Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities

Abstract

Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), are critical effectors of the Hippo pathway, as well as other biochemical and biophysical signals. Through their interaction with DNA-binding partners, YAP/TAZ can modulate the transcription of many genes critical for organ size regulation and tissue homeostasis maintenance. Aberrant expression or activation of YAP/TAZ is implicated in the pathogenesis of many cancers and noncancerous diseases. Notably, their functional outputs demonstrate remarkable diversity, with context-dependent roles emerging across distinct disease models and tissue microenvironments. Posttranslational modifications (PTMs) exert profound impacts on the stability, subcellular localization, and function of YAP/TAZ. The canonical Hippo pathway-mediated phosphorylation and ubiquitination have been well characterized as mechanisms that downregulate YAP/TAZ stability and transcriptional activity. Recent studies have identified novel phosphorylation sites, atypical ubiquitination patterns, along with ubiquitin-like modifications, glycosylation, methylation, acetylation, and lactylation on YAP/TAZ. These PTMs exhibit dynamic regulation in response to microenvironmental stimuli, providing molecular insights into the context-dependent functional versatility of YAP/TAZ. This review systematically synthesizes current understanding of YAP/TAZ PTM networks and discusses their therapeutic implications.

Graphical abstract

Introduction

YAP/TAZ: master transcriptional co-activators

YAP and TAZ share common functional domains such as the TEA domain transcriptional factors family proteins (TEADs) binding domain, WW domain, and PDZ binding domain [1]. They act as transcriptional co-activators and control the expressions of genes critical for cellular processes including proliferation, survival, differentiation, motility, metabolism, and immune modulation. Owing to the lack of a DNA binding domain, YAP/TAZ rely on the interaction with the transcriptional factors (TFs) to mediate transcriptional regulation [2]. For example, their partnership with TEAD family TFs drives the expression of connective tissue growth factor (CTGF), enhancing cell proliferation and cancer metastasis [3]. SMAD family proteins are another target TFs of YAP/TAZ. The YAP/TAZ-SMAD complex can regulate stem cell renewal and drive immune evasion in cancers [4, 5]. Other partner TFs include RUNX, p73, KLF5, TBX5, and so on [6].

YAP/TAZ are initially found as key regulators for organ size in mammals [7]. As research progresses, accumulating evidence has demonstrated that they play critical roles in regulating cellular homeostasis and associate with multiple pathological conditions [8]. In cancers, they typically promote tumor initiation, progression, metastasis, metabolic reprogramming, immune escape, and therapeutic resistance, though their functional outputs can be tissue-specific [9]. Recent studies have also revealed context-dependent tumor-suppressive roles of YAP/TAZ in breast cancer (BC) [10], malignant mesothelioma [11], colorectal cancer (CRC) [12], hematopoietic [13], and neuroendocrine cancers [14]. Moreover, their pathophysiological influence extends to cardiovascular diseases [15–17], organ fibrosis [18, 19], neurodegenerative diseases [20, 21], and metabolic diseases [22, 23].

Hippo-dependent regulation of YAP/TAZ

The functional diversity of YAP/TAZ is partly attributed to the intricate upstream signaling networks, with the Hippo pathway constituting the core regulatory module. The canonical mammalian Hippo pathway comprises a cascade whose core components are STE20-like protein kinase 1 and 2 (MST1/2) and serine/threonine kinase large tumor suppressor 1 and 2 (LATS1/2), and YAP/TAZ act as its final conduits [24]. When the Hippo pathway is activated, the MST1/2 homodimer phosphorylate LATS1/2 directly and induce their activation. Meanwhile, the MST1/2 can phosphorylate Salvador homolog 1 (SAV1) and MOB kinase activator 1(MOB1) to enhance the activity of LATS1/2. Then, the LATS1/2 phosphorylate YAP/TAZ [25]. As a result, YAP/TAZ interact with 14-3-3 protein, and are retained in the cytoplasm where they are further phosphorylated, ubiquitinated, and degraded [26]. When the Hippo pathway is inactive, YAP/TAZ can be translocated into the nucleus and interact with TFs to regulate gene expression.

Unlike pathways directly triggered by ligand–receptor interactions, the Hippo pathway has no dedicated receptors and is instead regulated by diverse upstream signals. These include cellular junctions and polarity, G protein-coupled receptors (GPCRs) signaling, mechanical cues, environmental stresses, and inflammatory signaling, as summarized in recent reviews [1, 2, 6]. Below, we provide a brief overview of these key regulatory factors.

Cellular junctions and polarity

It has been demonstrated that cellular junctions, such as tight junctions and adherens junctions, regulate YAP/TAZ activity through Hippo-dependent mechanisms. Mechanistically, the transmembrane protocadherin FAT1 is activated under intercellular tight junctions and assembles a multimeric complex with core Hippo signaling components, including MST, SAV1, neurofibromin 2 (NF2), angiomotin (AMOT), MOB, and PALS1-associated tight junction protein (PATJ). This complex subsequently activates the Hippo kinase cascade, leading to phosphorylation-mediated suppression of YAP/TAZ [27]. Notably, FAT1 deficiency has been demonstrated to promote tumorigenesis via the activation of YAP [28]. Similarly, triggered by intercellular tight junctions, AMOT facilitates the recruitment of LATS kinases along with YAP/TAZ proteins, thereby promoting their phosphorylation. In addition, adherens junctions, another form of cell junctions, are functionally associated with α-catenin and NF2, which cooperatively maintain membrane retention of the phosphorylated YAP [29]. Moreover, cell polarity complexes also affect the activity of the Hippo pathway. For instance, Crumbs, the transmembrane protein located at the apical of epithelial cells, promotes the phosphorylation of LATS1/2 and bridge the interaction between LATS1/2 and YAP, thereby inhibiting the nuclear translocation of YAP [30]. PAR polarity complex Par3-Par6-atypical protein kinase C (aPKC) suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhance the nuclear translocation of YAP, leading to the progression of cancers [31, 32]. The polarity protein Scribble localizes to the basement membrane and interacts with both MST1/2 and LATS1/2, thus promoting LATS1/2 activation, whereas the loss of Discs Large Homolog 5 (DLG5) and the antagonist of Scribble by KN motif and ankyrin repeat domain-containing protein 1(KANK1) disrupt the Scribble–MST/LATS interaction and promote YAP/TAZ activation in breast cancers [33, 34].

GPCR signaling

The GPCRs are the largest mammalian membrane receptor family [35]. They have been demonstrated to be critical upstream modulators of the Hippo pathway, and their impacts on YAP/TAZ are governed by ligands and coupled G proteins [36]. For example, activating GPCRs coupled to Gα12, Gα13, Gα, Gα11, or Gαi protein, such as lysophosphatidic acid (LPA) receptor [37] and angiotensin II receptors [38], can suppress LATS1/2 activity, and consequently promote YAP/TAZ nuclear translocation and transcriptional activity. Conversely, activating Gαs-coupled GPCRs, such as epinephrine [39] and glucagon receptors, can enhance protein kinase A (PKA)-mediated LATS1/2 phosphorylation to amplify their inhibitory efficacy toward YAP/TAZ [40].

Mechanical cues

Mechanical cues coordinate the Hippo signaling pathway through multilayered molecular mechanisms, with a central focus on regulating the activity of YAP/TAZ [41]. For example, mechanical signals activate Rho-associated kinase (ROCK) signaling, and then inhibit the MST1/2 kinase activity through actin polymerization [41] and striatin-interacting phosphatase and kinase (STRIPAK), which indirectly activates YAP [42]. However, an increasing matrix stiffness can inhibit the ROCK–YAP signaling [43]. Similarly, MST1/2 is inhibited by integrin-mediated focal adhesion signal, which synergistically enhances the transcriptional function of YAP [44]. In addition, cell–cell contacts can limit YAP/TAZ activity through activation of the upstream Hippo core kinase LATS [45]. These mechanism enables cells to dynamically adapt to the physical microenvironment such as tissue stiffness, and plays a key role in tissue regeneration, stem cell differentiation, and cancer progression.

Environmental stresses

Environmental stresses, including energy stress, osmotic stress, oxidative stress, and hypoxia, can regulate YAP/TAZ in Hippo-dependent manners. Under hyperosmotic conditions, LATS1/2 undergo phosphorylation-mediated activation, triggering downstream suppression of YAP transcriptional activity. [46]. Similarly, during oxidative stress conditions such as ischemia–reperfusion injury, LATS2 specifically becomes phosphorylated and subsequently catalyzes YAP phosphorylation, effectively reducing its nuclear accumulation [47]. In addition, under cellular energy stress (low energy level or glucose starvation), 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling activation induces LATS kinase-mediated phosphorylation of YAP, thereby suppressing its transcriptional activity [48, 49]. Furthermore, induced by hypoxia, hypoxia-inducible factor (HIF)-α mediates the reduction of LATS phosphorylation, which facilitates YAP activation through attenuation of its inhibitory phosphorylation [50].

Inflammatory signaling

A novel upstream signaling to regulate YAP/TAZ in Hippo-dependent manners is inflammation stress, which is mainly triggered by inflammatory factors. Recently, Deng et al. proposed that transforming growth factor-activated kinase 1 (Tak1), a central regulator of innate immunity and inflammatory signaling, inhibits the Hippo pathway suppressor STRIPAK, thus causing the activation of Hippo and inhibition of YAP [51]. The endotoxin lipopolysaccharide (LPS), a key mediator of macrophage M1 polarization, activates inflammatory and immune responses through Toll-like receptor 4 (TLR4) binding [52]. Following receptor activation, LPS promotes YAP activation by triggering MST1 lysosomal degradation and consequent Hippo pathway inactivation [53]. Other inflammatory signals including interferon-γ (IFN-γ) [54] and IL-17A and IL-22 [55] are also reported to regulate the Hippo-YAP pathway.

Hippo-independent regulation of YAP/TAZ

Beyond the canonical Hippo-dependent pathway, emerging research has identified Hippo-independent regulatory mechanisms governing YAP/TAZ activity, markedly expanding our understanding of their regulation in recent years. Notably, many of the above-mentioned factors can also modulate YAP/TAZ in a Hippo-independent manner. For example, in addition to being involved in recruiting LATS at tight junctions, angiomotin (AMOT) proteins can also directly bind to YAP/TAZ, leading to their cytoplasmic sequestration and subsequent functional inhibition [56, 57]. G protein Gαq stimulates actin polymerization and activates YAP via Rho GTPase signaling. This F-actin accumulation induces the dissociation of AMOT–YAP complexes, ultimately facilitating nuclear translocation of YAP and transcriptional activation of YAP-dependent targets in uveal melanoma cells [58]. Moreover, under high mechanical stress, nuclear F-actin enhances YAP/TAZ activity by directly engaging the inhibitory complex of YAP/TAZ, thereby liberating them and facilitating the association between TEAD and YAP/TAZ independently of LATS [59]. Also, hyperosmotic stress [46, 60] triggers Nemo-like kinase (NLK)-dependent YAP phosphorylation, facilitating its nuclear localization, whereas energy deprivation [48] activates AMPK to phosphorylate YAP, resulting in functional suppression of its transcriptional activity. Furthermore, in macrophages, TNF-α induces YAP upregulation and promotes its nuclear translocation through Rho GTPase-dependent mechanisms, thereby activating its downstream signaling and driving subsequent transcriptional activation of inflammatory mediators [61]. Interestingly, an emerging study demonstrated that the exposure of cells to a stiff environment can reduce the mechanical resistance of nuclear pores and increase active nuclear import of YAP, independently of the Hippo pathway [62].

Wnt/β-catenin signaling is an alternative pathway to regulate YAP/TAZ independently of Hippo pathway. When Wnt is off, the core component β-catenin can bind with TAZ, and they will undergo ubiquitin–proteasome-mediated degradation together. On the contrary, the activation of Wnt signaling can prevent TAZ from its degradation, and therefore lead to its nuclear translocation, amplifying its transcriptional activation potential [63]. Moreover, β-catenin can also directly bind to YAP. Then, the complex transports into the nucleus and locates to the common gene of TEAD and T cell factor (TCF) [64]. Notably, recent studies have identified noncanonical YAP/TAZ activation mechanisms independent of the Hippo pathway. Although the exact molecular determinants require further elucidation, accumulating data implicate posttranslational modifications (PTMs) participate in this noncanonical regulation, as we discuss in detail below (Fig. 1).

Fig. 1.

