Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein

Bin Zhao; Li Li; Qing Lu; Lloyd H. Wang; Chen-Ying Liu; Qunying Lei; Kun-Liang Guan

doi:10.1101/gad.2000111

Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein

¹Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA;
²Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
³Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA;
⁴Department of Biological Chemistry, School of Medicine, Fudan University, Shanghai, China 200032;
⁵Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai, China 200032

↵6 These authors contributed equally to this work.

Abstract

The Yes-associated protein (YAP) is a transcription coactivator that plays a crucial role in organ size control by promoting cell proliferation and inhibiting apoptosis. The Hippo tumor suppressor pathway inhibits YAP through phosphorylation-induced cytoplasmic retention and degradation. Here we report a novel mechanism of YAP regulation by angiomotin (AMOT) family proteins via a direct interaction. Knockdown of AMOT family protein AMOTL2 in polarized Madin-Darby canine kidney (MDCK) cells leads to YAP activation, as indicated by decreased YAP tight junction localization, attenuated YAP phosphorylation, accumulation of nuclear YAP, and induction of YAP target gene expression. Transcriptional coactivator with PDZ-binding motif (TAZ), the YAP paralog, is also regulated by AMOT in a similar fashion. Furthermore, AMOTL2 knockdown results in loss of cell contact inhibition in a manner dependent on the functions of YAP and TAZ. Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition.