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Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J et al.. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21: 2747-2761

Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Genes & Development (Impact Factor: 12.64). 12/2007; 21(21):2747-61. DOI: 10.1101/gad.1602907
Source: PubMed

ABSTRACT The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

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Available from: Weiquan Li, Oct 30, 2014
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    • "In the cultured mammalian cells, Hippo/Yap signaling has been shown to be central to contact inhibition: cell–cell contacts activate Hippo to restrain Yap, thereby limiting cell proliferation. Yap overexpression overcomes contact inhibition in a Tead-dependent manner (Zhao et al., 2007). Yap promotes cell proliferation by stimulating the expression of Ccna2, Ccnb1, Cdc2, Aurka, Aurkb, and Cdc25b (von Gise et al., 2012). "
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    • "Differential signals leading to changes in cell fate between inside and outside cells are associated with the density of cell-cell contacts. The Hippo pathway controls the localization of Yap/ Wwtr1 and therefore Tead activity in response to cell-cell contact in cultured cells (Ota and Sasaki, 2008; Zhao et al., 2007). Hippo signaling is activated by increased cell-cell contacts in insider cells, resulting in the exclusion of Yap1 from nucleus and inhibition of Tead4 transcription (Nishioka et al., 2009). "
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    Developmental Biology 08/2014; 395(1). DOI:10.1016/j.ydbio.2014.08.028
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    • "Activation of the Hippo pathway leads to phosphorylation of LATS1/2 by MST1/2. LATS1/2 in turn phosphorylate YAP on multiple sites, including S127, which promotes cytoplasmic retention of YAP (Zhao et al., 2007; Hao et al., 2008; Lei et al., 2008), and S381 (S397 in human YAP1), which promotes YAP turnover (Zhao et al., 2010b). Expression of ST decreased YAP S127 phosphorylation in BJ fibroblasts and in HMECs (Figure 2A). "
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    ABSTRACT: Primary human cells can be transformed into tumor cells by a defined set of genetic alterations including telomerase, oncogenic Ras(V12), and the tumor suppressors p53 and pRb. SV40 small T (ST) is required for anchorage-independent growth in vitro and in vivo. Here, we identify the Hippo tumor suppressor pathway as a critical target of ST in cellular transformation. We report that ST uncouples YAP from the inhibitory activity of the Hippo pathway through PAK1-mediated inactivation of NF2. Membrane-tethered activated PAK is sufficient to bypass the requirement for ST in anchorage-independent growth. PAK acts via YAP to mediate the transforming effects of ST. Activation of endogenous YAP is required for ST-mediated transformation and is sufficient to bypass ST in anchorage-independent growth and xenograft tumor formation. Our findings uncover the Hippo tumor suppressor pathway as a final gatekeeper to transformation and tumorigenesis of primary cells.
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