RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma - Archive ouverte HAL
Article Dans Une Revue Cancer Cell Année : 2017

RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma

Résumé

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.

Domaines

Cancer

Dates et versions

hal-04653035 , version 1 (18-07-2024)

Identifiants

Citer

Xu Chen, Qiuxia Wu, P. Depeille, Peirong Chen, Sophie Thornton, et al.. RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer Cell, 2017, 31 (5), pp.685-696.e6. ⟨10.1016/j.ccell.2017.04.002⟩. ⟨hal-04653035⟩
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