αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway
Open Access
- 24 March 2016
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 30 (7), 798-811
- https://doi.org/10.1101/gad.274951.115
Abstract
Cell–cell adhesion protein αE-catenin inhibits skin squamous cell carcinoma (SCC) development; however, the mechanisms responsible for this function are not completely understood. We report here that αE-catenin inhibits β4 integrin-mediated activation of SRC tyrosine kinase. SRC is the first discovered oncogene, but the protein substrate critical for SRC-mediated transformation has not been identified. We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC–YAP1-mediated transformation. We uncovered a marked increase in this YAP1 phosphorylation in human and mouse SCC tumors with low/negative expression of αE-catenin. We demonstrate that the tumor suppressor function of αE-catenin involves negative regulation of the β4 integrin–SRC signaling pathway and that SRC-mediated phosphorylation and activation of YAP1 are an alternative to the canonical Hippo signaling pathway that directly connect oncogenic tyrosine kinase signaling with YAP1.Keywords
Funding Information
- National Cancer Institute (CA188452, CA179914)
- National Institutes of Health (T32 CA09657)
This publication has 58 references indexed in Scilit:
- Governing epidermal homeostasis by coupling cell–cell adhesion to integrin and growth factor signaling, proliferation, and apoptosisProceedings of the National Academy of Sciences of the United States of America, 2012
- E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway componentsProceedings of the National Academy of Sciences of the United States of America, 2011
- Yap1 Acts Downstream of α-Catenin to Control Epidermal ProliferationCell, 2011
- The Hippo Signaling Pathway in Development and CancerDevelopmental Cell, 2010
- Adhesive and Signaling Functions of Cadherins and Catenins in Vertebrate DevelopmentCold Spring Harbor Perspectives in Biology, 2009
- α–E-catenin binds to dynamitin and regulates dynactin-mediated intracellular trafficThe Journal of cell biology, 2008
- The TEAD/TEF Family Protein Scalloped Mediates Transcriptional Output of the Hippo Growth-Regulatory PathwayDevelopmental Cell, 2008
- Bench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesisSeminars in Cancer Biology, 2008
- Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth controlGenes & Development, 2007
- β4 integrin activates a Shp2–Src signaling pathway that sustains HGF-induced anchorage-independent growthThe Journal of cell biology, 2006