title: αE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway.
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.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 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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Silvis
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
authors.forename: Yuchi
authors.initials: Y
authors.lastname: Honaker
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Lien
authors.affiliation: Department of Dermatology, University of California at San Fricisco, San Francisco, California, 94143, USA.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Arron
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
authors.forename: Valeri
authors.initials: V
authors.lastname: Vasioukhin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000473:pathology; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051178:alpha Catenin; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases
keywords: SCC; SRC; YAP1; keratinocytes; skin; αE-catenin