αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway

P Li, MR Silvis, Y Honaker, WH Lien… - Genes & …, 2016 - genesdev.cshlp.org
P Li, MR Silvis, Y Honaker, WH Lien, ST Arron, V Vasioukhin
Genes & development, 2016genesdev.cshlp.org
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 …
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.
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