RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

Cancer Cell. 2017 May 8;31(5):685-696.e6. doi: 10.1016/j.ccell.2017.04.002.

Abstract

Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.

Keywords: DAG; GNA11; GNAQ; MAPK; PKC; RasGEF; RasGRP3; melanoma; uveal melanoma.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Diglycerides / metabolism
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • MAP Kinase Signaling System* / drug effects
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice, Nude
  • Mutation*
  • Phosphorylation
  • Protein Kinase C-delta / antagonists & inhibitors
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism
  • Protein Kinase C-epsilon / antagonists & inhibitors
  • Protein Kinase C-epsilon / genetics
  • Protein Kinase C-epsilon / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Time Factors
  • Transfection
  • Tumor Burden
  • Uveal Melanoma
  • Uveal Neoplasms / drug therapy
  • Uveal Neoplasms / enzymology*
  • Uveal Neoplasms / genetics
  • Uveal Neoplasms / pathology
  • ras Guanine Nucleotide Exchange Factors

Substances

  • Diglycerides
  • GNA11 protein, human
  • GNAQ protein, human
  • GTP-Binding Protein alpha Subunits
  • Guanine Nucleotide Exchange Factors
  • Protein Kinase Inhibitors
  • RASGRP3 protein, human
  • ras Guanine Nucleotide Exchange Factors
  • PRKCD protein, human
  • PRKCE protein, human
  • Protein Kinase C-delta
  • Protein Kinase C-epsilon
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Protein alpha Subunits, Gq-G11