The outline of YAP/TAZ PTMs, the crosstalk between PTMs and their molecular function. Section A summarizes the canonical Hippo pathway (schematically depicted in dark gray) and YAP/TAZ posttranslational modifications. As transcriptional co-activators, YAP/TAZ translocate to the nucleus to function through interactions with transcription factors (TFs), thereby driving expression of downstream target genes including CTGF, PD-L1, MYC, and CYR61. Undergone different specific signaling (highlighted with boxes). Different kinases mediate the distinct PTMs of YAP/TAZ in a certain pattern, such as Ser127/Ser128/Tyr357/Ser94 phosphorylation, K48-linked poly-ubiquitination, K63-linked poly-ubiquitination, small ubiquitin-like modifier (SUMO)ylation, glycosylation, etc. (label next to the connecting lines in details). In particular, several specific environmental factors that trigger these PTMs are also highlighted with light-gray boxes. The solid arrows directed toward YAP/TAZ proteins are schematically designed on the basis of the activating or inhibitory effects of specific PTMs on their transcriptional activity. Conversely, dashed arrows originating from YAP/TAZ indicate inhibitory effects on their nuclear translocation. Of note, it is in Hippo-independent manners that the kinases directly point at YAP/TAZ, while the regulation through LATS1/2 or MST1/2 is in Hippo-dependent manners. Furthermore, the YAP/TAZ-TEAD targeting agents are also presented in the light-gray box. Section B details the functional mechanisms of YAP/TAZ PTMs, including nuclear/cytoplasmic degradation or stabilization, subcellular localization, and modulation of TFs affinity (organized into eight modules). Molecules are grouped by functional categories with corresponding PTM patterns annotated next to them. Section C examines regulatory crosstalk between PTM types, where left-sided modifications directly enhance or suppress right-positioned modification states. The graphic was created by Adobe Illustrator

The PTMs of YAP/TAZ: advances and opportunities

Protein posttranslational modifications (PTMs) refer to the covalent attachment of functional groups, such as chemical groups and polypeptide chains, onto substrate proteins [65]. In addition, it includes the proteolytic cleavage of peptide backbones via proteases or autocatalysis. PTMs can regulate substrates’ stability, location, and molecular interactions, and thus increase their functional diversity. Uncovering PTMs of crucial molecules can improve our understanding of pathophysiology, and facilitate the identification of new biomarkers. Directing interventions toward PTMs offer novel therapeutic opportunities. Unique PTMs, patterns of some proteins can be observed in certain illnesses or in a subset of patients, which indicates the possibility of precision therapy.

Many studies have shown that YAP/TAZ dynamically undergo PTMs including phosphorylation, ubiquitination, acetylation, and methylation. Recent studies have deepened our knowledge of these classical PTMs, and identified some novel PTMs such as SUMOylation, glycosylation, lactylation, and Interferon-stimulated gene (ISG)ylation of YAP/TAZ. In this review, we provide a summary of PTMs of YAP/TAZ and highlight potential target spots (Fig. 2).

Fig. 2.

Summary of PTM sites on YAP/TAZ. Sites of phosphorylation, ubiquitination, acetylation, methylation, SUMOylation, lactylation, N-GlcNAylation, O-GlcNAylation, and S-glutathionylation YAP/TAZ are shown. N and C indicate the N- and C- terminal end of the protein. The graphic was created with https://ibs.renlab.org

Phosphorylation

Protein phosphorylation is a crucial posttranslational modification in which phosphate groups from adenosine triphosphate (ATP) or guanosine triphosphate (GTP) are transferred to serine, threonine, or tyrosine residues of proteins through the catalysis of protein kinases. It can alter the conformations and activity of key proteins, and thus participate in regulating many cellular processes. On the basis of the preference to amino acid substrate, protein kinases can be classified as tyrosine kinases, serine/threonine kinases, and dual (Ser/Thr and Tyr) kinases [66]. Phosphatases can hydrolyze the phosphate group from substrate proteins and thus reverse phosphorylation. Many enzymes are identified to phosphorylate or dephosphorylate YAP/TAZ, and we summarize these in details below (Table 1).

Table 1.

Phosphorylation and dephosphorylation regulate YAP/TAZ activities and their functional implications

Name	Residues		Biological function	Physiological/pathological conditions	Model	Refs.
	YAP	TAZ
Phosphorylation
SRC	Y341/357/394		Promote nuclear localization	Promote cell proliferation and tumorigenesis	Keratinocytes allograft tumor mice and ApoE−/− mice	[106]
SRC	Y357		Promote nuclear localization	Promote NOK cell proliferation	Cell lines	[110]
SRC		S89	Promote TAZ cytoplasm localization		Cell lines	[114]
SRC				Confer trastuzumab resistance to HER2+ BCa	Xenograft nude mice	[109]
YES	Y357		Promote nuclear localization	Inhibit osteoblast activity	Cell lines	[111]
YES	Y391/407		Promote nuclear localization	Promote HCCb progression	Diethylnitrosamine-induced HCCb and orthotopic tumor mice	[112]
YES	Y357		Promote nuclear localization	Promote cancer cell proliferation	Colon epithelial organoids	[113]
LCK	Y357		Promote nuclear localization	Promote the pathogenesis of CCAc	CCAc PDX mice	[101]
ZAP70	Y357		Promote nuclear localization	Promote the cell softness of cytotoxic T lymphocytes	Transgenic mice model	[103]
FAK	Y357		Promote nuclear localization	Promote cell proliferation and tumorigenesis in iCCAd	AKT/YAP-induced iCCAd Fakf/f mice and K14CreER crossed mice	[104]
Abl	Y357		Promote TFs affinity (P73)	Promote atherosclerosis	YAP transgenic mice (EC-YAPtg)	[115]
FRK	Y391/407/444		Promote YAP degradation	Inhibit glioma cell growth	Intracranial nude mouse model	[75]
RTKs	Y391/407/444	Y305/321	Enhance YAP/TAZ stability	Promote tumorigenesis and metastasis	Cell lines	[78]
EphA2	Y357		Enhance YAP stability	Promote proliferation, migration, and chemoresistance of GCe cell	Cell lines	[79]
???	Y188		Inhibit the affinity to PTPN14	Inhibit BC proliferation and migration	Cell lines	[123]
LATS	S127/381	S89/311	Promote YAP/TAZ degradation	The core component of Hippo	Cell lines	[67, 70]
CK1	S384/387	S314	Promote YAP/TAZ degradation	Promote proliferation and metastasis of PCf	Cell lines	[69, 71]
NDR	S127		Promote cytoplasm localization	Inhibit colon carcinogenesis	Dextran sulfate sodium-induced CRCg mice	[72]
MAP3K3	S405		Inhibit YAP degradation	Promote resistance to BRAF inhibitor in BC	Xenograft tumor immunocompromised mice	[80, 81]
NLK	S128		Interfere YAP-S127 phosphorylation	Enhance cellular stress adaption	Cell lines	[46]
NLK	S128		Promote nuclear localization		Drosophila	[60]
NLK	S128		Promote nuclear localization	Promote downstream anabolic gene expression in normal human primary chondrocytes	Primary chondrocyte isolation	[73]
JNK	S317/T362			Promote apoptosis	Cell lines	[118]
AMPK	S61/94		Inhibit TF affinity (TEAD)	Inhibit the oncogenic potential	MEF xenograft nude mice	[48]
AMPK	T119/S61/94		Inhibit TF affinity (TEAD)	Inhibit cell growth in colon and liver cancers	Fasting mice	[49]
TSSK1B	S94		Promote TF affinity (TEAD)	Negatively regulate tumorigenesis	Xenograft nude mice	[117]
GSK3β		S58/62	Promote TAZ degradation	Inhibit cell proliferation in BC	Cell lines	[74]
NEK1	S163/164		Inhibit YAP degradation		Cell lines	[82]
NEK2	T143		Inhibit YAP degradation	Promote proliferation and migration of ESCCg	Xenograft tumor mice	[83]
IKKε	S403		Promote YAP lysosome degradation	Enhance innate antiviral response	VSV/HSV infectious mice	[77]
mTORC2	S436		Promote nuclear localization	Promote proliferation, motility, and invasiveness of glioblastoma	Xenograft tumor mice	[86]
mTORC2			Enhance YAP stability	Regulate YAP protein level	Wild-type (WT) FVB/N mice Rictorfl/fl mice	[88]
MARK2/3			Interfere the formation of YAP/TAZ-14–3-3 complexes	Promote cancer cell proliferation	TRE3G-MKIWT/MUT-PGK-rtTA3 cancer cells subcutaneously NSG mice	[84]
TAK1*			Promote YAP degradation	Inhibit cartilage degradation	Surgically induced osteoarthritic condition in Mst1f/f; Mst2f/f; Col2a1-Cre mutant mice	[76]
CDK1	S289/T119			Promote tumorigenesis and resistance to anti-tubulin drugs	Cell lines	[119, 120]
CDK8	T119/S128/289/367			Promote cells proliferation and migration in colon cancer	Xenograft tumor nude mice	[121]
CDK7	S127/397		Enhance YAP stability	Maintain stemness-associated properties of ESCC	Xenograft tumor nude mice	[93]
ULK	S227		Enhance YAP stability	Promote hypoxic glycolysis and tumorigenesis of PC	the KPC (Pdx1-Cre; LSL-KrasG12D/+; Trp53fl/+) mice	[95]
Aurora A	S397		Enhance YAP stability	Promote tumorigenesis and migration of lung cancer	cell lines	[90, 91]
MST4	T83		Inhibit nuclear import	Suppress tumorigenesis	Xenograft tumor mice	[99]
PRP4K			Promote nuclear export	Inhibit the growth of TNBCh	PRP4KEY11156 mutant Drosophila	[100]
Dephosphorylation
PTPN14	Y357		Promote cytoplasm localization	Retard atherosclerosis	Mice of ApoE−/− , LDLR−/−	[122]
PP1A/PPP1CA	S127/109		Inhibit YAP degradation	Advancement of CRCi	Xenograft tumor nude mice	[126]
		S89/311	Inhibit TAZ degradation	EMTj	Cell lines	[125]
PP2A	S127/381			Promote PC growth	Cell lines	[127]
PP2A				Regulate mammalian epimorphic ear regeneration	Acomys and mus mice	[128]

^aBreast cancer

^bHepatocellular carcinoma

^cCholangiocarcinoma

^dIntrahepatic cholangiocarcinoma

^eGastric cancer

^fPancreatic cancer

^gEsophageal squamous cell carcinoma

^hTriple-negative breast cancer

ⁱColorectal cancer

^jEpithelial-to-mesenchymal transition

LATS determines YAP/TAZ fate: the classical paradigm

Hippo core kinases LATS1/2 can phosphorylate YAP at Ser127 and Ser381 [67], as well as other serine in the HXRXXS motifs (such as Ser61, Ser109, and Ser164) [68], and restrain it in the cytoplasm through binding with 14-3-3. Notably, the phosphorylation of Ser127 contributes the most to this process. Following LATS-mediated phosphorylation, CK1δ/ε phosphorylate YAP on Ser384 and Ser387. This modification enhances the proteasome-mediated degradation of YAP by increasing its interaction with the ubiquitin ligase beta-transducin repeat-containing protein (β-TRCP) [69]. Like YAP, TAZ can be phosphorylated by LATS at Ser89 and Ser311 [70]. Then, CK1ϵ phosphorylates TAZ at Ser314 and enables β-TRCP-mediated degradation of it [71]. As the closest homolog of LATS, Dbf2-related protein kinase (NDR) can also phosphorylate YAP at Ser127 and inactivate it by promoting its cytoplasm retention in a LATS-independent manner, which suppresses colon carcinogenesis [72].

Although the phosphorylation at Ser127 of YAP is necessary for its degradation, two groups of researchers have independently demonstrated that Nemo-like kinase (NLK) blocks this process through phosphorylation at Ser128 [46, 60]. This phosphorylation is downregulated by high cell density and upregulated by osmotic stress and it interferes with Ser127 phosphorylation, enhancing YAP nuclear translocation. Anabolic stimuli also promote YAP phosphorylation at Ser128 through NLK, thereby promoting YAP nuclear translocation and downstream anabolic gene expression in normal human primary chondrocytes [73].

Phosphorylation regulates YAP/TAZ stability

Although the regulation of YAP/TAZ by the canonical Hippo signaling pathway is well established, recent studies have demonstrated that phosphorylation mediated by other kinases regulates their degradation through a LATS-independent mechanism. For example, in cancer cells with a dysregulated PI3K/AKT pathway, Glycogen synthase kinase 3 beta (GSK3β) can phosphorylate TAZ at Ser58 and Ser62 to decrease its stability by increasing its β-TRCP-mediated degradation [74]. In glioma cells, Fyn-lated Src family tyrosine kinase (FRK) has been shown to phosphorylate YAP at Tyr391/407/444 [75]. This phosphorylation facilitates the interaction between YAP and E3 ligase Siah1, and promotes the ubiquitination and degradation of YAP in the cytoplasm, thereby inhibiting the gene transcription and glioma cell growth. Moreover, mitogen-activated protein kinase kinase kinase 7 (MAP3K7, also known as TAK1) can directly phosphorylate YAP and promote its β-TRCP-mediated degradation when triggered by inflammatory cytokines [76]. The degradation of YAP increases the affinity of TAK1 to IKKα/β and thus promotes NF-κB signaling-mediated inflammation, ultimately exaggerating cartilage degradation during osteoarthritis [76].

