with tumor weight, as were Ifng (IFN-γ), Tnf (TNF), and Tnfsf10 (TRAIL). The increase in CD8+ T cells in tumors of Igfbp3-null mice suggests an inhibitory effect of host IGFBP-3 on T cell infiltration, which might then lead to enhanced tumor growth (291); however, the pathway of IGFBP-3 action in modulating cytotoxic T cells is unknown.
A similar inhibitory role has been proposed for IGFBP-2 in glioblastoma, where IGFBP-2 knockdown decreased the mesenchymal phenotype (associated with aggressive disease) and increased the tumor infiltration by CD8+, and also CD4+, T cells (292). This was interpreted as indicating a potentially immunosuppressive effect of IGFBP-2. In contrast to these inhibitory effects of IGFBPs on T cell migration, IGFBP-5 stimulates the migration of mononuclear cells into mouse lung tissue, with CD3+ T cells being the major migrating cell type and CD4+ predominating over CD8+. IGFBP-5-dependent migration was mediated by ERK but not Akt activation (293). In TNBC-associated fibroblasts, IGFBP6 is part of a multigene signature associated with cytotoxic T lymphocyte dysfunction (294), but specific functional studies are required to understand how IGFBP-6 acts. Regulatory T cells (Tregs), which modulate the immune response, help to prevent an excessive response but have the potential to adversely affect antitumor immune activity (295). Incubation of naïve CD4+ T cells with culture medium from marrow-derived MSCs (which have been proposed to have therapeutic benefit for rheumatoid arthritis) was found to induce FOXP3+ Tregs in an IGF- and IGF1R-dependent process (296). The MSC medium also contained a high level of IGFBP-4, immunoneutralization of which decreased the Treg population, suggesting that bone-marrow MSCs have a self-regulatory loop in which the stimulation of Treg production can be antagonized by endogenous IGFBP-4 (296).
Autoimmune disease
IGF1R activation has been proposed to have a pathogenic role in the development of autoimmune disease, which might potentially be modulated by IGFBPs (284). A number of studies have suggested that decreased IGF bioavailability, as indicated by low IGF levels and/or IGF/IGFBP-3 ratios, or high IGFBP-3 levels, might be associated with a range of autoimmune disorders including multiple sclerosis (297), rheumatoid arthritis (RA) (298), and β-cell autoimmunity (299). This is supported by preclinical experiments in which IGF-1/IGFBP-3 complexes administered therapeutically in mice were effective in delaying the onset of type 1 diabetes (300) and autoimmune encephalomyelitis (AE), a murine model of multiple sclerosis (301). In contrast, high-dose IGF-1/IGFBP-3 treatment exacerbated established AE, a proposed mechanism being the induction of encephalitogenic T cells by the combination therapy (301). Interestingly, the SphK inhibitor and S1P receptor modulator, fingolimod, which alleviates symptoms in the AE mouse model by preventing proinflammatory T cell egress from lymph nodes (302), also inhibits IGFBP-3-promoted tumorigenicity in experimental breast cancer models (303), suggesting that IGFBP-3 itself, which stimulates SphK (85), might have a direct proinflammatory effect.
A pathogenic role for IGFBP-6 in RA has been suggested by the demonstration of its chemotactic effect on RA T cells (227). Serum IGFBP-6 levels were higher in RA patients than controls, and IGFBP-6 was highly expressed in various cells of the RA synovium. In vitro studies showed that IGFBP-6 stimulated migration of RA immune cells, mostly CD3+ T cells, suggesting its involvement in the migration of T cells into inflamed joints in RA (227). In addition to high IGFBP-6 and IGFBP-3 levels in serum from RA patients, IGFBP-2 levels are also reported to be elevated (304). IGFBP-2 was also identified as a consistent autoantigen in an extensive screen of autoantibodies in RA sera (305), and autoantibodies against citrullinated IGFBP-6 have also been detected (306). Whether there is any potential for pathogenic effects of these antibodies (307) is unknown, but it is possible that they could be useful diagnostically. In overview, there are numerous studies in which IGFBPs are linked to autoimmune diseases (308), but to date there has been a paucity of mechanistic studies, providing a significant opportunity for further investigation in this area.
