Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP

Angus, Liselotte; Moleirinho, Susana; Herron, Lissa R.; Sinha, Alok; Zhang, X.; Niestrata, M; Dholakia, Kishan; Prystowsky, Michael B.; Harvey, Kieran F.; Reynolds, Paul A.; Gunn-Moore, Frank J.

doi:10.1038/onc.2011.224

Cited by 96 publications

(118 citation statements)

References 36 publications

(52 reference statements)

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“…Recent work by Gunn-Moore and colleagues [6] shows that the Hippo signaling pathway can be activated or blocked by FERM proteins; willin and merlin lead to activation of the pathway while ezrin and moesin block activation. Activation results in a kinase cascade resulting in the phosphorylation of YAP which inactivates this transcription factor resulting in translocation to the cytoplasm and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, they have now been shown to be involved in the control of several different signal transduction pathways, including RhoA, Hedgehog, membrane receptor (e.g. Patched, CD43 or CD44) signalling (reviewed in [3]) and, more recently, Hippo pathway signalling [4][5][6]. In addition to the many binding partners and multiple pathways they control, FERM proteins themselves can be controlled by post-translational modification, such as phosphorylation, and are differentially expressed in normal murine and human tissues [7,8].…”

mentioning

confidence: 99%

“…Altered expression of a subset of 4.1 family proteins is believed to contribute to carcinogenesis and metastasis, as exemplified by the following: merlin has been shown to function as a tumor suppressor [9]; ezrin is believed to play a role in the development of metastasis [10,11]; moesin has been implicated in oral squamous cell carcinomas [12][13][14]; and willin has been shown to antagonize some of the functions of the YAP oncogene [6]. We have shown previously that a high level of cytoplasmic ezrin correlates or that high levels of cytoplasmic ezrin correlate with poor survival in head and neck squamous cell carcinoma [15], and recent studies show that increased expression of ezrin is also associated with poor clinical outcome in a variety of human cancers [16][17][18][19][20][21].…”

mentioning

confidence: 99%

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Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

Brandwein-Gensler

Smith

Kawachi

et al. 2012

Head and Neck Pathol

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Members of the 4.1 superfamily of proteins, including ezrin, moesin, merlin, and willin regulate many normal physiologic processes such as cellular shape, motility, and proliferation. In addition, they contribute both to tumor development and tumor progression. We reported previously that strong cytoplasmic ezrin expression was independently associated with poorer patient survival. One hundred and thirty-one histologically confirmed primary head and neck squamous cell carcinomas were examined prospectively for cancer progression and survival at a large health care center in the Bronx, NY, USA. Immunohistochemical analysis of ezrin, moesin, merlin, and willin expression in tissue microarray samples of primary head and neck squamous cell carcinoma revealed a significant association of increased cytoplasmic ezrin with poor cancer survival. Global RNA analyses suggest that cancers with high cytoplasmic ezrin have a more invasive phenotype.This study supports our previous findings associating cytoplasmic ezrin with more aggressive behavior and poorer outcome and indicates the need for a multi-institutional study to validate the use of cytoplasmic ezrin as a biomarker for treatment planning in head and neck squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

Brandwein-Gensler

Smith

Kawachi

et al. 2012

Head and Neck Pathol

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“…The Hippo pathway core MST1/2-LATS1/2 kinase cascade inhibits YAP/TAZ through direct phosphorylation, which results in cytoplasmic retention via 14-3-3 binding and further promotes ␤-TrCP-mediated YAP/TAZ ubiquitination and degradation (Azzolin et al, 2014;Hansen et al, 2015). This Hippo signaling pathway can be inhibited by knock-down of Willin/FRMD6, which decreases the phosphorylation of MST1/2 and LATS1 (Angus et al, 2012). Upon inhibition of the Hippo pathway, YAP/TAZ are activated and translocated into the nucleus to bind TEAD family transcription factors to stimulate target gene expression involved in cell proliferation, stem cell self-renewal, and tumorigenesis (Azzolin et al, 2014).…”

Section: Promoting Nuclear Accumulation Of Yap/taz Leads To Mechanicamentioning

confidence: 99%

Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain

Deng

et al. 2016

J. Neurosci.

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“…The complex of Nf2 (neurofibromin2, a Mer ortholog), KIBRA and FRMD6 (also known as WILLIN, as potential Ex ortholog) inhibits YAP1 activity (Figure 1) [37]. Nf2, a tumour suppressor gene is currently the only one known Hippo pathway gene that is mutated in cancer (Table 2) [10], especially in cancers of central nervous system [38].…”

Section: Regulation Of the Yap1/taz Activitymentioning

confidence: 99%

The Hippo pathway in colorectal cancer

Wierzbicki

Rybarczyk

2015

Folia Histochem Cytobiol.

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Colorectal cancer (CRC) is one the most frequently diagnosed neoplastic diseases worldwide. Currently, aside from traditional chemotherapy, advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor (EGFR). Since up to 70% of metastasized CRCs are drug resistant, the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment. The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation, differentiation, apoptosis and tumourigenesis. Components of the Hippo pathway are deregulated in various human malignancies, and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer. In this review we focused on recent data regarding Hippo pathway, its up-stream signals and down-stream effectors. Hippo negatively regulates its major effectors, YAP1 and TAZ kinases, which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression. The deregulation of Hippo pathway components was found in many malignancies. The interactions between Hippo and Wnt/b-catenin signalling, crucial in the maintenance of cell homeostasis, have been described in relation to the control of intestinal stem cell proliferation and CRC development. The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal, ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy.

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Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP

Cited by 96 publications

References 36 publications

Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

Cytoplasmic Ezrin and Moesin Correlate with Poor Survival in Head and Neck Squamous Cell Carcinoma

Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain

The Hippo pathway in colorectal cancer

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