However, not all phosphorylation link to the ubiquitin–proteasome-mediated degradation of YAP/TAZ, while they could also be degraded in a lysosome-mediated pathway. IKKε is a member of the inhibitor of kappa B kinase (IKK) kinase family, which serves as a crucial regulator of innate immunity and inflammation by modulating the activities of the transcription factors NF-κB and IRF3 [77]. Virus-activated IKKε has been shown to phosphorylate YAP at Ser403, promoting its lysosome-mediated degradation [77]. This inhibits the negative regulation exerted by YAP on IRF3 dimerization and translocation to the nucleus, thereby enhancing antiviral immune responses.

Besides, several receptor tyrosine kinases (RTKs) are reported to take responsibility for the phosphorylation of YAP/TAZ and promote their stability, though the complete explanation of the mechanism has not been fully provided in methodology. In detail, Azad et al. screened an RTK library and found that fibroblast growth factor receptor (FGFR) phosphorylates YAP at Tyr391/407/444 and TAZ at Tyr305/321, while both proto-oncogene tyrosine-protein kinase receptor Ret (RET) and tyrosine-protein kinase Mer (MERTK) only phosphorylate YAP at Tyr444 [78]. The YAP/TAZ is demonstrated to be central mediators of these RTKs-regulated tumorigenesis and metastasis [78]. In addition, RTK erythropoietin-producing hepatocellular receptors (EphA2) can phosphorylate YAP at Tyr357 to enhance its stability and transcriptional activity, which induces tumor proliferation, migration, and chemoresistance of GC cells [79].

Notably, phosphorylation in other patterns can conversely stabilize YAP/TAZ by impeding their degradation. For instance, mitogen-activated protein kinase kinase kinase 3 (MAP3K3) interacts with YAP and phosphorylates it at Ser405 [80, 81]. This prevents the binding of YAP to E3 ligase FBXW7 and decreases its lysosome-mediated degradation. Suppressing the MAP3K3–YAP axis overcomes the resistance of luminal BC cells to targeted agents CDK4/6 inhibitor and BRAF inhibitor effectively [80, 81]. Moreover, NIMA-related kinase 1/2 (NEK1/2) respectively phosphorylates YAP at Ser163/164 [82] and Thr143 [83]. These phosphorylation patterns inhibit the ubiquitin-mediated degradation of YAP, and the migration and proliferation of cancer cells are promoted. Recently, Klingbeil et al. identified a crucial role for microtubule affinity-regulating kinase 2/3 (MARK2/3) in facilitating the activity of YAP/TAZ across a diverse range of human carcinomas and sarcomas [84]. MARK2/3 catalyze YAP/TAZ phosphorylation directly and suppress the upstream components of the Hippo pathway. As a result, they interfere with the formation of YAP/TAZ–14-3-3 complexes, which blocks the ubiquitin-mediated degradation pathway, and ensures the transcriptional activity of YAP/TAZ for cancer cell proliferation [84]. Interestingly, the CagA protein from Helicobacter pylori, a catalytic inhibitor of MARK2/3, leads to severe compromise of tumor growth in vivo [84]. Nevertheless, the YAP and β-catenin can synergistically promote H. pylori-induced gastric carcinogenesis through physical interaction [85].

Mechanistic target of rapamycin complex 2 (mTORC2) is important for enhancing the stability of YAP, which has been highly concerned in recent years. In detail, mTORC2 can directly phosphorylate YAP at Ser436 to stabilize it and increase its nuclear expression [86]. Meanwhile, mTORC2 can also activate YAP indirectly via inhibiting AMOT-mediated cytoplasmic retention of YAP [87]. As a result, the expression of YAP targeted genes is promoted, leading to the enhancement in proliferation and invasion of glioblastoma cells. Moreover, the activation of mTORC2 by HBV oncoprotein X (HBx) cascade can also inhibit YAP degradation, thus forming a counterbalance with Hippo regulation of YAP in a Hippo-independent manner [88]. Therefore, targeting mTORC2 with inhibitors of its core component mTOR, such as everolimus and ridaforolimus, may offer therapeutic potential for diseases driven by mTORC2/YAP pathway [89].

While cytoplasmic kinase-mediated regulation of YAP/TAZ is well documented, recent studies further reveal that phosphorylation events occurring at the nuclear level regulate their stability through distinct mechanisms. Aurora kinase A (AURKA), a member of the Aurora proteins, which play a vital role in regulating cell proliferation in the nucleus, is demonstrated to phosphorylate YAP at Ser397 to boost its transcriptional activity in triple-negative breast cancer (TNBC) cells [90]. In lung cancer cells, it increases YAP protein abundance through blocking autophagy [91]. As a result, the proliferation and migration of cancers are promoted. In addition, inhibiting the AURKA/YAP axis with alisertib, an AURKA antagonist, effectively restores the sensitivity of CRC cells to cetuximab and suppresses their stem cell phenotype [92]. Similarly, in esophageal squamous cell carcinoma (ESCC) [93], cyclin-dependent kinase 7 (CDK7) phosphorylates YAP at Ser127 and Ser397 in the nucleus and promotes its expression, enhancing its transcriptional activity to maintain the self-renewal and proliferative potential of cancer cells. This result is inconsistent with that of AURKA, implying that the phosphorylation of Ser397 is related to the stabilization of YAP in the nucleus. In addition, upon hypoxia stimulation, serine/threonine kinase Unc-51-like kinases1/2 (ULK1/2) [94] are activated and translocate into the nucleus, which stabilizes YAP by phosphorylating its Ser227 [95]. This phosphorylation not only counteracts the poly-ubiquitination degradation of YAP but also induces the interaction between YAP and HIF-α, and ultimately activates the transcription of PKM2, the rate-limiting enzyme responsible for glycolysis, to elevate energy support in pancreatic ductal adenocarcinoma (PDAC) cells.

Over the past two decades, advances in understanding protein kinase-mediated phosphorylation have translated into numerous clinical applications [66], as exemplified by FGFR inhibitors (e.g., pemigatinib and erdafitinib) [96] and RET inhibitors (e.g., selpercatinib and pralsetinib) [97]. These protein kinase inhibitors probably have unique application value in protein kinases-YAP/TAZ cascade-driven diseases. However, multitarget protein kinase inhibitor lenvatinib has been reported to cause endothelial ferroptosis and enhance hypertension incidence [98] by inhibiting YAP nuclear translocation. This underscores the need for deeper mechanistic studies elucidating YAP/TAZ-kinase inhibitor interactions prior to clinical implementation.

Phosphorylation regulates YAP/TAZ subcellular localization

Phosphorylation regulates the nuclear–cytoplasmic shuttling of YAP/TAZ dynamically, dictating their functional outcomes. For example, in gastric cancer, MST4 directly phosphorylates YAP at Thr83 and inhibits its nuclear import [99]. This noncanonical MST4 signaling inactivates YAP in a Hippo-independent manner and suppresses the tumorigenesis. Moreover, a subset of LATS phosphorylating sites is phosphorylated by serine/threonine-protein kinase PRP4 (PRP4K), and it inhibits the growth of TNBC by promoting nuclear export of YAP [100].

Intriguingly, abundant studies reported that the phosphorylation of YAP at Tyr357 contributes to its nuclear retention. For example, lymphocyte cell-specific protein-tyrosine kinase (LCK) is reported to phosphorylate YAP on Tyr357 and promotes its nuclear retention in cholangiocarcinoma (CCA) cells [101]. The further study demonstrated a LCK inhibitor NTRC 0652-0, which shows great preclinical efficacy in CCA cell lines [102]. Additionally, in TCR signaling, ZAP-70 (ZAP70) also phosphorylates Yes-associated protein (YAP) at Tyr357, triggering its activation, which contributes to the cell softness of cytotoxic T lymphocytes and thus confers resistance to perforin-mediated killing [103]. Moreover, the phosphorylation of YAP at Tyr357 can be directly triggered by focal adhesion kinase (FAK), which stabilizes its nuclear localization and enhances Akt/Jag1 gene transcription in intrahepatic cholangiocarcinoma (iCCA) cells, thereby promoting cell proliferation and tumorigenesis [104]. Besides, FAK can regulate YAP’s activity in stem cells or their proliferative descendants via CDC42 and phosphatase PP1A in parallel with the canonical Hippo pathway [105].

Furthermore, the role of proto-oncogene Src (SRC) in YAP nuclear localization has received considerable attention in recent years. In detail, integrin β4 signaling-activated SRC phosphorylates YAP at Tyr341/357/394 in keratinocytes in a canonical Hippo-independent manner [106]. This phosphorylation is crucial for YAP’s nucleus import and its interaction with TEAD. Cell adhesion protein αE-catenin downregulates the integrin–SRC–YAP cascade, and thus disrupts the malignant transformation of keratinocytes to inhibit skin squamous cell carcinoma [106]. Notably, latent membrane protein 1 from Epstein–Barr virus enhances YAP activity in oral keratinocytes by activating the SRC–YAP cascade [107]. Ibrutinib, an Src family kinases (SFKs) inhibitor [108], suppresses YAP activity successfully in these keratinocytes to reinstate their spontaneous differentiation and suppress their proliferation [107]. Moreover, in human epidermal growth factor receptor 2 (HER2)-positive BC, SRC-catalyzed YAP phosphorylation facilitates the assembly of YAP/TF complex to enhance the expressions of genes related to cell stemness and survival [109]. Therefore, the SRC–YAP cascade contributes to the trastuzumab (a monoclonal antibody targeting HER2) resistance of these cancer cells, and verteporfin effectively relieves the therapy resistance. Curaxin CBL0137, an anticancer compound, has recently been shown to decrease YAP Tyr357 phosphorylation via interrupting SRC, hence helping to alleviate endothelial inflammation and atherogenesis [110]. In osteoblasts, the proto-oncogene Src/tyrosine-protein kinase yes (SRC/YES) is found to phosphorylate YAP and determine its subnuclear distribution without affecting its nucleo-cytoplasmic trafficking [111]. The activation of SRC/YES-YAP axis in these cells enhances the interaction between YAP and TF Runx2 to attenuate osteocalcin gene expression and inhibit osteoblast activity. In addition, Yes-mediated phosphorylation of YAP at Tyr391/407 is found to promote the nuclear accumulation of YAP to some extent, and lead to HCC progression [112]. Besides, in Wnt/β-catenin signaling-driven cancer cells, YES also phosphorylates YAP at Tyr357. This phosphorylation is necessary for the formation and nuclear localization of YAP/β-catenin complex, which increases the transcriptional activities of YAP and enhances the proliferation of cancer cells, the growth of colon epithelial organoids, and the intestinal hyperplasia [113].

The specific phosphorylation pattern governing TAZ subcellular localization remains largely uncharacterized. A single study in basal BC cell lines illustrated that SRC mediates the phosphorylation of TAZ at Ser89 but induces its cytoplasmic sequestration upon hypoxia stimulation [114]. While the phosphorylation of YAP at Tyr357 has been well documented to drive nuclear retention, analogous regulatory phosphorylation events in TAZ warrant systematic exploration.

Phosphorylation regulates YAP/TAZ TF affinity

Phosphorylation can directly control the transcriptional activity of YAP/TAZ via regulating their affinity to TFs. For example, AMPK served as a key responder to energy stress and can directly phosphorylate Ser61, Ser94, and Thr119 of YAP [48, 49]. This phosphorylation breaks the binding between YAP Ser94 and TEAD Tyr406, and suppresses the expression of YAP’s target genes including glucose-transporter 3, resulting in the inhibition of the glycolysis and oncogenic transformation of cells. Moreover, Abelson tyrosine-protein kinase 1 (ABL) member c-Abl is found to phosphorylate YAP on Tyr357 in response to irradiation- or cisplatin-induced DNA damage [115]. This phosphorylation increases the interaction between YAP and TF p73, and preferentially promotes the expression of pro-apoptotic genes. In oscillatory shear stress-treated endothelial cells, integrin α5β1 signaling activates the c-Abl–YAP pathway and enhances the transcriptional activity of YAP on inflammatory genes ICAM-1 and VCAM-1 [116], which promotes endothelial atherogenic responses. Administering integrin α5β1-blocking peptide or tyrosine kinase inhibitor to ApoE−/− mice postponed the onset of atherosclerosis (AS) [116]. In addition, after upstream kinase LKB1-mediated activation, testis-specific kinase 1 (TSSK1B) phosphorylates YAP Ser94 to disrupt the YAP-TEAD interaction in HEK293A cells [117]. Besides, TSSK1B can also promote LATS1/2-mediated Ser127 phosphorylation of YAP and increase its cytoplasmic retention. In these ways, TSSK1B inhibits the transcriptional activity of YAP and negatively regulates tumorigenesis.

