Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)

Oka, Tsutomu; Mazack, Virginia; Sudol, Marius

doi:10.1074/jbc.m804380200

Cited by 313 publications

(369 citation statements)

References 66 publications

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“…Upon Hippo pathway activation, Lats phosphorylates Yap at Ser 127 . 9,28,29 In the densely plated cells, phosphorylation of Yap at Ser 127 was detected, demonstrating that the Hippo pathway was active (Figures 1b-d). To demonstrate that inhibition of apoptosis at high cell density was not cell type specific, we tested other cell lines.…”

Section: Resultsmentioning

confidence: 90%

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

et al. 2013

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The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.

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Section: Resultsmentioning

confidence: 90%

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

et al. 2013

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“…[51][52][53][54][55][56][57] In many of these cases, this pro-apoptotic function has been linked to YAP's ability to bind to p73 and promote p73-dependent gene expression. As Drosophila p53 is most closely related to mammalian p73, we tested the involvement of Drosophila p53 in caffeine-induced toxicity.…”

Section: Resultsmentioning

confidence: 99%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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“…have verified WWC2 directly binds to LATS1/2 via their WW domains, and phosphorylates and activates LATS1/2 22. Activated LATS1/2 phosphorylate YAP, which inhibited cell proliferation in mammalian cells 38, 39, 40. In confirmation that WWC2 activates the Hippo pathway in HCC, overexpression of WWC2 in SMMC‐7721 cells (which express low levels of WWC2) increased phosphorylation of both LATS and YAP, which has been previously shown to negatively regulate the Hippo pathway 11, 41, 42.…”

Section: Discussionmentioning

confidence: 96%

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

Zhang

Yan

Chen

et al. 2017

J Cellular Molecular Medi

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WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes‐associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down‐regulated in 95 clinical HCC tissues compared to the paired adjacent non‐cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5‐year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co‐activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC.

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Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)

Cited by 313 publications

References 66 publications

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

The Hippo pathway promotes cell survival in response to chemical stress

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

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