RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.
Cancer Cell
; 31(5): 685-696.e6, 2017 05 08.
Article
em En
| MEDLINE
| ID: mdl-28486107
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 É 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 É-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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MEDLINE
Assunto principal:
Neoplasias Uveais
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Sistema de Sinalização das MAP Quinases
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Fatores de Troca do Nucleotídeo Guanina
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Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP
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MAP Quinases Reguladas por Sinal Extracelular
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Melanoma
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Mutação
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article