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

School of Biology, University of St Andrews, St Andrews, UK.
Oncogene (Impact Factor: 8.56). 06/2011; 31(2):238-50. DOI: 10.1038/onc.2011.224
Source: PubMed

ABSTRACT The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Drosophila melanogaster protein Expanded acts in the Hippo signaling pathway to control organ size. Previously, willin/FRMD6 has been proposed as the human orthologue of Expanded. Willin lacks C-terminal sequences that are present in Expanded and, to date, little is known about the functional role of willin in mammalian cells. When willin is expressed in D. melanogaster epithelial tissues, it has the same subcellular localization as Expanded, but cannot rescue growth defects associated with expanded deficiency. However, we show that ectopic willin expression causes an increase in phosphorylation of the core Hippo signaling pathway components MST1/2, LATS1 and YAP, an effect that can be antagonized by ezrin. In MCF10A cells, loss of willin expression displays epithelial-to-mesenchymal transition features and willin overexpression antagonizes YAP activity via the N-terminal FERM domain of willin. Therefore, in mammalian cells willin influences Hippo signaling activity by activating the core Hippo pathway kinase cassette.

  • Source
    • "Overexpression of hYAP1 S127A increased the expression of three Hippo signal transduction pathway genes at both 20 h and 40 h that have been reported to inhibit Yap activity. They are Willin/Frmd6 (Angus et al., 2012), angiomotin-like 2 (amotl2) (Zhao et al., 2011) and ajuba (Das Thakur et al., 2010). After 40 h of doxycycline treatment another putative Yap inhibitor and Hippo pathway member, WWc2 [WW and C2 domain containing 2; kibra homologue (Yoshihama et al., 2012)], is additionally upregulated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Satellite cells are the resident adult stem cells of skeletal muscle. Mitotically quiescent in mature muscle, they can be activated to proliferate and generate myoblasts to supply further myonuclei to hypertrophying or regenerating muscle fibres, or self-renew to maintain the resident stem cell pool. Here, we identify the transcriptional co-factor Yap as a novel regulator of satellite cell fate decisions. Yap expression increases during satellite cell activation and Yap remains highly expressed until after the differentiation versus self-renewal decision is made. Constitutive expression of Yap maintains Pax7(+) and MyoD(+) satellite cells and satellite cell-derived myoblasts, promotes proliferation but prevents differentiation. In contrast, Yap knock down reduces the proliferation of satellite cell-derived myoblasts by ≈40%. Consistent with the cellular phenotype, microarrays show that Yap increases expression of genes associated with Yap inhibition, the cell cycle, ribosome biogenesis and that Yap represses several genes associated with angiotensin signalling. We also identify known regulators of satellite cell function such as BMP4, CD34 and Myf6 (Mrf4) as genes whose expression is dependent on Yap activity. Finally we confirm in myoblasts that Yap binds to Tead transcription factors and co-activates MCAT elements which are enriched in the proximal promoters of Yap-responsive genes.
    Journal of Cell Science 10/2012; 125(24). DOI:10.1242/jcs.109546 · 5.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diese Leistung kann mit Hilfe eines elektrodynamischen Meßwerkes gemessen werden. Dazu schickt man den Strom I durch die Feldspule (Widerstand R WA) und legt die Spannung U an die Drehspule (Widerstand R WV) an. Abbildung 8.1 zeigt die entsprechende Schaltung mit dem elektrodynamischen Meßwerk.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic and biochemical studies have defined the Hippo pathway as a central mediator of developmental and pathogenic signals. By directing intracellular signaling events, the Hippo pathway fine-tunes cell proliferation, cell death, and cell-fate decisions, and coordinates these cues to specify animal organ size. Recent studies have revealed that Hippo pathway-mediated processes are interconnected with those of other key signaling cascades, such as those mediated by TGF-β and Wnt growth factors. Moreover, several reports have described a role for cell contact-mediated polarity proteins in Hippo pathway regulation. Emerging details suggest that crosstalk between these signals drives fundamental developmental processes, and deregulated intercellular communication influences disease progression, such as cancer. We review recent data with a focus on how the Hippo pathway integrates its activity with other signaling pathways.
    Trends in cell biology 12/2011; 22(2):88-96. DOI:10.1016/j.tcb.2011.10.002 · 12.31 Impact Factor
Show more