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. Gene Dev 21: 2747-2761

Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Genes & Development (Impact Factor: 10.8). 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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    • "The overproliferative phenotype was strongly exacerbated upon overexpression of a Yap mutant construct where Ser-98 was replaced by an alanine (Yap S98A ) (Figure 1I). This residue (Ser-127 in mammalian YAP) is a conserved Lats phosphorylation site that has been shown to mediate the growth-suppressive output of the Hippo signaling cascade in vivo (Zhao et al., 2007). In contrast, overexpression of a truncated construct lacking the TEAD binding site (Yap ΔTBS ) was unable to trigger enhanced proliferation in the CMZ, suggesting that the overproliferative phenotype requires interaction with a TEAD protein (Figure 1—figure supplement 3). "
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    ABSTRACT: The adult frog retina retains a reservoir of active neural stem cells that contribute to continuous eye growth throughout life. We found that Yap, a downstream effector of the Hippo pathway, is specifically expressed in these stem cells. Yap knock-down leads to an accelerated S-phase and an abnormal progression of DNA replication, a phenotype likely mediated by upregulation of c-Myc. This is associated with an increased occurrence of DNA damage and eventually p53-p21 pathway-mediated cell death. Finally, we identified PKNOX1, a transcription factor involved in the maintenance of genomic stability, as a functional and physical interactant of yes-associated protein (YAP). Altogether, we propose that YAP is required in adult retinal stem cells to regulate the temporal firing of replication origins and quality control of replicated DNA. Our data reinforce the view that specific mechanisms dedicated to S-phase control are at work in stem cells to protect them from genomic instability.
    eLife Sciences 08/2015; 4. DOI:10.7554/eLife.08488.001 · 9.32 Impact Factor
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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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    ABSTRACT: The adult mammalian heart exhibits limited regenerative capacity after myocardial injury, a shortcoming that is responsible for the current lack of definitive treatments for heart failure. A search for approaches that might enhance adult heart regeneration has led to interest in the Hippo/YAP signaling pathway, a recently discovered signaling pathway that regulates cell proliferation and organ growth. Here we provide a brief overview of the Hippo/YAP pathway and its known roles in the developing and adult heart. We discuss the implications of Hippo/YAP signaling for regulation of cardiomyocyte death and regeneration.
    Stem Cell Research 11/2014; 13(3). DOI:10.1016/j.scr.2014.04.010 · 3.69 Impact Factor
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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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    ABSTRACT: In the developmental process of the early mammalian embryo, it is crucial to understand how the identical cells in the early embryo later develop different fates. Along with existing models, many recently discovered molecular, cellular and developmental factors play roles in cell position, cell polarity and transcriptional networks in cell fate regulation during preimplantation. A structuring process known as compaction provides the "start signal" for cells to differentiate and orchestrates the developmental cascade. The proper intercellular junctional complexes assembled between blastomeres act as a conducting mechanism governing cellular diversification. Here, we provide an overview of the diversification process during preimplantation development as it relates to intercellular junctional complexes. We also evaluate transcriptional differences between embryonic lineages according to cell- cell adhesion and the contributions of adhesion to lineage commitment. These series of processes indicate that proper cell fate specification in the early mammalian embryo depends on junctional interactions and communication, which play essential roles during early morphogenesis.
    Developmental Biology 08/2014; 395(1). DOI:10.1016/j.ydbio.2014.08.028 · 3.55 Impact Factor
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