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.

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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:	19 Jan 2023 07:01
DOI:	10.1016/j.ccell.2017.04.002
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3008240