In addition, multiple phosphorylation sites and their cognate kinases have been identified in some original research, although their regulatory mechanisms governing the functional consequences of YAP/TAZ remain unclear. For example, in ultraviolet (UV)-treated cells, c-Jun N-terminal kinase (JNK) phosphorylates YAP’s Ser317 and Thr362 [118], which results in enhanced expression of pro-apoptosis genes. Moreover, other cyclin-dependent kinases (CDK) such as CDK1 and CDK8 have been reported to take responsibility for the phosphorylation of YAP/TAZ. In detail, CDK1 can phosphorylate YAP at Ser289 and Tyr119, which can lead to mitotic defects to contribute to tumorigenesis [119] and inhibit anti-tubulin drug-induced apoptosis of cancer cells [120]. In colon cancer, CDK8 directly phosphorylates YAP at Thr119/Ser128/Ser289/Ser367, which promotes YAP activation and the proliferation and migration of cancer cells [121].

Dephosphorylation

As the reverse process of phosphorylation, dephosphorylation catalyzed by phosphatases also significantly influences the activity of YAP/TAZ. Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) can dephosphorylate Tyr357 on YAP directly to stabilize it in the cytoplasm and thus downregulates its transcriptional activity [122]. This blunts the activation of shear stress-induced endothelial cell (EC) and retards the development of atherogenesis. Of note, the affinity of YAP to PTPN14 is downregulated by Tyr188 phosphorylation in BC cells, which indicates the existence of dynamic competition between phosphorylation and dephosphorylation, although the underlying mechanisms warrant further researches [123]. Harmine is an extract of Peganum harmala that can enhance the expression of PTPN14 by inhibiting its degradation [122]. Its potential in treating PTPN14/YAP/TAZ-related diseases deserves further evaluation.

Protein phosphatase (PPP) is a Ser/Thr phosphatase superfamily that shares common catalytic mechanism. Its members include PP1, PP2A, PP2B, and PP4-7 [124]. Among them, PP1 and PP2A show enzymatic activity to YAP/TAZ. PP1 catalytic subunit alpha (PP1A, or called PPP1CA) is the main catalytic subunit of PP1. It can dephosphorylate TAZ at Ser89 and Ser311 [125], stabilize TAZ by interfering with its binding to SCF E3 ubiquitin ligase, and stimulate TAZ nuclear translocation, hence stimulating cell growth and EMT. Similarly, it facilitates the dephosphorylation of YAP at Ser127 and Ser109 [126], enabling YAP to translocate into the nucleus and subsequently drive the expression of oncogenes associated with CRC development. PP2A has been shown to regulate YAP activity both directly and indirectly. Its regulatory subunit PR55 can dephosphorylate YAP directly, which promotes the transcription of oncogenes to enable the growth of pancreatic cancer cells [127]. The direct regulation of PP2A on YAP is also observed in wound healing models [128]. In addition, PP2A is reported to downregulate the activities of LATS1/2 in cancer cells [127] and that of MST1/2 in tumor-associated macrophages [129].

Ubiquitination

Ubiquitin (Ub) is an evolutionarily conserved 76-amino-acid peptide. Protein ubiquitination is a PTM in which the C-terminal end of Ub is covalently attached to proteins’ lysine residues through the sequential catalysis of ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-ligating enzymes (E3 ubiquitin ligase) [130]. In addition, serine, threonine [131], and cysteine [132] residues on some proteins can undergo ubiquitination as well.

Ub has seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and an N-terminal methionine residue (M1). These residues can be further attached by other Ub molecules’ C-terminal end. Therefore, on the residue of the substrate, the modification pattern can be divided into several forms: mono-ubiquitination (where a single ubiquitin molecule is attached to one lysine residue on the target substrate), multi-ubiquitination (where multiple ubiquitin molecules are attached to different lysine residues on the same target substrate, each as a monomer), and poly-ubiquitination (where a chain of ubiquitin molecules is formed and attached to one lysine residue on the target substrate). In some cases, poly-ubiquitin chains exhibit branching, where a single ubiquitin within the chain is connected to two or more ubiquitins via different lysine residues [133]. The ubiquitination pattern affects the biological outcomes of substrates. For example, K48-linked poly-ubiquitination generally represents a degradation signal, while mono-ubiquitination and K63-linked poly-ubiquitination usually affect protein interactions and substrates’ trafficking [134]. The substrate selection during ubiquitination and the ubiquitination pattern are mainly determined by E3 ubiquitin ligases [135].

Deubiquitination is the reverse process of ubiquitination, which removes Ub monomers or Ub chains from the substrate and is catalyzed by deubiquitinating enzymes (DUBs) [130]. The DUBs are classified into seven families: ubiquitin-specific proteases (USPs), ovarian tumor domain-containing or otubain proteases (OTUs), Machado–Joseph disease protein domain proteases (MJDs), ubiquitin carboxyl-terminal hydrolases (UCHs), motif interacting with ubiquitin-containing novel DUB (MINDYs), Zn finger and UFSP domain protein (ZUP), and JAMM/MPN domain-associated metallopeptidases (JAMMs) [136].

Recent studies have demonstrated that ubiquitination and deubiquitination dynamically regulate YAP/TAZ stability, subcellular localization, and functional activity, directly contributing to the pathogenesis of diverse diseases (Table 2).

Table 2.

Ubiquitination and deubiquitination regulate YAP/TAZ activities and their functional implications

Name	Residues		Biological function	Physiological/pathological conditions	Model	Refs.
	YAP	TAZ
Ubiquitination
SCF β-TRCP			Promote YAP/TAZ degradation	The core component of Hippo	Cell lines	[69, 71]
CRL4 DCAF12			Promote YAP/TAZ degradation	Decrease the expression of target genes of Hippo	Xenograft tumor NSG mice	[149]
Siah1			Promote YAP degradation	Inhibit the proliferation and migration of glioma	Intracranial nude mouse model	[75]
SHARPIN			Promote YAP degradation	Inhibit the invasion and migration of ESCCa	Cell lines	[163]
SCF Fbxw7			Promote YAP degradation	Promote the cell apoptosis and growth arrest of HCCb	Hep3B cell xenograft nude mice	[161]
RNF31	K76		Promote YAP degradation	Inhibit the cell progression and immune evasion of TNBCc	Xenograft tumor nude mice	[137]
RNF187			Promote YAP degradation	Inhibit the migration and invasion of TNBC	Cell lines	[164]
RNF187			Promote YAP degradation	Inhibit the migration and invasion of ESCC	Cell lines	[165]
RBCK1	K76/204/321		Promote YAP degradation	Inhibition and cell apoptosis of TNBC	MDA-MB-231 cell xenograft BALB/c nude mice and original MCF-7 human epithelial breast cancer cell	[138]
PARK2	K90		Promote YAP degradation	Inhibit the progression of ESCC	Xenograft tumor nude mice	[139]
MIB2			Promote YAP degradation	Inhibit angiogenesis	EC-Fat1-KO mice	[175]
ITCH			Promote YAP degradation	Inhibit the metastasis of CRCd	Subcutaneous xenograft and metastasis nude mice	[166]
UBR4			Promote YAP degradation	Inhibit endometrial fibrotic progression	Isolation and culture of MenSCs and EndoSCs	[176]
TRIM15	K254		Promote nuclear localization	Drives chondrocyte senescence and osteoarthritis progression	Trim15 cKO mice	[185]
SCF SKP2	K321/497		Promote nuclear localization	Regulate BCe	Xenograft tumor NSG mice	[183]
SCF SKP2			Promote nuclear localization	Promote the progression of tubulointerstitial fibrosis	jck eIF2α+/SA mice	[182]
TRAF6	K252		Promote nuclear localization	Boost atherosclerosis	YAP transgenic mice (YapTg−flox or Yapflox/−)	[180]
TRAF6	K497		Increase TFs affinity	Promote PD-L1 transcription in melanoma	Melanoma lung metastasis C57BL/6 mice	[181]
TRIM11			Enhance YAP stability	Promote the proliferation, migration, and chemoresistance of ATCf	Xenograft tumor BALB/c athymic nude mice	[153]
Deubiquitination
OTUD1			Inhibit YAP nuclear translocation	Confer erlotinib sensitivity in NSCLCg	Xenograft tumor nude mice	[184]
OTUD1	K321/497		Inhibit YAP nuclear translocation	Regulate BC	Xenograft tumor NSG mice	[183]
JOSD2			Enhance YAP/TAZ stability	Promote the tumor progression of CCAh	CCA PDX nude mice	[159]
OTUB2			Enhance YAP/TAZ stability	Promote the stemness and metastasis of BC	Xenograft tumor nude mice	[171]
OTUB2			Enhance YAP/TAZ stability	Promote the vascular calcification in CKDi	Induction of VC in C57BL/6J mice	[178]
USP9X			Enhance YAP stability	Promote the proliferation and chemoresistance of BC	Xenograft tumor athymic nu/nu mice	[174]
USP7	K90		Enhance YAP stability	Promote the tumorigenesis of HCC	Fg-usp7-CA, Fg-usp7-ΔMATH, Fg-hausp, and UAS-yki-1w transgenic flies	[150]
USP47			Enhance YAP stability	Promote the progression of CRC	Cell lines	[157]
USP40	K252/315		Enhance YAP stability	Promote the proliferation, metastasis, and invasion of HCC	Xenograft tumor nude mice	[142]
USP36			Enhance YAP stability	Promote the proliferation and metastasis of ESCC	Xenograft tumor nude mice	[167]
USP19	K76/90		Enhance YAP stability	Promote the proliferation and invasion of HCC	Xenograft tumor nude mice	[141]
USP15			Enhance YAP stability	Proliferation and migration of PASMCj	Sham, SuHx-PH, SuHx-PH + NCsh-1-p, SuHx-PH + mUSP15-sh1-p, and SuHx-PH + mUSP15-sh2-p mice	[177]
USP12	K315		Enhance YAP stability	Promote the growth and migration of GC	Xenograft tumor nude mice	[140]
USP10			Enhance YAP stability	Promote the proliferation of HCC	HCC PDX immunodeficient mice model	[154]
USP10			Enhance YAP stability	Promote the immune escape and metastasis of PCk	Xenograft tumor nude mice	[172]
UCHL3			Enhance YAP stability	Promote the progression, stemness, and metastasis of ATC	Xenograft tumor nude mice	[173]
OTUD7B			Enhance YAP stability	Promote the migration and invasion of GCl	Xenograft tumor nude mice	[160]
OTUB1	K90/280/343/494/497		Enhance YAP stability	Promote the proliferation and metastasis of GC	Xenograft tumor NSG mice	[143]
JOSD1			Enhance YAP stability	Promote the growth of colon cancer	Xenograft tumor nude mice	[158]
EIF3H			Enhance YAP stability	Promote the invasion and metastasis of BC	4T1 cell xenograft Balb/C mice and MDA-MB-231 cell xenograft nu/nu mice	[170]
CYLD			Enhance YAP stability	Inhibit proliferation and enhance the sensitivity to cell ferroptosis of PCam	Xenograft tumor nu/nu mice	[162]
ATXN3			Enhance YAP stability	Promote the tumor progression of PCa and BC	Cell lines	[168]
ATXN3			Enhance YAP stability	Promote the progression of PCa	Xenograft tumor nude mice	[169]
USP7			Enhance YAP stability	Promote the proliferation, migration, and invasion of HNSCCn	HNSCC xenograft nude mice and PDX nude mice	[151]
USP36			Enhance TAZ stability	Promote the progression of GC	Xenograft tumor nude mice	[152]
USP26			Enhance TAZ stability	Promote the growth and migration of ATC	Xenograft tumor nude mice	[156]
USP14			Enhance TAZ stability	Promote the tumor growth and liver metastasis of PC	Xenograft tumor nude mice	[155]
USP1			Enhance TAZ stability	Promote OS15 growth and metastasis	143B stable cell orthotopic/subcutaneous xenograft nude mice	[146]
USP1			Enhance TAZ stability	Promote HCC progression	Xenograft tumor nude mice	[145]
USP1		K45/46	Enhance TAZ stability	Promote the proliferation and migration of TNBC	shControl or shUSP1 MDA-MB-231 cell xenograft SCID mice	[144]
USP1			Enhance TAZ stability	Accelerate the development of inflammatory diseases	C57BL/6, Usp1fl/fl, Usp1CKO, Tazfl/fl, TazCKO, and Usp1CKOTazCKO mice	[147]
PSMA1		K214	Enhance TAZ stability	Promote the proliferation, migration, and invasion of GC	Xenograft tumor thymus-null BALB/c nude mice	[148]

^aEsophageal squamous cell carcinoma

^bHepatocellular carcinoma

^cTriple-negative breast cancer

^dColorectal cancer

^eBreast cancer

^fAnaplastic thyroid cancer

^gNon-small cell lung cancer

^hCholangiocarcinoma

ⁱChronic kidney disease

^jPulmonary artery smooth muscle cells

^kPancreatic cancer

^lGastric cancer

^mProstate cancer

ⁿHead–neck squamous cell carcinoma

^oOsteosarcoma

Ubiquitination and deubiquitination regulate YAP/TAZ stability

Several E3 ligases have been reported to catalyze the ubiquitination of YAP and promote its degradation. The E3 ligase RNF31 interacts with YAP and promotes its degradation by catalyzing poly-ubiquitination at Lys76 in TNBC cells [137]. This process inhibits TNBC cell growth, migration, and metastasis. Moreover, RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) binds to YAP and promotes its K48-linked poly-ubiquitination at Lys76, Lys204, and Lys321, leading to YAP degradation and facilitating cell apoptosis, thereby inhibiting the progression of TNBC [138]. E3 ligase Parkinson disease protein 2 (PARK2) catalyzes the K48-linked poly-ubiquitination of YAP at Lys90 [139]. Depleting PARK2 to increase the expression of YAP promotes the proliferation and invasion of ESCC cells effectively.