Concluding Questions and Comments
How do IGFBPs Exert Opposite Effects Under Different Conditions?
A common paradox in IGFBP research is the observation of contradictory effects in different cell systems or under different conditions. At the broadest level, IGFBPs can either inhibit or potentiate IGF activation of IGF1R, as discussed in Section II. This may occur extracellularly as a simple consequence of post-translational modification: for example, hyperphosphorylated IGFBP-1, or intact IGFBP-4, bind IGFs with high affinity and block their access to the receptor, whereas dephosphorylated IGFBP-1 (48), or proteolytically cleaved IGFBP-4 (59), have reduced affinity and permit IGF1R signaling. IGFBP regulation of IGF1R may also involve complex intracellular signals, for example, the inhibition of IGF1R by IGFBP-3, through the activation of phosphatases that impair receptor-dependent phosphorylation cascades (50, 51), or its potentiation of IGF1R by stimulating sphingosine 1-phosphate production, activating G-protein coupled S1P receptors and transactivating IGF1R in an EGFR-dependent manner (78).
These biochemical mechanisms provide a partial explanation for disparate IGFBP effects, although they do not define the exact cellular conditions under which a particular effect may be expected to occur. In other cases, apparently conflicting results have no known biochemical explanation: for example, IGFBP-2 interaction with integrin α5β1 inhibits FAK and ERK phosphorylation in breast cancer cells (101) but activates FAK-ERK signaling in glioma cells (124); similarly, IGFBP-4 inhibits Wnt–β-catenin signaling in cardiomyocytes (115) but stimulates this pathway in renal cell carcinoma cells (116). Some notable studies have specifically explored how different cell lines, matrix proteins, or extracellular stimuli can modify IGFBP signaling (85, 105); these 2 concerned the roles of integrins and sphingolipids, which have an intimate functional link through their colocation in plasma membrane lipid rafts and the effects of sphingolipids on integrin mobility and signaling (309, 310). Such studies provide important clues to the regulation of IGFBP actions by the cellular environment; however, it is clear that further research is needed in this area.
Do IGFBPs Have Specific Receptors; Are They Potential Therapeutic Targets?
Although IGFBPs initiate or modulate a wide variety of cell signaling pathways, as detailed in the previous sections, their ubiquity in the circulation, the extracellular space, and inside the cell make them very challenging targets for therapy. For example, IGFBP-3, which has an essential role in IGF transport, circulates at around 100 nmol/L (3-4 mg/L) in healthy adults (34), and there is little understanding of the relationship between its circulating level and the concentration inside the nucleus, where it might be targeted to treat cancer chemoresistance (140). Another challenge for therapeutic targeting arises from the disparate results of signaling studies under different conditions, as discussed previously. IGFBP-3, previously shown to be pro-apoptotic (and therefore potentially advantageous) in prostate cancer based on cell biology studies (147), is now described as a poor prognostic feature and a potential therapeutic target (176, 177) due to its role in prostate cancer progression. A further issue arises from the disparate roles of IGFBPs in different disorders. IGFBP-2 is proposed as an attractive target in metabolic disorders, where interventions would aim to increase its concentration or activity to treat obesity-related insulin resistance (129). In patients with glioblastoma (311) or melanoma (158), however, IGFBP-2 is believed to drive tumor progression, and therapy would aim to downregulate or block its actions.
