αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway

P, Li; Silvis, Mark R.; Honaker, Yuchi; Lien, Wen-Hui; Arron, Sarah T.; Vasioukhin, Valeri

doi:10.1101/gad.274951.115

Cited by 159 publications

(205 citation statements)

References 58 publications

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“…Our findings re-enforce the important oncogenic function of YAP (21) and explain the basis for its frequent activation in CRC and possibly other epithelial tumors that are devoid of mutations that disrupt Hippo signaling. Indeed, the SFK-YAP module also functions in skin cancer (33). YAP up-regulation in epithelial cancers is also known to account for acquired drug resistance (21), but the underlying mechanisms were not reported.…”

Section: Discussionmentioning

confidence: 99%

YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Taniguchi

Moroishi

Jong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.colorectal cancer | adenomatous polyposis coli | IL-6ST/gp130 | YAP | STAT3

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Section: Discussionmentioning

confidence: 99%

YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Taniguchi

Moroishi

Jong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…One possible mechanism for this observation could be physical interactions between α-catenin and Merlin [66], which could localize Merlin to adherens junctions, although Merlin also associates with tight junction proteins [67]. It was also recently reported that α-catenin inhibits a direct activation of YAP by Src [68]. Whether mammalian homologues of Ds and Fat (Dchs1 and Fat4) regulate the Hippo pathway in mammalian cells is also controversial, as there have been conflicting reports about whether they influence Yap activity [69-71].…”

Section: Dynamic Localization Of Hippo Pathway Componentsmentioning

confidence: 99%

“…As activation of FAK by integrins can be modulated by substrate stiffness [97], regulation of Hippo signaling through FAK could also contribute to influences of the mechanical environment on Hippo signaling, . An alternative mechanism by which Src can promote YAP activity, involving direct phosphorylation of tyrosines residues on YAP by Src, has also recently been described [68, 98]. …”

Section: Regulation Of Hippo Signaling By the Extracellular Matrixmentioning

confidence: 99%

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

Sun

Irvine

2016

Trends in Cell Biology

125

131

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The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo.

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“…On the other hand, p120 directly stabilizes and retains E-cadherin at the cell surface by suppressing E-cadherin endocytosis (19,(24)(25)(26) and coordinates local interactions with the cytoskeleton through recruitment of various RhoGTPase modulators (e.g., RhoGEFs, RhoGAPs, Rho kinase 1 [ROCK1], FRMD5) (27)(28)(29)(30). Other important signaling systems that interface physically and/or functionally with the E-cadherin complex include the Wnt pathway (e.g., APC, β-catenin) (31), the HIPPO pathway (including downstream effectors YAP and TAZ) (32,33), receptor tyrosine kinase (RTK) pathways (e.g., EGFR and downstream effectors) (34)(35)(36), the TGFβRII pathway (37), and NF-κB signaling (38,39). Most of these pathways have oncogenic potential when dysregulated and function in opposition to the growth-suppressive effects of the E-cadherin complex in differentiated epithelia.…”

Section: P120 Functions As An Obligatory Haploinsufficient Tumor Suppmentioning

confidence: 99%

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

Short¹,

Kondo²,

Smalley-Freed³

et al. 2017

Journal of Clinical Investigation

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IntroductionThe vast majority of human colorectal cancer (CRC) is triggered by inactivation of the tumor suppressor adenomatous polyposis coli (APC) in one of several intestinal stem cells (ISCs) present in each intestinal crypt. The result is unscheduled translocation of β-catenin to the nucleus where tumorigenesis is initiated via interaction with the transcription factor TCF4 and unregulated transactivation of Wnt pathway target genes (e.g., AXIN2, MYC) (1-4). The ISC contributes several stem cell-restricted properties (e.g., self-renewal, mesenchymal characteristics) that are hijacked by the constitutively activated Wnt pathway and are essential for tumor initiation. Progression to malignancy involves subsequent genetic and epigenetic alterations, including mutations in genes such as KRAS, SMAD4, and TP53, which are frequently targeted in CRC, and a much larger number of less frequently mutated genes uncovered recently by whole genome sequencing. The transition to malignancy is often accompanied by the onset of metastasis, a phenomenon responsible for most cancer-related mortality and frequently linked to genetic and/or epigenetic dysregulation of the cell-cell adhesion receptor epithelial cadherin (E-cadherin) (5-8).E-cadherin is widely regarded as the principle organizer of the epithelial phenotype (9, 10). It functions as a classic tumor suppressor in diffuse gastric cancer (11) and lobular carcinoma of the breast (12), where germline mutations in the E-cadherin gene (CDH1) are responsible for familial inheritance of one mutant allele. Early loss of the second allele (i.e., loss of heterozygosity [LOH]) then plays a causal role in tumorigenesis (11)(12)(13). In the vast majority of epithelial cancers, however, E-cadherin is considered a metastasis suppressor because it is downregulated in advanced tumors and plays a causal role in the transition to metastasis (5,7,(14)(15)(16). Although factors underpinning the distinct differences in timing of E-cadherin loss between these groups are not understood, the former is frequently irreversible (e.g., gene mutation) while the latter often occurs by epithelial-to-mesenchymal transition (EMT) and is later reversed during colonization of distant sites (17).As with all classical cadherins, E-cadherin mediates specific adhesion of adjacent cells via homophilic interaction between extracellular domains (9). Strong E-cadherin-mediated adhesion, however, is absolutely dependent upon formation of a multimeric complex with 3 cytoplasmic binding partners, namely α-, β-, and p120-catenins (p120) (9,18). All members of the classical cadherin family, in fact, use these same core components to organize the actin cytoskeleton and coordinate signaling (9, 19). p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated wi...

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αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway

Cited by 159 publications

References 58 publications

YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

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