RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Xu Chen, Qiuxia Wu, Philippe Depeille, Peirong Chen, Sophie Thornton, Helen Kalirai, Sarah E. Coupland, Jeroen P. Roose, Boris C. Bastian
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.

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Teaser

Chen et al. find that Ras is required for GNAQ-mediated MAPK activation and identify PKC δ,ɛ and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM). RasGRP3 is selectively overexpressed in response to GNAQ/11 mutations in UM.


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