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


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
    • "These genes are transcriptionally regulated by the family of TEAD (TEA/ATTS domain) transcription factors, to which YAP and TAZ serve as co-activators (Pobbati and Hong 2013 Zhao et al., 2008). The activity of YAP and TAZ is controlled by the Hippo signaling pathway, which has been suggested to play a key role in the maintenance of contact inhibition (Yu and Guan 2013; Zhao et al., 2007). The fact that the genes controlled by this pathway were induced upon the release of WB-F344 cells from contact inhibition prompted us to analyze the effects of TCDD, an efficient and persistent AhR ligand, on expression of Birc5, which encodes survivin, another known YAP/TAZ – TEAD transcriptional target (Pobbati and Hong, 2013 Zhao et al., 2008). "

    Toxicology Letters 10/2015; 238(2):S298. DOI:10.1016/j.toxlet.2015.08.854 · 3.26 Impact Factor
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    • "For example , the amplification of the YAP gene locus at 11q22 is found in several types of cancers (Snijders et al, 2005; Overholtzer et al, 2006; Zender et al, 2006; Fernandez et al, 2009; Kang et al, 2011; Muramatsu et al, 2011). Overexpression and nuclear localization of the YAP protein has been noted in colon, liver, lung, ovarian, and prostate cancers (Snijders et al, 2005; Zhao et al, 2007; Steinhardt et al, 2008; Zhang et al, 2011; Yu & Guan, 2013; He et al, 2015). "
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    ABSTRACT: The Hippo signaling pathway controls organ size and tumorigene-sis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-a and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-a, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.
    EMBO Molecular Medicine 09/2015; 7(11):e201404976. DOI:10.15252/emmm.201404976 · 8.67 Impact Factor
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    • "*For correspondence: Lecaudey@bio.uni-frankfurt.de Contact inhibition of proliferation was found to be largely mediated by the Hippo signaling pathway (Zhao et al., 2007). Downstream of cell–cell adhesion and apicobasal polarity, many junction-associated proteins including E-cadherin, α-catenin, and proteins of the Crumbs and Par complexes promote Hippo signaling (Kim et al., 2011; Schlegelmilch et al., 2011; Silvis et al., 2011; Enderle and McNeill, 2013). "
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    ABSTRACT: During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. Here we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08201 · 9.32 Impact Factor
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