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

RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.

Author information

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

PMID:
28486107
PMCID:
PMC5499527
DOI:
10.1016/j.ccell.2017.04.002
[Indexed for MEDLINE]
Free PMC Article

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