Many DUBs have been demonstrated to facilitate the deubiquitination of YAP and enhance its stability. USP12 can bind directly to and stabilize YAP by removing its K48-linked poly-ubiquitination at Lys315, which promotes the proliferation of GC cells [140]. USP19 interacts with and stabilizes YAP by inhibiting its K48-linked and K11-linked poly-ubiquitination at Lys76 and Lys90 in HCC, contributing to the proliferation and invasion of cancer cells [141]. Similarly, USP40 can associate with YAP in HCC cells and inhibit its degradation by removing K48-linked ubiquitin chain at Lys252 and Lys315. As a result, the proliferation, metastasis and invasion of cancer cell are significantly promoted. Interestingly, USP40 expression is transcriptionally stimulated by YAP. Thus, forming a positive feedback cycle of USP40/YAP [142]. OTUB1 also links to the YAP protein and decreases its ubiquitination at multiple lysine sites (Lys90, Lys280, Lys343, Lys494, and Lys497), thereby suppressing YAP degradation and driving the progression of GC [143].

Several lysine residues on TAZ that undergo ubiquitination and deubiquitination have been identified. For example, Lys45 and Lys46 of TAZ serve as primary deubiquitination targets catalyzed by USP1, whose activity promotes the proliferation of TNBC cells [144]. USP1 reduces TAZ proteasomal degradation by inhibiting its K11-linked and K29-linked poly-ubiquitination, which enables the expression of target genes of TAZ to promote the development of HCC and osteosarcoma (OS) [145, 146]. In addition, the USP1–TAZ axis downregulates Foxp3 expression in CD4⁺ T cells to boost the differentiation of Th17-cell, thereby disrupting the immune homeostasis during the development of inflammatory diseases [147]. Inhibiting USP1 with selective antagonist ML323 has shown significant effects in suppressing the development of OS and inflammation in animal models [146, 146]. The DUB PSMA1 directly interacts with TAZ and inhibits its K27-linked and K48-linked poly-ubiquitination at Lys214, hence stabilizing and activating TAZ, leading to GC cell proliferation and cancer development [148].

YAP/TAZ ubiquitination also occurs within the nuclear compartment. RL4^DCAF12 can target YAP/TAZ and mediate its ubiquitination and proteasomal degradation [149]. Therefore, CRL4^DCAF12 decreases the expression of YAP/TAZ target genes. Of note, CDK7-mediated phosphorylation on YAP/TAZ inhibits their interaction with CRL4^DCAF12 and blunts these effects. Moreover, USP7 directly binds to YAP/TAZ in the nucleus and stabilizes it by catalyzing its deubiquitination, thereby increasing its nuclear protein levels and transcriptional output to promote HCC tumorigenesis and head–neck squamous cell carcinoma (HNSCC) progression [150, 151]. In HCC, the ubiquitination of YAP at Lys90 is removed during this process. Inhibitor of USP7, such as P5091, can significantly inhibit the proliferation of these cancer cells. Additionally, USP36 (also known as DUB1) can bind to TAZ directly in the nucleus of GC cells, which reduces its K48-linked poly-ubiquitination, and increases its stability. As a result, the expressions of TAZ target genes are upregulated, which facilitates the stemness of GC cells and drives GC progression [152].

YAP/TAZ ubiquitination was also found to be regulated by many other enzymes across various diseases contexts, though the specific lysine residues involved remain uncharacterized. The typical example is the SCF^β-TRCP in the canonical Hippo pathway. SCF^β-TRCP targets YAP/TAZ for ubiquitination and proteasome-mediated destruction after LATS and CK1-mediated phosphorylation of YAP/TAZ in the cytoplasm [69, 71]. Emerging evidence establishes close associations between YAP/TAZ ubiquitination dynamics and human malignancies. We have systematically classified tumor phenotypes influenced by YAP/TAZ ubiquitination/deubiquitination processes, with the precise mechanistic basis summarized below.

Abnormal cell proliferation is closely associated to the growth of tumors. FRK interacts with and phosphorylates YAP, and then E3 ubiquitin ligase Siah1 catalyzes the ubiquitination of YAP and ultimately leads to its destruction, thus inhibiting the proliferation of glioma [75]. Although most E3 ligases catalyzes YAP/TAZ for degradation, the E3 ligase TRIM11 can bind to YAP and enhance its stability. It can inhibit the K11-/K48-linked poly-ubiquitination of YAP via promoting its mono-ubiquitination. As a result, the degradation of YAP is inhibited and anaplastic thyroid cancer cell proliferation is promoted [153]. The USP10 interacts with YAP/TAZ and stabilizes them by removing their poly-ubiquitin chains [154]. The upregulated YAP/TAZ increases the expression of genes related to cell proliferation and stemness in HCC cells. Moreover, USP14 eliminates the K48-linked ubiquitin chains on TAZ and stabilizes it in PDAC [155]. The upregulated expression of TAZ promotes the proliferation of these cancer cells. Notably, like the USP40/YAP positive feedback loop, there is a USP14/TAZ positive feedback loop in PDAC [155]. IU1 is a small molecule catalytic inhibitor of USP14. It prevents the growth and the metastasis of PDAC, which suggests that inhibiting USP14 would be a promising strategy for treating tumors with TAZ hyperactivation. USP26 eliminates the K48-linked ubiquitin chains on TAZ and stabilizes it in anaplastic thyroid cancer (ATC) [156]. USP47 facilitates YAP deubiquitination, and enhances its stability and transcriptional activity [157], which promotes its progression. Notably, USP47 inhibitor P5091 can promote the degradation of YAP, thereby attenuating the progression of cancers. Josephin domain-containing (JOSD) proteins 1 promotes colon cancer growth by inhibiting the YAP K48-linked poly-ubiquitination to increase Hippo/YAP activity. Additionally, YAP increases JOSD1 expression, suggesting the existence of a positive feedback loop between JOSD1 and Hippo signaling [158]. Similarly, JOSD2 is necessary for stabilizing YAP/TAZ protein by cutting poly-ubiquitin chains in CCA cells [159]. Downregulating the expression of JOSD2 leads to considerable inhibition of CCA cell proliferation. Moreover, OTUD7B stabilizes YAP by inhibiting its K48-linked poly-ubiquitination and thus increases downstream oncogene NUAK2 expression to induce the proliferation and metastasis of GC cells [160].

YAP/TAZ can also affect the apoptosis of cells. In hepatic cancer, another SCF ligases complex SCF^Fbxw7 can bind to YAP and mediate its ubiquitination and proteasomal degradation [161], which promotes HCC cell apoptosis and growth arrest. In prostate cancer, CYLD is also a USP family member that interacts with YAP and stabilizes YAP by catalyzing deubiquitination. Thus, the expression of downstream genes, including ferroptosis-related factors ACSL4 and TFRC, is increased, which facilitates the ferroptosis of prostate cancer cells [162].

Cell migration is an important phenotype associated with cancer metastasis. In esophageal squamous cell carcinoma, the E3 ligase SHARPIN is upregulated, and it enhances K48-linked poly-ubiquitination of YAP, thereby boosting YAP breakdown to inhibit cancer cell invasion and migration [163]. In breast cancers, RNF187 interacts with YAP and facilitates its K48-linked poly-ubiquitination and degradation, which hinders the migration and invasion of TNBC [164, 165]. In intestinal cancer, the E3 ubiquitin ligase ITCH plays important roles in the cancer metastasis through ubiquitination switching. Normally, ITCH mediates K63-linked poly-ubiquitination of receptor-interacting protein kinase 2 (RIPK2), activating NF-κB/MAPK pathways to drive metastasis. Upon RIPK2 inhibition, AMOT recruits ITCH to catalyze YAP degradation via K48-linked poly-ubiquitination, suppressing metastasis through Hippo pathway inactivation [166]. USP36 also reduces the K48-linked poly-ubiquitination of YAP, thus promoting the proliferation and metastasis of ESCC [167]. Ataxin-3 (ATXN3) has been identified as a potential oncogene in several human cancers [168]. ATXN3 is also discovered to eliminate the K48-linked ubiquitin chain on YAP, and thus increases its protein stability. Downregulating the ATXN3/YAP pathway attenuates the progression prostate cancer [169]. Furthermore, the subunit of the eukaryotic translation initiation factor 3 (eIF-3) complex EIF3H is a JAMM family deubiquitinase member. It can also remove the poly-ubiquitin chain on YAP in BC cells [170] to stabilize YAP and thus encourages their invasion and metastasis. Researchers also demonstrated that OTUB2 promotes the stemness and metastasis of BC cells through mediating YAP/TAZ deubiquitination [171]. Interestingly, the OTUB2-YAP/TAZ interaction requires EGF-RAS signaling-regulated poly-SUMOylation (a ubiquitin-like modification, see Sect. “Ubiquitin-like modifications” for more details) of OTUB2. Moreover, a conserved SUMO interaction domain in YAP/TAZ, which enables the noncovalent binding of YAP/TAZ to SUMOylated OTUB2, has been identified. These findings enhance our understanding of YAP/TAZ interaction mechanisms with binding partners, and suggest that OTUB2 and the SUMO interaction domain in YAP/TAZ as potential therapeutic targets for cancers with dysregulated EGF-RAS signaling.

Immune escape and chemoresistance represent critical determinants of therapeutic efficacy in cancer treatment. In pancreatic cancer, the USP10–YAP cascade increases the expression of PD-L1 and galectin-9, which ultimately not only improves pancreatic adenocarcinoma (PAAD) cell proliferation and invasiveness, but also enhances their immune escape by triggering M2 macrophage polarization in the tumor microenvironment [172]. In anaplastic thyroid cancer cells, the UCH member UCHL3 also stabilizes YAP by eliminating its K48-linked ubiquitin chain, through which UCHL3 promotes ATC stemness and metastasis, and reduces its sensitivity to chemotherapy [173]. However, UCHL3 inhibitor TCID can inhibit the growth and metastasis of ATC cells by promoting YAP ubiquitination and degradation. USP9X also promote the chemoresistance of breast cancer through deubiquitinating and stabilizing YAP1, while the USP9X inhibitor WP1130 can attenuate this process [174].

Ubiquitination and deubiquitination of YAP/TAZ are also involved in non-oncological diseases. For example, The E3 ligase Mind Bomb-2 (MIB2) promotes the ubiquitination and degradation of YAP/TAZ in endothelial cells [175]. The degradation rate can be regulated by the interaction between MIB2 and proto-cadherin FAT1. Depleting endothelial FAT1 or MIB2 stabilizes YAP/TAZ protein and increases their transcriptional activity to promote angiogenesis. Nevertheless, whether MIB2 mediates YAP/TAZ degradation directly remains elusive. E3 ubiquitin-protein ligase UBR4 in mesenchymal stem cell-derived exosomes (MenSCs-EXO) promotes YAP ubiquitination and subsequent proteasomal degradation in endometrial stromal cells (EndoSCs). The resultant nuclear exclusion of YAP suppresses transcription of fibrosis-promoting genes, ultimately attenuating endometrial fibrotic progression in intrauterine adhesion (IUA) [176]. In contrast, USP15 can enhance YAP stability by inhibiting its K48-linked poly-ubiquitination to elevate its transcriptional activity in PASMCs [177]. Therefore, the proliferation and migration of PASMC are promoted. Furthermore, the deubiquitination of YAP induced by OTUB2 enhances its stability and significantly stimulates the vascular calcification in chronic kidney disease (CKD) [178].

