JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis

Tomlinson, V A L; Gudmundsdottir, Katrin Kemp; Luong, Phuong; Leung, KY; Knebel, Axel; Basu, Soumalee

doi:10.1038/cddis.2010.7

Cited by 117 publications

(120 citation statements)

References 43 publications

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“…As shown in Figure 1, we confirmed 4 potential serine phosphorylation sites in YAP1 by Lats1/2 at 61, 109, 127 and 164; 25,26 4 potential phosphorylation sites by JNKs at T119, S138, T154 and S317; 27 and 5 potential phosphorylation sites at T119, S128, S138, S289 and S367 by CDK1. 28,29 More importantly, we identified several additional serine/threonine phosphorylation sites (Fig.…”

Section: Ip-mass Spectrometry Analysis Of Yap1 Post-translational Modsupporting

confidence: 63%

“…14 Also, c-Jun N-terminal kinases (JNKs) phosphorylates YAP at T119, S138, T154, S317 and T362 and enhances its stabilization of DNp63. 27 Last, the CDK1 phosphorylates YAP at T119, S128, S138, S289 and S367, which promotes mitotic defects and decreases YAP mediated anti-apoptosis potential induced by the anti-tubulin drugs. 28,29 In the present study, we confirmed most of these post-translational modifications in YAP (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

Guo

Shen

et al. 2016

Cell Cycle

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The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP1, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-tomesenchymal transition (EMT) and malignant transformation. The Hippo tumor suppressor pathway has been suggested to inhibit the YAP1 function through serine phosphorylation-induced cytoplasmic retention and degradation. Here we report that the tyrosine188 (Y188) site of YAP1 isoform with 2 WW domains (known as YAP1-2) plays an important role in YAP1-induced cellular transformation. IP-Mass Spectrometry analysis of YAP1 identified the phosphorylation of Y188 but not other tyrosine residues. In contrast to the aberrant 3D acinus formation observed in YAP1-WT transduced cells, overexpression of YAP1-Y188F (non-phosphorylated mimic) displayed normal 3D structures. In addition, knockdown of the endogenous YAP1 in MDA-MB231 breast cancer cells inhibited cell proliferation and migration, which were then successfully rescued by the exogenous YAP1-WT and YAP1-Y188E but not Y188F. Mechanistically, we also demonstrated that YAP1-Y188F had a higher affinity to the upstream negative regulator PTPN14 and was extensively localized in the cytoplasm. Since the Y188 is located in the conserved aromatic core of the WW domain of YAP1, our finding has a wide implication for WW domain signaling in general, where Y phosphorylation may act as a common positive regulator of the complex formation via WW domains. In summary, our results indicate that tyrosine 188 plays an important role in the YAP1-induced cellular transformation and its phosphorylation may intriguingly serve as a positive indicator of YAP1 activation.

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Section: Ip-mass Spectrometry Analysis Of Yap1 Post-translational Modsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

Guo

Shen

et al. 2016

Cell Cycle

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“…During the Our findings indicate that dysregulation of DNp63 triggered by YAP inactivation is functionally related to lung cancer transdifferentiation in the context of LKB1 mutant ADC and Ad-SCC with mixed pathologies. Previous study has shown that YAP can bind to and stabilize p63 in keratinocytes to protect damage from ultraviolet irradiation 42 . Interestingly, we find that YAP and DNp63 show a reverse correlation in lung ADC and SCC, which might be resulted from the default transcriptional repression of DNp63 by YAP.…”

Section: Discussionmentioning

confidence: 99%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

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Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

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“…42 This suggests that the contextdependent role of YAP in preventing or promoting stressinduced apoptosis is conserved in Drosophila Yki. The exact molecular nature of the context-dependent cue(s) that determine this 'apoptotic switch' 57 remain to be established, but are likely to involve posttranslational modification of Yki and/or p53, as well as the activation status of other signaling cascades, such as the JNK pathway 64 or c-Abl, 65 both of which have been shown to drive YAP-dependent apoptosis. The conserved nature of this dual behavior of Yki in damage response may reflect its proposed ancient function as a mediator of tissue damage repair.…”

Section: Discussionmentioning

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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JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis

Cited by 117 publications

References 43 publications

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

The Hippo pathway promotes cell survival in response to chemical stress

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