RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.

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 has been implicated as a link, but the mechanistic details remained unclear. We identified 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 duanyu1531 δ- and ɛ-dependent phosphorylation and DAG-mediated membrane recruitment, possibly explaining the limited effect of duanyu1531 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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