Ubiquitination and deubiquitination regulate YAP/TAZ subcellular localization

The E3 ligases TRAF6 and SCF^SKP2 have been reported to catalyze K63-linked poly-ubiquitination on YAP/TAZ, and thus regulate their subcellular localization. The E3 ligase TRAF6 belongs to the tumor necrosis factor receptor-associated factor (TRAF) protein family, which plays a decisive role in the immune system and inflammatory diseases [179]. In IL1β-stimulated macrophages, TRAF6 improves the protein stability of YAP and promotes its nuclear localization by catalyzing its K63-linked poly-ubiquitination at Lys252. The upregulated YAP increases the expression of pro-inflammatory genes, and thus exacerbates atherosclerosis [180]. In addition, TRAF6 mediates K63-linked poly-ubiquitination of YAP at Lys497 in melanoma cells. Subsequently, YAP forms complex with TFCP2 and promotes the transcription of PD-L1 gene [181]. SCF^SKP2 also affects the subcellular localization of YAP, which is inversely regulated by OTUD1. SCF^SKP2 promotes K63-linked non-proteolytic poly-ubiquitination of YAP [182], which induces its nuclear localization, and enhances the expression of MYC and CTGF to increase cyst formation and the progression of tubulointerstitial fibrosis in polycystic kidney disease (PKD) cyst epithelial cells. Another study further identified that Lys321 and Lys497 of YAP are the targets of SKP2 [183], and the deubiquitinase OTUD1 reverses SKP2’s effects. The balance between ubiquitination and deubiquitination can be affected by cell density in a Hippo-independent manner, but the exact mechanisms are yet to be elucidated. In addition, the protective role of the OTUD1–YAP axis is observed in non-small cell lung cancer. Furthermore, OTUD1 inhibits the nuclear translocation of YAP and downregulates the expression of drug resistance-associated genes, which reverses the resistance of cancer cells to tyrosine kinase inhibitor (TKI) erlotinib [184].

A recent study reported TRIM15-mediated K48-linked poly-ubiquitination at YAP Lys254. Unlike canonical proteolytic K48 ubiquitination, TRIM15 catalyzes this modification through a nondegradative mechanism that disrupts YAP–AMOT binding and promotes YAP nuclear translocation. Eventually, it promotes the senescence of chondrocytes to accelerate the progression of osteoarthritis [185].

Ubiquitin-like modifications

Ubiquitin-like proteins, such as SUMO, NEDD8, and ISG15, share similar structures and functions with ubiquitin. SUMOylation, Neddylation, and ISGylation occur when these ubiquitin-like proteins are covalently attached to substrate proteins via consecutive enzymatic processes. Notably, SUMO can also engage in noncovalent interactions with proteins through SUMO-interaction motifs (SIMs), a mechanism distinct from covalent SUMOylation [171, 186]. Several studies have shown that YAP undergo SUMOylation, Neddylation, and ISGylation dynamically (Table 3).

Table 3.

Other PTMs of YAP/TAZ and their functional implications

Name	Residues		Biological function	Physiological/pathological conditions	Model	Refs.
	YAP	TAZ
SUMOylation
PML	K97/242		Enhance YAP stability	Promote cell apoptosis	Cell lines	[187]
TRIM29			Enhance YAP stability	Promote the growth of pancreatic cancer cells	Xenograft tumor nude mice	[191]
DeSUMOylation
SENP1			Decrease verteporfin-induced YAP SUMOylation	Endometrial cancer	Cell lines	[189]
SENP3*			Enhance YAP stability	Aggravate the adipose tissue and the system inflammation	Lyz2-Cre mice and Senp3flox/flox littermates	[190]
Glycosylation
OGT	S109		Disrupt the interaction between YAP and LATS	Promotes papillary thyroid cancer malignancy	Xenograft tumor nude mice	[199]
OGT	S109		Disrupt the interaction between YAP and LATS	Promote tumorigenesis	Xenograft tumor nude mice	[200]
OGT	T241		Disrupt the interaction between YAP and LATS	Promote tumorigenesis	Xenograft tumor athymic nude mice	[201]
OGT	T83		Recruit EIF3H to YAP and facilitate its deubiquitination	Promote obesity-driven BCa progression	Orthotopic xenograft tumor nude mice	[202]
OGT	T241		Enhance YAP stability	Enhance sensitivity to ferroptosis in liver cancer	Xenograft tumor nude mice	[204]
OGT			Enhance YAP stability	Regulate the ferroptosis in LUADb	LUAD PDX mouse model	[205]
OGT			Enhance YAP stability	Inhibit the autophagy of CKDc	High phosphate-induced VC in rats by 5/6 nephrectomized (Nx)	[207]
OGT			Enhance YAP stability	Promote the ferroptosis of corneal epithelial cells	Cigarette smoke exposure mice	[209]
PDLIM7	S21		Promote nuclear localization	Castration treatment resistance in PCad	Xenograft tumor nude mice	[192, 193]
B4GALT1		N256	Enhance stability	Establish the immunosuppressive microenvironment	A549 cells subcutaneous xenograft BALB/c nude mice and LLC cells subcutaneous xenograft C57BL/6 mice	[210]
???	T383		Enhance YAP stability	Drive diabetic retinopathy	Oxygen-induced retinopathy (OIR) mice	[208]
Methylation
SET1A	K342		Inhibit nuclear export	Promote the proliferation and tumorigenesis in CRCe	K327M Yap knockin mice and intestine organoid model	[212]
SET1A	K342		Inhibit nuclear export	Suppress the anti-tumor immunity and promotes the tumor progression of LUAD	C57BL/6JGpt, Yap-flox, and B6-KrasLSL-G12D/+ mice	[213]
SETD7	K494*		Promote cytoplasm localization	Promote tumorigenesis and regeneration in intestine	Intestinal organoid model	[215]
SETD7			Promote cytoplasm localization	Promote myocardial ischemia injury	Ischemia/reperfusion injury SETD7 knockout mice	[216]
SETD7			Promote YAP degradation	Promote autophagy in HCCf Initiation and development	Sptbn1 ± liver injury mice model	[217]
SETD7			Enhance YAP stability	Promote the proliferation and metastasis of GCg	Xenograft tumor nude mice	[218]
ISGylation
?	K497		Enhance YAP stability	Allow metabolic reprogramming in cancer cells	LUAD PDX mouse model	[195]
Dimethylation
PRMT1	R124		Promote nuclear localization	Promote tumorigenesis and drug resistance	Xenograft tumor C57BL/6J mice and Balb/c nude mice	[206, 219]
Acetylation
CBP/p300	K494/497	K54		Affect the sensitivity of HeLa cells to SN2 alkylating agents	Cell lines	[220]
CBP/p300	K265		Promote YAP cytoplasmic localization	Inhibit heart regeneration	αMHC-MCM/+; Yapflox/K265R mice and control αMHC-MCM/+; Yapflox/+ mice	[228]
Deacetylation
SIRT1	K494		Promote TFs affinity (TEAD)	Promote HCC tumorigenesis	Cell lines	[221]
SIRT1			Promote TFs affinity (TEAD)	Drive NSCLCh progression	Xenograft tumor nude mice	[222]
SIRT1			Promote YAP nuclear export	Promote autophagy	Transgenic mice model and zebrafish	[223]
SIRT1			Promote YAP nuclear export	Against atherosclerosis	ApoE−/− mice	[224]
SIRT2			Lead to K63-linked poly-ubiquitination	Liver enlargement and regeneration	C57BL/6J mice	[226]
SIRT6	K236		Inhibit nuclear export	Antagonize cardiac hypertrophy	Sprague–Dawley rats	[227]
SIRT5		K54	Promote nuclear retention	Increase melanoma cells’ ability to invade and metastasize	Melanoma subcutaneous xenograft C57BL/C mice	[229]
Lactylation
AARS1	K90		Promote nuclear localization	Promote the development of GC	Orthotopic and subcutaneous xenograft tumor mice	[231]
???	K90		Promote nuclear localization	Promote cell proliferation and stemness in HCC	Xenograft tumor mice	[233]
Neddylation
xiap ligase	K159		Promote nuclear localization		nedd8-null zebrafish	[196]
S-glutathionylation
?		C261/315/358	Enhance TAZ stability	Promote tissue repair	Ischemia/reperfusion injury model	[236]

^aBreast cancer

^bLung adenocarcinoma

^cChronic kidney disease

^dProstate cancer

^eColorectal cancer

^fHepatocellular carcinoma

^gGastric cancer

^hNon-small cell lung cancer

The promyelocytic leukemia (PML) protein, also known as TRIM19, is reported to mediate the SUMOylation of YAP on Lys97 and Lys242 upon cisplatin treatment in cancer cells [187]. These SUMOylation inhibits the ubiquitination and degradation of YAP, and increases its binding with the TF P73 to enhance the expression of pro-apoptotic genes as well as PML itself, thereby promoting cell apoptosis in an auto-positive regulation manner. Of note, this process is dependent on PKC-mediated phosphorylation on YAP Ser61, 127, and 164 [188]. In endometrial cancer cells, verteporfin increases the SUMOylation of YAP, which can be abolished by overexpressing SUMO-specific protease SENP1 [189]. This SUMO modification is phosphorylation-dependent as well, because it can be inhibited when the Ser127 on YAP is mutated into alanine. Jiang et al. [190] found the SUMO-specific protease SENP3 is upregulated in adipose tissue macrophages in mice models of obesity. SENP3 deSUMOylates YAP and increases its protein level to promote the release of inflammatory cytokines. As a result, the inflammation in adipose tissue and in circulation are aggravated. Therefore, targeting the SENP3–YAP axis represents a potential approach to treat obesity. TRIM29 is conventionally viewed as a E3 ubiquitin ligase. Interestingly, it can bind directly to YAP and reduce its ubiquitination and degradation to promote the growth of pancreatic cancer cells [191], but the underlying mechanism remains elusive. One possible explanation is that TRIM29 functions as a SUMO ligase, as demonstrated in cardiomyocytes recently [192], rather than a E3 ubiquitin ligase in these cells. In fact, several TRIM ubiquitin ligases, such as TRIM28 [193] and TRIM38 [194], have been identified to be SUMO ligases to inhibit substrate ubiquitination. Overall, despite the limited number of studies on the subject, YAP’s SUMOylation status has been shown to be crucial for its stability and activity.

A recent study reported that YAP underwent ISGylation at Lys497 in lung cancer cells [195]. This PTM stabilizes YAP by blocking its binding to E3 ligase β-TRCP and subsequent proteasome degradation. Elevated YAP expression boosts the transcription of 6-phosphogluconolactonase, a time-limiting enzyme in the pentose phosphate pathway, which allows metabolic reprogramming in cancer cells. It remains unclear which enzymes are involved in this process. Moreover, the xiap ligase has been shown to mediate the neddylation of YAP at Lys159 and increase its nuclear localization and subsequent transcriptional activity [196]. However, further study is necessary to determine the involvement of YAP neddylation in diseases.

Glycosylation

Protein glycosylation refers to the covalent attachment of glycans, glycosaminoglycans, glycosylphosphatidylinositol (GPI), or α-mannopyranosyl to proteins [197]. Main types of glycosylation in humans include O-GlcNAcylation, N-linked glycosylation, and so on [197]. O-GlcNAcylation is known as the attachment of O-linked β-N-acetylglucosamine (O-GlcNAc) moieties to Ser or Thr residues [197, 198]. N-linked glycosylation occurs when N-acetylglucosamine (N-GlcNAc) is bound to Asn residues [197].

Several studies have uncovered the roles of YAP O-GlcNAcylation in cancers (Table 3). In cancer cells where the hexosamine biosynthesis pathway (HBP) is activated by environmental stimulations such as high glucose-treatment to provide UDP-N-acetyl-d-glucosamine (UDP-GlcNAc), the O-GlcNAc transferase (OGT) catalyzes YAP O-GlcNAcylation at Ser109 [199, 200] and Thr241 [201]. This PTM disrupts the interaction between LATS1 and YAP to inhibit YAP’s phosphorylation at Ser127, and subsequent YAP ubiquitination and destruction. Meanwhile, YAP’s nuclear translocation and transcriptional activity are increased, which promotes tumorigenesis and the growth of tumors. Furthermore, a study by Cui et al. identifies Thr83 as the glycosylation site on YAP [202]. The glycosylation triggered by OGT recruits EIF3H to YAP and facilitates its deubiquitination, which promotes the stability of YAP and enhances obesity-driven BC progression. In addition, the YAP O-GlcNAcylation influences the sensitivity of cancer cells to ferroptosis. Inhibiting the cystine-glutamate antiporter system Xc- or glutathione peroxidase 4 (GPX4) are effective strategies to induce cell ferroptosis since they blunt the glutathione (GSH)–GPX4 antioxidant system [203]. According to Zhu et al., YAP Thr241 O-GlcNAcylation increases the GPX4 inhibitor-induced ferroptosis of liver cancer cells via promoting the expression of transferrin receptors to increase intracellular iron concentration [204]. In Xc-inhibitor-treated lung adenocarcinoma cells, endogenous glutamate accumulation disrupts the HBP and thus decreases YAP’s O-GlcNAcylation, stability, and transcriptional activity [205]. Finally, the expression of ferritin is downregulated and intracellular labile iron concentration is increased, which promotes the ferroptosis sensitivity of cancer cells. Therefore, the O-GlcNAcylation of YAP appears to play complicated roles in controlling ferroptosis sensitivity in liver and lung cancer. More research is needed to understand this discrepancy. Apart from Ser109 and Thr241 O-GlcNAcylation, YAP also underwent Ser21 O-GlcNAcylation. Integrin adhesome protein PDLIM7 can bind to YAP and promote its Ser21 O-GlcNAcylation. This O-GlcNAcylation increases YAP nuclear translocation in prostate cancer cells, and contributes to castration treatment resistance in patients [193, 206].

