Article

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

Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States
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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    • "Therefore, there is an urgency to identify an alternative " druggable " molecule, that 1) mediates (or acts coordinately with HIF-1α) the malignant cellular behavior such as hypoxic resistance and 2) could be easily targeted with small molecules agents, thus opening the unexplored routes for therapeutic intervention aiming at combat with drug resistance under hypoxia. Recent studies reported that YAP overexpression and activation is correlated with poor prognosis of cancer patients[18,40], likely because it promotes tumor progression[27,41]and/or metastasis424344. Accumulating evidence suggests that the activated YAP contributes to the drug resistance of cancer cells. "
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    ABSTRACT: Although hypoxia is a prominent feature contributing to the therapeutic resistance of hepatocellular carcinoma cells (HCC) against chemotherapeutic agents, including the Topoisomerase I inhibitor SN38, the underlying mechanism is not fully understood and its understanding remains a major clinical challenge. In the present study, we found that hypoxia-induced nuclear translocation and accumulation of YAP acted as a survival input to promote resistance to SN38 in HCC. The induction of YAP by hypoxia was not mediated by HIF-1α because manipulating the abundance of HIF-1α with CoCl2, exogenous expression, and RNA interference had no effect on the phosphorylation or total levels of YAP. The mevalonate-HMG-CoA reductase (HMGCR) pathway may modulate the YAP activation under hypoxia. Combined YAP inhibition using either siRNA or the HMGCR inhibitor statins together with SN38 treatment produced improved anti-cancer effects in HCC cells. The increased anti-cancer effect of the combined treatment with statins and irinotecan (the prodrug of SN-38) was further validated in a human HepG2 xenograft model of HCC in nude mice. Taken together, our findings identify YAP as a novel mediator of hypoxic-resistance to SN38. These results suggest that the administration of SN28 together with the suppression of YAP using statins is a promising strategy for enhancing the treatment response in HCC patients, particularly in advanced stage HCC cases presenting hypoxic resistance.
    Preview · Article · Jan 2016 · Oncotarget
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    • "Therefore, MST1/2 and MAP4Ks have partially redundant roles in LATS1/2 regulation. Phosphorylation of YAP and TAZ leads to their binding with 14-3-3, and the 14-3-3 binding causes cytoplasmic sequestration of YAP/TAZ (Zhao et al. 2007). Moreover, LATS-induced phosphorylation triggers subsequent phosphorylation of YAP/TAZ by Casein kinase 1δ/ε and recruitment of the SCF E3 ubiquitin ligase, leading to eventual YAP/TAZ ubiquitination and degradation (Liu et al. 2010; Zhao et al. 2010). "
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    ABSTRACT: The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell– cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.
    Preview · Article · Jan 2016 · Genes & Development
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    • "YAP, in turn, is essential to modulate cell proliferation and differentiation, apoptosis, organ size, and morphogenesis of various tissues (Zhao et al., 2011). In epithelial tissues, for example, YAP has been shown to be regulated by the formation of cell–cell contacts, to be required for contact inhibition of cell proliferation (Zhao et al., 2007), and to respond to mechanical perturbation of the epithelial sheet (Aragona et al., 2013). In all these situations, actin cytoskeletal–based mechanical forces have been shown to be the overarching regulator of the activity of YAP and its related molecule TAZ, setting responsiveness to a variety of key signaling axes, including the Hippo, WNT, and G protein–coupled receptor pathways. "
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    ABSTRACT: Vascular endothelial (VE)-cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14-3-3-YAP associates with the VE-cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity.
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