Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.

By Bin Zhao, Xiaomu Wei, Weiquan Li, Ryan S. Udan, Qian Yang, Joungmok Kim, Joe Xie, T. Ikenoue, Jindan Yu, Li Li and 6 more. Genes & Development, 2007

3,019 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/750c8dc3454734d7b04ebd2025be75042597c035

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In Cell Biology

1. K. Guan
2. S. Piccolo
3. Bin Zhao
4. Duojia Pan
5. M. Cordenonsi
6. Xaralabos Varelas
7. S. Dupont
8. G. Halder

In Molecular Biology

1. K. Guan
2. Bin Zhao
3. Duojia Pan
4. S. Piccolo
5. Xaralabos Varelas
6. M. Cordenonsi
7. Yonggang Zheng
8. S. Dupont

Citations in the corpus

• Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. (2012, background): “Phosphorylation of YAP S127 generates a 14-3-3-binding motif responsible for YAP cytoplasmic retention (Zhao et al. 2007; Hao et al. 2008).”
• CDK8/9 drive Smad transcriptional action, turnover and YAP interactions in BMP and TGFβ pathways (2009, neutral): “A Link to the Hippo Pathway Activation of the Hippo pathway by cell density cues triggers a kinase cascade that culminates in the inactivation of YAP (Yorkie in Drosophila), a transcriptional coactivator that acts through interactions with enhancer-binding factors, including TEAD/scalloped, Runx, p7”
• The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. (2008, background): “As abnormal activation of YAP is associated with multiple types of cancer (Dong et al., 2007; Overholtzer et al., 2006; Zender et al., 2006; Zhao et al., 2007), disrupting YAP-TEAD/TEF interaction may provide a new strategy for cancer therapeutics.”
• Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “EZH2 expression is negatively regulated by miR-101, and miR-101 expression decreases during cancer progression, concomitant with somatic loss of one or both miR-101 alleles (Zhao et al. 2007).”
• The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain (2012, methodology): “The human YAPS127A construct was cloned from pCDNA-YAPS127A (a kind gift from Kun-Liang Guan, University of California at San Diego, La Jolla, CA) (1) into the indicated versions of the murine stem cell virus (MSCV) retroviral vector (Table S1).”
• Mechanisms of Hippo pathway regulation (2016, neutral): “For example, cell–cell contact at high cell density produces a growth inhibitory signal that is in large part mediated by the Hippo pathway (Zhao et al. 2007; Ota and Sasaki 2008; Nishioka et al. 2009).”
• The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease (2014, background): “Cell contact-mediated adhesion has been shown to potently restrict TAZ/YAP in the cytoplasm, contributing to the contact inhibition phenotypes observed in non-transformed cells (Zhao et al., 2007).”
• TEAD mediates YAP-dependent gene induction and growth control. (2008, methodology): “This mechanism of YAP regulation is involved in cell contact inhibition and tissue growth control (Zhao et al. 2007).”
• KRAS and YAP1 converge to regulate EMT and tumor survival (2014, background): “Manipulating KRAS expression did not affect phosphorylation of YAP1 serine-127, a site implicated in regulation of YAP1 by Hpo signaling (Zhao et al., 2007), nor phosphorylation of components of the Hpo cascade such as LATS-1/2 and MST2 (Fig.”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “The existence of an evolutionarily conserved kinase cascade culminating on the phosphorylation of YAP and TAZ, the mammalian counterpart of Yki, was soon demonstrated in mammalian cells (Dong et al., 2007; Lei et al., 2008; Zhao et al., 2007).”