| Literature DB >> 30773340 |
Xiaodong Feng1, Nadia Arang2, Damiano Cosimo Rigiracciolo3, Joo Sang Lee4, Huwate Yeerna5, Zhiyong Wang2, Simone Lubrano5, Ayush Kishore5, Jonathan A Pachter6, Gabriele M König7, Marcello Maggiolini8, Evi Kostenis7, David D Schlaepfer5, Pablo Tamayo9, Qianming Chen10, Eytan Ruppin11, J Silvio Gutkind12.
Abstract
Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.Entities:
Keywords: FAK; G protein; GNA11; GNAQ; Hippo; MOB1; PTK2; YAP; signal transduction; uveal melanoma
Mesh：
Substances：
Year: 2019 PMID： 30773340 PMCID： PMC6737937 DOI： 10.1016/j.ccell.2019.01.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743