Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Ho, King Ching; Zhou, Zhansong; She, Yi‐Min; Chun, Alex; Cyr, Terry D.; Yang, Xiaolong

doi:10.1073/pnas.1101273108

Cited by 113 publications

(114 citation statements)

References 32 publications

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“…One notable post-translational regulation of LATS1/2 is ubiquitination. A WW domain-containing HECT class E3 ubiquitin ligase, ITCH, ubiquitinates LATS1 and promotes cell growth and survival (Ho et al 2011;Salah et al 2011). Another E3 ubiquitin ligase, CRL4 (DCAF1), which is activated in NF2-deficient tumor cells, inhibits LATS1 and LATS2 by ubiquitination in the nucleus (Li et al 2014b).…”

Section: Spatial Regulation Of Mst and Latsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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Section: Spatial Regulation Of Mst and Latsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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“…Interestingly, we found that the protein levels of the ubiquitin-ligase ITCH increased almost twofold within 24 hours (Fig 4B). ITCH has been reported to ubiquitinate the tumour suppressor LATS1 leading to its degradation (41,42). In addition to this potential ubiquitin-regulated mechanism of LATS1 downregulation, we detected that A-Raf, a potent inhibitor of MST2 (43,44), was elevated.…”

Section: Hgf Regulates the Hippo-pathwaymentioning

confidence: 99%

HGF Induces Epithelial-to-Mesenchymal Transition by Modulating the Mammalian Hippo/MST2 and ISG15 Pathways

et al. 2014

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Epithelial to Mesenchymal Transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarised and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into highly motile, elongated, mesenchymal cells lacking cell-to-cell adhesions. To explore how the proteome is affected during EMT we profiled protein expression and tracked cell biological markers in Madin-Darby kidney epithelial cells undergoing hepatocyte growth factor (HGF) induced EMT. We were able to identify and quantify over 4000 proteins by mass spectrometry. Enrichment analysis of this revealed that expression of proteins associated with the ubiquitination machinery was induced, whereas expression of proteins regulating apoptotic pathways was suppressed. We show that both the mammalian Hippo/MST2 and the ISG15 pathways are regulated at the protein level by ubiquitin ligases. Inhibition of the Hippo pathway by overexpression of either ITCH or A-Raf promotes HGF-induced EMT.Conversely, ISG15 over-expression is sufficient to induce cell scattering and an elongated morphology without external stimuli. Thus, we demonstrate for the first time that the Hippo/MST2 and ISG15 pathways are regulated during growth-factor induced EMT.3

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“…The immunoprecipitated YAP was subjected to 10% SDS-PAGE and stained with commassie blue. The phosphorylated YAP band was cut and identification of YAP and phosphorylated YAP peptides was performed as described (16).…”

Section: Identification Of Yap Phosphorylation Sites By Mass Spectrommentioning

confidence: 99%

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

et al. 2014

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Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients. Cancer Res; 74(16); 4493-503. Ó2014 AACR.

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Itch E3 ubiquitin ligase regulates large tumor suppressor 1 stability

Cited by 113 publications

References 32 publications

Mechanisms of Hippo pathway regulation

Mechanisms of Hippo pathway regulation

HGF Induces Epithelial-to-Mesenchymal Transition by Modulating the Mammalian Hippo/MST2 and ISG15 Pathways

YAP-Induced Resistance of Cancer Cells to Antitubulin Drugs Is Modulated by a Hippo-Independent Pathway

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