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

Cancer Cell. 2019 Mar 18;35(3):457-472.e5. doi: 10.1016/j.ccell.2019.01.009. Epub 2019 Feb 14.

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.

Keywords: FAK; G protein; GNA11; GNAQ; Hippo; MOB1; PTK2; YAP; signal transduction; uveal melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Computational Biology
  • Focal Adhesion Kinase 1 / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Genes, Lethal*
  • Hippo Signaling Pathway
  • Humans
  • Melanoma / metabolism*
  • Mice
  • Neoplasm Transplantation
  • Phosphorylation
  • Prognosis
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • Survival Analysis
  • Uveal Neoplasms / metabolism*

Substances

  • GNAQ protein, human
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Protein Serine-Threonine Kinases
  • GTP-Binding Protein alpha Subunits, Gq-G11

Supplementary concepts

  • Uveal melanoma