?E-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway.

ABSTRACT: Cell-cell adhesion protein ?E-catenin inhibits skin squamous cell carcinoma (SCC) development; however, the mechanisms responsible for this function are not completely understood. We report here that ?E-catenin inhibits ?4 integrin-mediated activation of SRC tyrosine kinase.SRCis 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 ?E-catenin. We demonstrate that the tumor suppressor function of ?E-catenin involves negative regulation of the ?4 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.

SUBMITTER: Li P 

PROVIDER: S-EPMC4826396 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature