SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity

Yao, Fan; Zhou, Zhicheng; Kim, Jongchan; Hang, Qinglei; Xiao, Zhenna; Ton, Baochau N.; Chang, Liang; Liu, Na; Zeng, Liyong; Wang, Wenqi; Wang, Yumeng; Zhang, Peijing; Hu, Xiaoyu; Su, Xiaohua; Liang, Han; Sun, Yutong; Ma, Li

doi:10.1038/s41467-018-04620-y

Cited by 135 publications

(104 citation statements)

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“…Together with these studies, our current work further demonstrates a complicated machinery for fine and tight control of YAP activity under various cellular contexts. Interestingly, some negative regulators of YAP, such as MST4 kinase characterized here, and the reported SET1A (Fang et al, 2018), RUNX3 (Qiao et al, 2016), and OTUD1 (Yao et al, 2018), were found to be down-regulated in different cancer specimens and to be associated with poor prognosis. Perhaps dysregulation of these YAP-related tumor suppressors could explain the hyperactivation of YAP in cancer cells without apparent change of the classic Hippo kinase cascade.…”

Section: Discussionmentioning

confidence: 53%

“…The Hippo–YAP pathway can respond to a wide range of stress signals, eventually leading to the manifestation of different states of YAP-dependent gene transcription. Recently, a burst of studies have identified various types of PTMs including ubiquitination, methylation, and O-GlcNAcylation to regulate YAP activation in Hippo-independent manners (Fang et al, 2018; Peng et al, 2017; Yao et al, 2018; Zhang et al, 2017, 2019). Together with these studies, our current work further demonstrates a complicated machinery for fine and tight control of YAP activity under various cellular contexts.…”

Section: Discussionmentioning

confidence: 99%

“…Despite various types of posttranslational modifications (PTMs) including dephosphorylation (Huang et al, 2013; Liu et al, 2013; Wang et al, 2012; Wilson et al, 2014), ubiquitination (Cho et al, 2020; Sun et al, 2019; Yao et al, 2018), methylation (Fang et al, 2018; Oudhoff et al, 2013), and O-GlcNAcylation (Peng et al, 2017; Zhang et al, 2017) that have been implicated in fine-tuning YAP activity, phosphorylation is regarded as a dominant manner of YAP regulation. The classic Hippo-YAP signaling features sequential phosphorylation of YAP at Ser127 (Zhang et al, 2008, 2015; Zhao et al, 2007) and Ser381/Ser384 (Zhao et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Nie

Chen

et al. 2020

Journal of Experimental Medicine

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Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

Nie

Chen

et al. 2020

Journal of Experimental Medicine

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“…This is consistent with the findings of a different study, which reported that the ectopic expression of CSIG did not influence p16 INK4a expression and that CSIG negatively regulated p27 Kip1 expression to promote cell proliferation by inhibiting PTEN translation 21 . Skp2 may stabilize CSIG through nonproteolytic polyubiquitination, as demonstrated by its regulation of yes-associated protein and liver kinase B1 22,23 , and thereby promote p27 Kip1 degradation. Although p53 expression was also induced by Skp2 ectopic expression, its level actually was decreased in replication-induced old EPCs (Fig.…”

Section: Discussionmentioning

confidence: 99%

S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo

Wang

Lee

et al. 2020

Sci Rep

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Cell cycle slowdown or arrest is a prominent feature of cellular senescence. S-phase kinase-associated protein-2 (Skp2), an F-box subunit of SCF Skp2 ubiquitin ligase, is a key regulator of G1/S transition. We investigated whether Skp2 plays a role in the regulation of endothelial progenitor cell (EPC) senescence, which is closely associated with aging-related vasculopathy. Replication-induced senescent EPCs demonstrated more pronounced senescence markers and lower Skp2 levels in comparison with those of their younger counterparts. Depletion of Skp2 induced increases in senescence-associated β-galactosidase (SA-βGal) activity and a reduction of telomere length and generated a senescent bioenergetics profile, whereas adenoviral-mediated Skp2 expression reversed the relevant senescence. EPCs isolated from older rats displayed a reduced proliferation rate and increased SA-βGal activity, both of which were significantly reversed by Skp2 ectopic expression. In addition to reversing senescence, Skp2 also rescued the angiogenic activity of senescent EPCs in the ischemic hind limbs of nude mice. The results revealed that ectopic expression of Skp2 has the potential to rejuvenate senescent EPCs and rescue their angiogenic activity and thus may be pivotal in the development of novel strategies to manage aging-related vascular disease. Endothelial integrity is paramount for the maintenance of normal vascular function. Several cardiovascular (CV) risk factors, including smoking habit, diabetes, hypertension, and hyperlipidemia, have been shown to harm this integrity and result in endothelial dysfunction or even death. Without appropriate repair, blood vessels progress to advanced atherosclerosis, causing CV events to occur. The discovery of adult endothelial progenitor cells (EPCs) in 1997 greatly advanced knowledge of vascular repair 1. A growing amount of evidence suggests that EPC number and function are reduced in patients with coronary artery disease or CV risk factors and that the number of circulating EPCs is positively associated with vascular function 2-4. EPCs play a crucial role in the regulation of angiogenesis, which is vital to prevent organs or tissues from critical ischemia in terminal atherosclerotic diseases, in addition to vascular repair 3,5. Advanced age is a strong and independent risk factor for the development of atherosclerosis-related diseases. This is in line with evidence suggesting that the number of EPCs decreases with age in both humans and animals 6-8. EPC senescence may account for this reduction and contribute to the occurrence of atherosclerosis in elderly patients. The therapeutic potential of EPCs has attracted considerable attention in the treatment of patients with ischemic cardiovascular disease or diabetic ischemic foot. However, the quantity and quality of EPCs limit autologous application in this population. Therefore, overcoming replication-induced senescence of EPCs to gain sufficient and functional cells would benefit older adult patients with diabetic ischemic diseases. Cell cyc...

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“…4b). 327 The Wnt signaling pathway, associated with CSC stemness maintenance, also plays an important role in regulating the stability and degradation of TAZ. Phosphorylated β-catenin can serve as a platform for TAZ and β-TrCP1 and promotes TAZ degradation by β-TrCP1.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

464

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity

Cited by 135 publications

References 53 publications

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo

The role of ubiquitination in tumorigenesis and targeted drug discovery

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