β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

Rosenbluh, Joseph; Nijhawan, Deepak; Cox, Andrew G.; Li, Xingnan; Neal, James T.; Schafer, Eric J.; Zack, Travis I.; Wang, Xiaoxing; Tsherniak, Aviad; Schinzel, Anna C.; Shao, Diane D.; Schumacher, Steven E.; Weir, Barbara A.; Vázquez, Francisca; Cowley, Glenn S.; Root, David E.; Mesirov, Jill P.; Beroukhim, Rameen; Kuo, Calvin J.; Goessling, Wolfram; Hahn, William C.

doi:10.1016/j.cell.2012.11.026

Cited by 680 publications

(661 citation statements)

References 69 publications

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“…YAP mutant analysis should eventually test this idea. There is also cross talk between YAP and Wnt signaling on different levels, including beta catenin (34) and Disheveled (64; for a review, see reference 65). In these situations, it is the phosphorylated YAP that is active.…”

Section: Figmentioning

confidence: 99%

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Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Hwang

Fernando

Faure

et al. 2014

J Virol

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Murine polyomavirus small t antigen (PyST) regulates cell cycle, cell survival, apoptosis, and differentiation and cooperates with middle T antigen (MT) to transform primary cells in vitro and in vivo. Like all polyomavirus T antigens, PyST functions largely via its interactions with host cell proteins. Here, we show that PyST binds both Yes-associated protein 1 (YAP1) and YAP2, integral parts of the Hippo signaling pathway, which is a subject of increasing interest in human cancer. The transcription factor TEAD, which is a known target of YAP, is also found in PyST complexes. PyST enhanced YAP association with protein phosphatase 2A (PP2A), leading to decreased YAP phosphorylation. PyST increased YAP levels by decreasing its degradation. This effect was mediated by a reduction in YAP association with ␤-transducin repeat protein (␤TRCP), which is known to regulate YAP turnover in a phosphorylation-dependent manner. Genetic analysis has identified PyST mutants defective in YAP binding. These mutants demonstrated that YAP binding is important for PyST to block myoblast differentiation and to synergize with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) to promote cell death in 3T3-L1 preadipocytes placed under differentiation conditions. In addition to YAP binding, both of these phenotypes require PyST binding to PP2A. IMPORTANCEThe Hippo/YAP pathway is a highly conserved cascade important for tissue development and homeostasis. Defects in this pathway are increasingly being associated with cancer. Polyomavirus small t antigen is a viral oncogene that cooperates with middle T antigen in transformation. On its own, small t antigen controls cell survival and differentiation. By binding YAP, small t antigen brings it together with protein phosphatase 2A. This work shows how this association of small t antigen with YAP is important for its effects on cell phenotype. It also suggests that PyST can be used to characterize cellular processes that are regulated by YAP.

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Section: Figmentioning

confidence: 99%

“…YAP also has been shown to play a role in myoblast (31) and neuronal stem cell (32,33) differentiation. Additionally, recent evidence suggests that YAP is involved in cell survival in Wnt-and ␤-catenin-dependent colorectal cancers (34). Clearly, YAP and PyST are both pleiotropic in their actions, with considerable overlap in their biology.…”

mentioning

confidence: 99%

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Hwang

Fernando

Faure

et al. 2014

J Virol

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“…Wnt signaling stabilizes TAZ and promotes TAZ‐dependent transcriptional activation of genes regulated by the TEA domain/Transcription Enhancer Factor (TEAD) family of transcription factors, the main binding partners of both TAZ and YAP1 (Azzolin et al ., 2012). Moreover, β‐catenin and Yes‐associated protein (YAP) act as coactivators of the T‐BOX 5 (TBX5) nuclear factor (Rosenbluh et al ., 2012). Although recent results of Park et al .…”

Section: Discussionmentioning

confidence: 99%

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

Janečková

Fafílek

Krausová

et al. 2016

Genesis

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SummaryThe Wnt pathway plays a crucial role in self‐renewal and differentiation of cells in the adult gut. In the present study, we revealed the functional consequences of inhibition of canonical Wnt signaling in the intestinal epithelium. The study was based on generation of a novel transgenic mouse strain enabling inducible expression of an N‐terminally truncated variant of nuclear Wnt effector T cell factor 4 (TCF4). The TCF4 variant acting as a dominant negative (dn) version of wild‐type (wt) TCF4 protein decreased transcription of β‐catenin‐TCF4‐responsive genes. Interestingly, suppression of Wnt/β‐catenin signaling affected asymmetric division of intestinal stem cells (ISCs) rather than proliferation. ISCs expressing the transgene underwent several rounds of division but lost their clonogenic potential and migrated out of the crypt. Expression profiling of crypt cells revealed that besides ISC‐specific markers, the dnTCF4 production downregulated expression levels of epithelial genes produced in other crypt cells including markers of Paneth cells. Additionally, in Apc conditional knockout mice, dnTCF activation efficiently suppressed growth of Apc‐deficient tumors. In summary, the generated mouse strain represents a convenient tool to study cell‐autonomous inhibition of β‐catenin‐Tcf‐mediated transcription. genesis 54:101–114, 2016. © 2016 The Authors genesis Published by Wiley Periodicals, Inc.

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“…15 Furthermore, the Hahn laboratory reported that in colon cancer, YAP and the transcription factor TBX5 form a complex with b-catenin and phosphorylation of YAP by the YES tyrosine kinase leads to localization of this complex to the promoter of anti-apoptotic genes, including BCL2L1 and BIRC5, defining a b-catenin-YAP-TBX5 complex essential for the transformation and survival of b-catenin-driven colon malignancy. 17 Most recently, using advanced tools of proteomics and proximity ligation, the O'Neill laboratory documented that Ras association domain family 1C (RASSF1C) was able to target Src and Yes kinases to epithelial cell to cell junctions to promote tyrosine phosphorylation of YAP along with b-catenin and E-cadherin and thereby promoting YAP-mediated invasion of carcinomas. 16 All these studies implicate tyrosine phosphorylation in the function of YAP.…”

Section: Introductionmentioning

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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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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β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

Cited by 680 publications

References 69 publications

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

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

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