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A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK.

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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Feng X,Arang N,Rigiracciolo DC,Lee JS,Yeerna H,Wang Z,Lubrano S,Kishore A,Pachter JA,König GM,Maggiolini M,Kostenis E,Schlaepfer DD,Tamayo P,Chen Q,Ruppin E,Gutkind JS

doi

10.1016/j.ccell.2019.01.009

subject

Has Abstract

pub_date

2019-03-18 00:00:00

pages

457-472.e5

issue

3

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(19)30043-1

journal_volume

35

pub_type

杂志文章

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