RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

Xu Chen; Qiuxia Wu; Philippe Depeille; Peirong Chen; Sophie Thornton; Helen Kalirai; Sarah E Coupland; Jeroen P Roose; Boris C Bastian

doi:10.1016/j.ccell.2017.04.002

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.

Authors

Xu Chen¹, Qiuxia Wu², Philippe Depeille³, Peirong Chen², Sophie Thornton⁴, Helen Kalirai⁴, Sarah E Coupland⁴, Jeroen P Roose³, Boris C Bastian⁵

Affiliations

¹ Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: xu.chen@ucsf.edu.
² Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Molecular and Clinical Cancer Medicine, Institute of Translational Mewdicine, University of Liverpool, Liverpool L7 8TX, UK.
⁵ Departments of Dermatology and Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: boris.bastian@ucsf.edu.

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 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

Supplementary concepts

Uveal melanoma

Abstract

MeSH terms

Substances

Supplementary concepts

Grants and funding