Zyxin Links Fat Signaling to the Hippo Pathway

Rauskolb, Cordelia; Pan, Guohui; Reddy, B. V. V. G.; Oh, Hyangyee; Irvine, Kenneth D.

doi:10.1371/journal.pbio.1000624

Cited by 151 publications

(179 citation statements)

References 51 publications

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“…Similar processes appear operative in epithelial cells, and available data points to E-cadherin 52 /α catenin 51,61 as an important input, with little direct support thus far for other cell surface and polarity complexes. A variety of proteins in addition to WW45/Salvador have been shown to bind the kinase components and regulate their activity in a positive or negative manner, e.g., Mst1/Mst2 (e.g., the Rassf polypeptides 62,63 ) and Lats1/Lats2 (e.g., Zyxin, 64 Kibra, 65-67 ASPP1, 68,69 LIM domain proteins 70 ). YAP is also found bound to proteins (other than the Src family kinases cYes and cSrc) that modify its activity and localization.…”

Section: Yap Polypeptide Degradation Is Regulated By the Hippo Pathwaymentioning

confidence: 99%

YAP oncogene overexpression supercharges colon cancer proliferation

2012

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The transcriptional co-activator YAP is an evolutionarily conserved regulator of organ size and progenitor cell proliferation. YAP is overexpressed at high frequency in many common human cancers and can directly drive cancer development in mouse models. YAP abundance and nuclear localization are negatively regulated by the Hippo kinase cascade, which, in epithelia, is activated by physiological cell-cell contact. Recent work in intestinal epithelium has established that YAP is constitutively inhibited by the Hippo pathway and entirely dispensable for normal development and homeostasis. YAP serves only in a standby capacity; should cell-cell contact be abrogated, as after intestinal damage, the loss of Hippo input permits increased YAP abundance and nuclear residence. In turn, YAP cooperates with beta-catenin to transactivate genes that promote stem cell expansion for epithelial repair. This interplay between overexpressed YAP and beta-catenin also drives proliferation of colon cancer cells. The dispensability of YAP in normal intestine makes YAP's expression or outputs attractive targets for cancer therapy.NIH [DK17776, CA136567]; Sidney Kimmel Foundation for Cancer Research; Linda J. Verville Cancer Research Foundation; 111 Project of Education of China [B06016]; Fundamental Research Funds for the Central Universities of China [2010111079]; National Natural Science Foundation of China [81101503]; Natural Science Foundation of Fujian [2011J05096

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Section: Yap Polypeptide Degradation Is Regulated By the Hippo Pathwaymentioning

confidence: 99%

YAP oncogene overexpression supercharges colon cancer proliferation

2012

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“…Fat activity is regulated by binding to another protocadherin, Dachsous (Ds) (Matakatsu and Blair, 2006), and is modulated by several proteins such as the casein kinase Discs overgrown (Dco) (Feng and Irvine, 2009;Sopko et al, 2009), the Golgi-resident kinase Four-jointed (Fj) (Rogulja et al, 2008;Willecke et al, 2008;Simon et al, 2010), and the Fat/Ds-interacting protein Lowfat (Lft) (Mao et al, 2009). A LIM domain-containing protein Zyxin (Zyx) also inhibits Hippo signaling possibly by physical interaction with Wts and Dachs downstream of Fat (Rauskolb et al, 2011). dJub, another LIM domain-containing protein that physically interacts with Wts and Sav, was shown to negatively regulate Hippo signaling, although the detailed mechanism has not been delineated (Das Thakur et al, 2010).…”

Section: The Drosophila Hippo Pathwaymentioning

confidence: 99%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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“…A group of apically localised proteins including Crumbs (Crb, CRB1/2/3 in humans), Merlin (Mer, NF2 in humans), Expanded (Ex, similar to Willin and AMOT in humans) and Kibra (Kib, KIBRA or WWC1 in humans) were found to activate Hippo signalling (repressing Yki activity) in Drosophila epithelia (Baumgartner et al, 2010;Chen et al, 2010;Genevet et al, 2010;Hamaratoglu et al, 2006;Ling et al, 2010;Varelas et al, 2010;Yu et al, 2010) and in mice (Szymaniak et al, 2015). In addition, a group of adherens junction-localised proteins including Ajuba (Jub), Zyxin (Zyx), Dachs, Mib and Riquiqui (Riq), were shown to inhibit Hippo signalling (activating Yki) in Drosophila epithelia Das Thakur et al, 2010;Degoutin et al, 2013;Gaspar et al, 2015;Mao et al, 2006;Rauskolb et al, 2011). Finally, manipulation of the level of F-actin in Drosophila can also affect Hippo signalling, possibly via signalling through the Src kinase, which can promote Yki activation (Enomoto and Igaki, 2013;Fernandez et al, 2011Fernandez et al, , 2014Sansores-Garcia et al, 2011).…”

Section: Introductionmentioning

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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Zyxin Links Fat Signaling to the Hippo Pathway

Abstract: Using genetic and molecular analyses, the authors identify Zyx as a positive regulator of Hippo signaling and characterize its role within the pathway.

Cited by 151 publications

References 51 publications

YAP oncogene overexpression supercharges colon cancer proliferation

YAP oncogene overexpression supercharges colon cancer proliferation

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

Integrin signalling regulates YAP and TAZ to control skin homeostasis

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