The OGT-mediated YAP glycosylation is also involved in the development of CKD, diabetic retinopathy, and corneal injury. Xu et al. demonstrated that the high phosphate stimulation upregulated the OGT–YAP axis to promote the autophagy activation of vascular smooth muscle cells, and thus deteriorates the vascular calcification in CKD models [207]. In retinal capillary endothelial cells, high glucose exposure stabilizes and activates YAP by enhancing its Thr383 O-GlcNAcylation and inhibiting its Ser397 phosphorylation, which drives the pathogenesis of diabetic retinopathy by promoting the expression of pro-angiogenic and glucose metabolic genes [208]. In corneal epithelial cells, exposure to cigarette smoke upregulates OGT. Then, the OGT-mediated YAP glycosylation inhibits K48-liked poly-ubiquitination-induced degradation of YAP and promotes its nuclear translocation [209]. As a result, YAP induced the expression of the TFRC and ACSL4 genes, triggering the ferroptosis of corneal epithelial cells.

TAZ was also found to be glycosylated recently. During the development of early-stage lung adenocarcinoma, the galactosyltransferase B4GALT1 is upregulated. B4GALT1 mediates the N-linked glycosylation of TAZ at Asn256 and stabilizes it, which increases the gene promoter activity of PD-L1 and facilitates its expression [210]. Therefore, the TAZ glycosylation contributes to establishing the immunosuppressive microenvironment.

Methylation

Protein methylation is catalyzed by protein methyltransferases and reversely regulates by protein demethylases. It occurs when methyl groups are attached to Lys or Arg residues [211]. A single Lys residue can have up to three methyl groups linked to it, whereas a single Arg residue can have up to two.

Lysine methyltransferase SET1A binds to YAP in the nucleus and mono-methylates it at Lys342 [212]. This maintains the transcriptional activity of YAP by blocking its nuclear export, and thus promotes cell proliferation and colorectal tumorigenesis. Similarly, SET1A-mediated methylation of YAP also facilitates YAP-dependent fibrinogen-like protein 1 (FGL1) transcription and immune evasion in Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung adenocarcinoma [213]. Furthermore, Gu et al. reported that lipolytic activator ABHD5 can bind to DYP30, a core subunit of SET1A complex, and prevent its nuclear translocation [214]. Loss of ABHD5 activates the SET1A–YAP axis to increase stemness-related genes expression in CRC cells [214].

Oudhoff et al. showed that methyltransferase SETD7 mediates the mono-methylation of YAP at Lys494 in mouse embryonic fibroblasts and contributes to the cytoplasmic retention of YAP, without significantly affecting its stability and Ser127 phosphorylation status [215]. They further showed that this methylation enables the Wnt/β-catenin signaling by stabilizing the interaction between YAP and β-catenin and increasing the nuclear import of β-catenin, and thus facilitates the Wnt signaling-driven methylation participates in driving myocardial ischemic injury [216]. Interestingly, in HCC cells, the loss of the cytoskeletal protein SPTBN1 decreases SETD7 transcription, and thus reduces the methylation and proteasomal degradation of YAP, which suppresses hepatic cells autophagy and promotes the tumorigenesis and tumor development [217]. However, a recent study revealed that SETD7-mediated methylation of YAP hinders its ubiquitination and destruction in GC cells [218], without significantly affecting its nuclear localization. In conclusion, SETD7-mediated YAP methylation appears to have diverse effects on YAP stability and function in different cells, highlighting the need for further investigation.

In addition to being mono-methylated, YAP can be dimethylated (Table 3). Recently, Qian et al. [206] identified that SOX9 can bind to YAP and is potent for promoting its nuclear entry in HCC cells. More importantly, protein arginine methyltransferase 1 (PRMT1) catalyzes asymmetrical dimethylation of YAP at Arg124, which dramatically enhances the interaction between YAP and SOX9. S-A1, a cell-permeable competitive peptide blocking the interaction between SOX9 and YAP, blunts YAP nuclear translocation and suppresses tumor growth effectively. Of note, the further study demonstrates that methionine promotes the dimethylation of YAP at Arg124, and drives anticancer drug resistance [219].

Acetylation

The acetylation of YAP was first reported by Hata and colleagues [220]. They discovered that DNA damage caused by SN2 alkylating agents enhances YAP import into the nucleus where acetyltransferase CBP/p300 and deacetylase sirtuin 1 (SIRT1) dynamically controls its acetylation on Lys494 and Lys497 [220]. Acetylation alters YAP transcriptional activity and Hela cells’ sensitivity to SN2 alkylating agents. Mao et al. confirmed that SIRT1 promotes YAP deacetylation and TEAD affinity, and thus contributes to HCC cell proliferation and cisplatin resistance [221]. In NSCLC, the coactivator zinc finger MIZ-type containing 2 (ZMIZ2) directly binds to and enhances SIRT1 deacetylase activity. This interaction induces deacetylation of YAP, thereby potentiating their affinity to TEAD and transcriptional activity and driving NSCLC progression [222]. However, researchers have reported an inhibitory effect of SIRT1 on YAP, and SIRT1-mediated deacetylation of YAP induces its nuclear export upon fluid flow, thereby promoting autophagy [223] and anti-atherosclerosis [224]. Interestingly, the protein level of acetylated YAP in nucleus can be precisely controlled. According to Kim et al., the 26S proteasome subunit protein PSME4 facilitates the degradation of acetylated YAP in a poly-ubiquitination-independent manner in the nucleus [225]. In cytoplasm, the acetylation state of YAP can influence its stability and localization in a ubiquitination-dependent manner. Zhang et al. showed that p300-mediated acetylation of YAP increases its K48-linked poly-ubiquitination and subsequent degradation in a mouse model of liver enlargement and regeneration [226]. When the pregnane X receptor (PXR) is activated by agonists, it binds to YAP and stimulates YAP deacetylation via SIRT2. Then, the YAP underwent K63-linked poly-ubiquitination, which contributes to its nucleus translocation and transcriptional activity during liver enlargement and regeneration. Another study identified Lys236 as a novel acetylation site on YAP, which cause the nucleus export of YAP and the downregulation of the cardiac protective gene expression. However, SIRT6 can deacetylate it and antagonize cardiac hypertrophy [227]. Similarly, YAP can be deacetylated at Lys265 by the activated sirtuin. However, after myocardial infraction, sirtuin activity is downregulated, and it ultimately causes the accumulation of YAP in the cytoplasm, which blocks the cardiac regeneration [228].

TAZ is dynamically acetylated as well. CBP acetylates TAZ at Lys54 in response to growth factor stimulation, which contributes to TAZ nucleus export [229]. The connection between TAZ and LATS1 is then increased, resulting in Ser89 phosphorylation and subsequent TAZ breakdown. However, this pathway is downregulated in melanoma owing to the increased SIRT5-mediated TAZ deacetylation. Deacetylation boosts TAZ nuclear retention and TAZ-TEAD binding, which promotes connective tissue growth factor expression to increase melanoma cells’ ability to invade and metastasize (Table 3).

Lactylation

Lactate is historically regarded as metabolic waste. In 2019, Zhao and colleagues discovered a novel PTM in which lactate is bound covalently to histone lysine residues and named it as lactylation [230]. Since then, many studies have shown that lactylation can occur on histone and nonhistone proteins to modulate their functions, and exerts substantial impacts on development of many diseases. Recently, Ju et al. reported that the alanyl-tRNA synthetase 1 (AARS1) is a lactyl-transferase for YAP Lys90 lactylation and TEAD lactylation [231]. The lactylation of YAP inhibits its binding with exportin, XPO1, and thus maintains its nuclear sequestration in GC and HCC cells [231, 232]. As a result, the activity of the YAP–TEAD complex is enhanced to increase the expression of cell proliferation-related genes. The researchers also identified that the conventional deacetylase SIRT1 can act as a direct delactylase for YAP and TEAD [231, 233].

S-glutathionylation

Cysteine ranks among the least abundant amino acids in humans, yet its presence correlates strongly with organismal biological complexity [234]. S-glutathionylation, a well-characterized posttranslational modification targeting cysteine thiol groups, occurs when oxidized glutathione (GSSG) forms mixed disulfide bonds with reactive cysteine residues. This modification, typically induced by factors such as mild oxidative stress through elevated reactive oxygen species (ROS), serves as a functional switch capable of dynamically regulating protein activity [235].

Interestingly, TAZ contains three conserved cysteine residues absent in its paralog YAP, suggesting distinct roles in redox regulation. Gandhirajan et al. [236] demonstrated that oxidative stress induces S-glutathionylation at TAZ Cys261, Cys315, and Cys358, with Cys315 serving as the primary modification site. This redox-sensitive posttranslational modification stabilizes TAZ, enhances its activation, and promotes tissue repair, establishing TAZ as a direct redox sensor within the Hippo pathway (Table 3).

Targeting YAP/TAZ: a potential but challenging approach

Given that YAP/TAZ serve as core integrators of cellular signaling pathways to regulate diverse physiological and pathophysiological processes, they are considered promising therapeutic targets for precision interventions. However, their nonenzymatic nature and disordered protein structure have conventionally deemed them “undruggable” through standard pharmacological approaches [2].

Current targeting strategies primarily focus on disrupting YAP/TAZ–transcription factor interactions. For example, verteporfin (VP), an Food and Drug Administration (FDA)-approved drug for macular degeneration, inhibits YAP/TAZ–TEAD binding [237]. However, its dual interference with both Hippo and STAT3 signaling pathways raises concerns about proteotoxic effects and target specificity [238, 239]. Additionally, suboptimal pharmacokinetic properties [240] restrict its clinical applicability. In addition to VP, the IAG933, a specific small-molecule inhibitor against the YAP–TEAD interaction, shows potent anticancer activity and is now in phase I clinical trial in Patients With Advanced Solid Tumors (clinical trial no. NCT04857372) [241, 242]. Another approach involves targeting TEAD auto-palmitoylation, a biochemical switch essential for YAP/TAZ–TEAD interactions. Inhibitors such as VT3989 (under evaluation in a phase I trial for solid tumors and mesotheliomas, NCT04665206) [243] and IK930 (in phase I trials for advanced solid tumors, NCT05228015) exemplify this strategy [244, 245]. Disrupting the interaction surface of YAP/TAZ–TEAD with synthetic peptide is another approach, but relevant clinical advances are rare, as well summarized recently [2]. Altogether, while disrupting the YAP/TAZ–TEAD interaction represents a theoretical approach, clinical progress in this area remains limited, and challenges such as toxicity, suboptimal pharmacokinetics, and off-target effects underscore the need for further optimization.

RNA-based methods also hold potential for YAP/TAZ targeting. An antisense oligonucleotide that specifically targets YAP mRNA has shown preclinical efficacy in solid tumor models, with ongoing clinical evaluation (NCT04659096) [10]. Moreover, noncoding RNAs also exert impacts on the function and stability of YAP/TAZ, and targeting the interplay between noncoding RNAs and YAP/TAZ offers an additional therapeutic avenue, as highlighted in recent reviews [246]. However, obstacles such as RNA delivery inefficiency and off-target effects must be addressed before clinical translation.

The advances in YAP/TAZ PTMs offer new therapeutic opportunities. For example, studies using single inhibitors to disrupt the YAP/TAZ PTMs show therapeutic value in animal models. For example, kinase SRC inhibitor Curaxin CBL0137 [110], SFKs inhibitor ibrutinib [107], and AURKA inhibitor alisertib [92] suppress the interaction of their target with YAP/TAZ, respectively, thereby greatly inhibiting tumor progression. Several selective deubiquitinases inhibitors, such as USP1 inhibitor ML323, USP7/USP47 inhibitor P5091 [151, 157], USP9X inhibitor WP1130 [174], USP14 inhibitor IU1 [155], and UCHL3 inhibitor TCID [173], have been showed to inhibit YAP/TAZ-driven cancer progression and metastasis as well.

