Alternative Wnt Signaling Activates YAP/TAZ

Park, Hyun Woo; Kim, Young Chul; B, Yu; Moroishi, Toshiro; Mo, Jung Soon; Plouffe, Steven W.; Meng, Zhipeng; Lin, Kai; Yu, Fa-Xing; Alexander, Caroline M.; Wang, Cun Yu; Guan, Kun Liang

doi:10.1016/j.cell.2015.07.013

Cited by 575 publications

(612 citation statements)

References 67 publications

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“…These results provide multiple lines of evidence supporting a novel function of APC in regulating YAP activity, separate from its well-established role in the β-catenin destruction complex. In agreement with our findings, Guan and colleagues (Park et al 2015;K.-l. Guan, pers. comm.…”

Section: Yap Is a Critical Downstream Effector Of Apc Independent Ofsupporting

confidence: 83%

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

et al. 2015

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Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo-YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex.

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Section: Yap Is a Critical Downstream Effector Of Apc Independent Ofsupporting

confidence: 83%

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

et al. 2015

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“…Consistent with recent findings, we did not observe direct regulation of YAP or TAZ protein levels or activity by the Wnts or β-catenin (71,72). The negative regulation of the YAP/TAZ/Notch positive feedback loop by Wnt/β-catenin signaling is critically important in both cell fate regulation, metabolic zonation (73), and tumor formation in the liver (Figure 7).…”

Section: Stat3 Activation Is Not Required For Hcc Formation Caused Bysupporting

confidence: 78%

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

Kim

Khan

Gvozdenović-Jeremić

et al. 2016

Journal of Clinical Investigation

207

158

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“…Our model raises interesting questions about the possible physiological roles of other YAP regulators identified in cell culture, namely that YAP is controlled by Wnt signalling (Azzolin et al, 2014;Cai et al, 2015;Park et al, 2015), GPCR signalling , PKA signalling , LKB1-MARK signalling (Mohseni et al, 2014), protease-activated receptors (Mo et al, 2012) or the Mevalonate pathway (Sorrentino et al, 2014). Further work is necessary to understand in which tissues and under what conditions these diverse signals are utilised and integrated in vivo.…”

Section: Discussionmentioning

confidence: 99%

Integrin signalling regulates YAP and TAZ to control skin homeostasis

Elbediwy¹,

Vincent‐Mistiaen²,

Spencer‐Dene³

et al. 2016

Journal of Cell Science

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The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

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Alternative Wnt Signaling Activates YAP/TAZ

Cited by 575 publications

References 67 publications

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

Integrin signalling regulates YAP and TAZ to control skin homeostasis

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