RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma



Chen, Xu, Wu, Qiuxia, Depeille, Philippe, Chen, Peirong, Thornton, Sophie ORCID: 0000-0001-7693-7279, Kalirai, Helen ORCID: 0000-0002-4440-2576, Coupland, Sarah E ORCID: 0000-0002-1464-2069, Roose, Jeroen P and Bastian, Boris C
(2017) RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer Cell, 31 (5). 685 - 696.e6.

[img] Text
Combined PDF.pdf - Accepted Version

Download (6MB)

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.

Item Type: Article
Uncontrolled Keywords: PKC, uveal melanoma, GNAQ, GNA11, RasGRP3, MAPK, DAG, melanoma, RasGEF
Depositing User: Symplectic Admin
Date Deposited: 30 Jun 2017 10:24
Last Modified: 25 Oct 2021 20:11
DOI: 10.1016/j.ccell.2017.04.002
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3008240