Despite the well-documented anticancer efficacy of YAP/TAZ-targeted therapies in preclinical models, monotherapy approaches are likely to be not enough in clinical settings owing to the high mutational burden of cancers and the complexity of the tumor microenvironment. Recent studies on YAP/TAZ PTMs in drug resistance suggest that combining YAP/TAZ PTM-targeted therapies with conventional agents could improve outcomes. For instance, MAP3K3 inhibitor ponatinib enhances the efficacy of BRAF inhibitor vemurafenib and CDK4/6 inhibitor palbociclib in melanoma and luminal breast cancer by suppressing YAP activity [81]. Similarly, SRC inhibitor reverses trastuzumab resistance in HER2⁺ breast cancer by blocking YAP-driven transcription [109]. OTUD1 inhibitor restores sensitivity to the EGFR inhibitor erlotinib of cancer cells [184]. Besides, combinatorial therapy using FGFR inhibitor infigratinib and YAP inhibitor can significantly improve the efficacy of infigratinib [247]. These findings underscore the potential clinical value of integrating YAP/TAZ PTM-targeted therapies with clinically approved targeted agents to improve treatment outcomes.

Concluding remarks and perspectives

Acting as transcriptional coactivators, YAP/TAZ regulate the expression of genes essential for critical cell activities, exerting significant impacts on both normal physiological processes and various pathological conditions. Their functions exhibit remarkable context-dependent diversity across disease models and tissue microenvironments.

The functional diversity of YAP/TAZ partly stems from the complexity of upstream regulatory networks governing YAP/TAZ activity. The canonical Hippo pathway is the central upstream signaling, and many biochemical and biophysical signals have been shown to directly influence the Hippo kinase cascades, thereby regulating YAP/TAZ stability, nuclear translocation, and transcriptional output. In recent years, accumulating evidence has highlighted the importance of Hippo-independent regulatory factors, such as mechanical stress, energy stress, osmotic stress, and some soluble factors activating specific subtype of GPCRs. Intriguingly, many of these stimuli, such as mechanical and osmotic stress, exhibit dual regulatory mechanisms involving both Hippo-dependent and Hippo-independent pathways, further complicating the functional regulation of YAP/TAZ. Furthermore, disease-associated YAP/TAZ PTMs patterns driven by Hippo-independent mechanisms have been broadly reported, as reviewed in this study, though the specific upstream factors underlying these modifications remain poorly defined. Altogether, the canonical Hippo signalling and Hippo-independent mechanisms create a context-sensitive regulatory network, and their overall effect on YAP/TAZ activity varies by tissue type and cellular microenvironment. However, how YAP/TAZ integrate these factors remains largely elusive.

In recent years, extensive research has focused on the PTMs of YAP/TAZ, revealing their role as critical “control hubs” that govern YAP/TAZ activity by regulating stability, subcellular location, and interactions with transcriptional factors. Many phosphorylation sites on YAP/TAZ have been identified, with the most well-characterized including YAP’s Ser127, Ser128, Tyr357, and Ser94, as well as TAZ’s Ser89. Phosphorylation of YAP at Ser127 and TAZ at Ser89 enhances their affinity to protein 14-3-3 in cytoplasm, thereby diminishing their stability, hindering their nuclear translocation, and reducing their transcriptional activity. Phosphorylation of YAP Ser128 counteracts the effects of Ser127 phosphorylation, leading to increased transcriptional activation. In contrast, phosphorylation of YAP Tyr357 plays a crucial role in promoting nuclear location and stabilizing the YAP–TFs complex, while phosphorylation of Ser94 disrupts the YAP–TFs interaction and decreases transcriptional activity. The functional significance of many other phosphorylation sites—whether they represent regulatory redundancies, bystander modifications, or context-specific switches—warrants more investigation. In addition, numerous E3 ubiquitin ligases and deubiquitinases that regulate YAP/TAZ stability have been identified. Intriguingly, YAP/TAZ appear to exhibit low selectivity toward these enzymes, and the underlying mechanisms remain poorly understood. Elucidating these mechanisms holds significant implications for developing targeted therapeutic strategies against YAP/TAZ. The regulatory roles of K63- and K48-linked ubiquitination in governing YAP/TAZ subcellular localization offer novel therapeutic avenues. Studies on other posttranslational modifications (PTMs), while still in their exploratory stages, have substantially expanded our understanding of the multifaceted regulatory networks controlling YAP/TAZ activity. Notably, despite the ambiguity in many studies, some PTM patterns, such as AMPK-mediated phosphorylation induced by energy stress, ULK-mediated phosphorylation induced by hypoxia, NLK-mediated phosphorylation induced by osmotic stress, OGT-mediated glycosylation induced by high phosphate/glucose environment, provide important mechanistic basis for understanding the context-dependent functional diversity of YAP/TAZ.

The PTMs of substrates are dynamically regulated in cells, with crosstalk between distinct modifications being a common phenomenon. Though several studies have reported some crosstalk between YAP/TAZ PTMs, the competitive or cooperative relationships among enzymes mediating the same or distinct PTMs, and their regulator factors, remain poorly defined. deeper mechanistic investigation in this aspect is critical for advancing both fundamental understanding of YAP/TAZ regulation and its clinical translation.

Several other key knowledge gaps persist in YAP/TAZ PTM research. First, while most studies identified disease-associated PTM alterations, the mechanistic basis of their context-dependent regulation across diverse disease models and tissue-specific microenvironments are insufficiently characterized. Second, despite reported instances of crosstalk between distinct PTMs, the integrative mechanisms by which YAP/TAZ process and coordinate their multifaceted PTMs remain poorly understood. Third, current research predominantly focuses on canonical YAP/TAZ-TEAD-mediated proliferative programs, potentially oversimplifying the complexity of their transcriptional outputs. The extent to which PTMs influence selective activation of specific transcriptional targets, particularly noncanonical or context-dependent gene networks, requires systematic exploration. Addressing these gaps will deepen our understanding of how PTM networks regulate YAP/TAZ-driven transcriptional diversity across physiological and pathological contexts.

The identification of enzymes responsible for catalyzing YAP/TAZ PTMs and the mapping of specific PTM sites on these proteins provide novel therapeutic opportunity. Compared with conventional YAP/TAZ inhibitors, therapies targeting PTM processes may achieve superior precision owing to the inherent cell-type specificity, tissue/organ selectivity, and tumor heterogeneity of PTM regulation. In fact, preliminary studies have suggested that regulating YAP/TAZ PTMs could offer critical opportunities to overcome resistance to clinically established targeted therapies. Furthermore, targeting PTMs can circumvent a key limitation of traditional YAP/TAZ-TEAD inhibition strategies—their neglect of the functional contributions of other transcriptional partners of YAP/TAZ. Additionally, integrating YAP/TAZ PTMs-targeted strategies with immunotherapies or microenvironment-modulating agents may unlock novel therapeutic synergies.

Abbreviations

AARS1

Alanyl-tRNA synthetase 1

ABL

Abelson tyrosine-protein kinase 1

aPKC

Par3-Par6-atypical protein kinase C

AMOT

Angiomotin

AS

Atherosclerosis

ATC

Anaplastic thyroid cancer

AURKA

Aurora kinase A

BRCA

Breast cancer

CCA

Cholangiocarcinoma

CDK

Cyclin dependent kinase

CKD

Chronic kidney disease

CRC

Colorectal cancer

CTGF

Connective tissue growth factor

DCAF12

DDB1- and CUL4-associated factor 12

DDB1

DNA damage-binding protein 1

DLG5

Discs Large Homolog 5

DUBs

Deubiquitinases

EC

Endothelial cell

eIF-3

Eukaryotic translation initiation factor 3

EMT

Epithelial-to-mesenchymal transition

EndoSCs

Endometrial stromal cells

EphA2

Erythropoietin-producing hepatocellular receptor

ESCC

Esophageal squamous cell carcinoma

FAK

Focal adhesion kinase

FGFR

Fibroblast growth factor receptor

FGL1

Fibrinogen-like protein 1

FRK

Fyn-lated Src family tyrosine kinase

GPI

Glycosylphosphatidylinositol

GPX4

Glutathione peroxidase 4

GSH

Glutathione

GSK3β

Glycogen synthase kinase 3 beta

GSSG

Oxidized glutathione

HBP

Hexosamine biosynthesis pathway

HBx

HBV oncoprotein X

HCC

Hepatocellular carcinoma

HNSCC

Head neck squamous cell carcinoma

iCCA

Intrahepatic cholangiocarcinoma

IFN-γ

Interferon-γ

IKK

Inhibitor of kappa B kinase

IL-1β

Interleukin-1β

IUA

Intrauterine adhesion

JAMMs

JAB1/MPN/MOV34 proteases

JNK

C-Jun N-terminal kinase

JOSD

Josephin domain-containing

KANK1

KN motif and ankyrin repeat domain-containing protein 1

KRAS

Kirsten rat sarcoma viral oncogene homolog

LATS1/2

Large tumor suppressor 1 and 2

LCK

Lymphocyte cell-specific protein-tyrosine kinase

LPA

Lysophosphatidic acid

LPS

Lipopolysaccharide

LUAD

Lung adenocarcinoma

MAP2Ks

Mitogen activated protein kinase kinases

MAP3Ks

Mitogen activated protein kinase kinase kinases

MAPKs

Mitogen activated protein kinases

MARK

Microtubule affinity-regulating kinase

MenSCs-EXO

Mesenchymal stem cell-derived exosomes

MERTK

Tyrosine-protein kinase Mer

MIB2

E3 ligase Mind Bomb-2

MJDs

Machado–Joseph disease protein domain proteases

MOB1

MOB kinase activator 1

MST1/2

STE20-like protein kinase 1 and 2

mTORC2

Mechanistic target of rapamycin complex 2

NDR

Dbf2-related protein kinase

NEK

NIMA-related kinase

NF2

Neurofibromin 2

N-GlcNAc

N-acetylglucosamine

NRTKs

Nonreceptor tyrosine kinases

NSCLC

Non-small cell lung cancer

O-GlcNAc

O-linked β-N-acetylglucosamine

OGT

O-GlcNAc transferase

OS

Osteosarcoma

OTUs

Ovarian tumor domain-containing or otubain proteases

PAAD

Pancreatic adenocarcinoma

PASMC

Pulmonary artery smooth muscle cell

PATJ

PALS1-associated tight junction protein

PDAC

Pancreatic ductal adenocarcinoma

PH

Pulmonary hypertension

PKD

Polycystic kidney disease

PML

Promyelocytic leukemia

PP1A

PP1 catalytic subunit alpha

PPP

Protein phosphatase

PRMT1

Protein arginine methyltransferase 1

PRP4K

Serine/threonine-protein kinase PRP4

PTMs

Posttranslational modifications

PTPN14

Protein tyrosine phosphatase non-receptor type 14

PXR

Pregnane X receptor

RBCK1

RANBP2-type and C3HC4-type zinc finger-containing 1

RET

Proto-oncogene tyrosine-protein kinase receptor Ret

RIPK2

Receptor-interacting protein kinase 2

ROS

Reactive oxygen species

RTKs

Receptor tyrosine kinases

SAV1

Salvador homolog 1

SFKs

Src family kinases

SHARPIN

SHANK-associated RH domain interacting protein

SIMs

SUMO-interaction motifs

SIRT

Sirtuin

SRC

Proto-oncogene Src

STAT

Signal transducer and activator of transcription

STRIPAK

Striatin-interacting phosphatase and kinase

Tak1

Transforming growth factor-β activated kinase 1

TAZ

Transcriptional coactivator with PDZ-binding motif

TEADs

TEA domain family proteins

TCF

T cell factor

TFs

Transcriptional factors

TKI

Tyrosine kinase inhibitor

TLR4

Toll-like receptor 4

TNBC

Triple-negative breast cancer

TNF-α

Tumor necrosis factor-α

TRAF

Tumor necrosis factor receptor-associated factor

TSSK1B

Testis-specific kinase 1

Ub

Ubiquitin

UCHs

Ubiquitin carboxyl-terminal hydrolases

ULK1/2

Unc-51-like kinases1/2

USPs

Ubiquitin specific proteases

VP

Verteporfin

YAP

Yes-associated protein

YES

Tyrosine-protein kinase yes

ZAP70

Tyrosine-protein kinase ZAP-70

ZMIZ2

Zinc finger MIZ-type containing 2

Author contributions

Zhenxiong Zhang: writing—original draft, conceptualization, methodology, funding acquisition. Peiheng He: writing—original draft, visualization, conceptualization, methodology. Li Yang: writing—original draft, visualization, conceptualization, methodology. Jun Gong: writing—review and edit, conceptualization, methodology, supervision. Renyi Qin: writing—review and edit, conceptualization, supervision, funding acquisition. Min Wang: writing—review and edit, conceptualization, supervision, funding acquisition. All authors reviewed and approved the final manuscript.

Funding

This study was supported by the China State Key Basic Research Program (2024YFA1307204), the grants from the National Natural Science Foundation of China (82403125, 82472876 and 82273438), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2022-I2M-1-010).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read and approved the final version of the manuscript and its publication.

Competing interests

The authors declare no competing interests.