As detailed in Section III, many IGF1R-independent effects of IGFBPs are initiated by interaction with cell-surface proteins, some of which have been designated as IGFBP receptors. These might, if suitably specific, be more attractive therapeutic targets than the IGFBPs themselves. IGFBP-1, -2, -3, and -5 can all signal through integrins, and in the case of IGFBP-1 (99) and IGFBP-2 (124), integrin α5β1 is generally regarded as their main IGF1R-independent mediator. Despite these well-studied actions, however, integrins are not designated as IGFBP receptors—integrin α5β1 is described as a fibronectin receptor (312), and IGFBP-1 and −2 are “incidental” ligands due to their carboxyterminal RGD motif. Notwithstanding the lack of IGFBP specificity of integrins, an RGD-based peptide has been shown to improve insulin sensitivity in a preclinical obesity model, with the suggestion of possible clinical benefit (120).
Similarly, for IGFBP-4 and the Wnt receptors LRP6 and Frz8 (115), IGFBP-6 and the multifunctional PHB2 (117, 226), and other systems described in Section III, these proteins are not regarded as IGFBP receptors, even though their roles in IGFBP signaling are clearly demonstrated. Reflecting the broad ligand specificities of these IGFBP-interacting proteins, their involvement in many cell functions make them difficult therapeutic targets to modulate IGFBP-dependent signaling pathways. In the case of IGFBP-3, 2 unrelated proteins have been described as receptors, both mediating growth-inhibitory effects. LRP1/TβRV, described earlier, binds IGFBP-3, -4, and-5 (190) and mediates growth-inhibitory signaling by IGFBP-3 (51), which could potentially be explored as a cancer therapeutic. However, LRP1 is reported to have more than 40 ligands, most of which act to promote cell survival (313). Among other functions, it is also a scavenging receptor for lipoproteins and other macromolecules and modulates phospholipid metabolism, liver and lung function, endothelial cell metabolism, and oligodendrocyte differentiation (188, 313) through mechanisms that are not known to involve IGFBPs. A peptide LRP1 agonist appears to have benefit in cardioprotection (313), but it is unclear how IGFBP-3-dependent pathways mediated by LRP1 would be affected.
The other protein designated as a IGFBP-3 receptor is TMEM219, described previously as a mediator of IGFBP-3-dependent autophagy (162) and apoptosis (183). In a recent study reporting the contribution of TMEM219 and IGFBP-3 to pancreatic beta cell homeostasis, the IGFBP-3-dependent induction of beta cell apoptosis was abrogated by a prototype therapeutic peptide based on the extracellular domain of TMEM219 (187), with the potential to be beneficial as a diabetes treatment. This appears to be a more promising therapeutic approach than targeting IGFBP-3 itself. In contrast, IGFBP-3–TMEM219 signaling alleviates airway inflammation in bronchial asthma, and upregulation of this pathway is proposed as a potential therapy, although an effective therapeutic agent has not yet been demonstrated (185). These examples illustrate how the complexity of IGFBP cell biology across different systems may confound therapeutic approaches based on IGFBP signaling pathways.
Conclusion
Four decades of IGFBP research have produced some remarkable advances in knowledge. While there is now a broad understanding of the endocrine functions of IGF-IGFBP complexes, the details of IGFBP-dependent cell signaling have been slower to emerge, leading to numerous pathways in which IGFBPs have clear initiating or modulating roles that do not depend on their ability to bind IGFs. Through the use of genetic and proteomic screens, many unexpected IGFBP ligands have been recognized, revealing that their sphere of influence extends from the extracellular space to the cytoplasm and its organelles to the cell nucleus. Despite the wealth of recent discovery of novel IGFBP ligands, knowledge of most of the protein-protein interactions involved in IGFBP signaling is still at a germinal stage. Many of these interactions are likely to be modulated by post-translational modification, as is well understood for other cell signaling components, but this has been investigated in relatively few cases, despite the fact that all 6 IGFBPs have numerous potential sites of phosphorylation and other modification. A better understanding of the regulation of IGFBP-ligand interactions is likely to present new opportunities to modulate these interactions, with the potential to influence disease development or progression.
Disclosure
The author confirms that there are no financial or other interests to disclose in relation to the writing or content of this article.
Funding
The writing of this paper was not supported by any grants or fellowships.
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