Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells.
Biochem Biophys Res Commun
; 483(1): 82-87, 2017 01 29.
Article
en En
| MEDLINE
| ID: mdl-28057484
ABSTRACT
Although type II cGMP-dependent protein kinase (PKGII) is a major downstream effector of cGMP in chondrocytes and attenuates the FGF receptor 3/ERK signaling pathway, its direct target proteins have not been fully explored. In the present study, we attempted to identify PKGII-targeted proteins, which are associated with the inhibition of FGF-induced MAPK activation. Although FGF2 stimulation induced the phosphorylation of ERK1/2, MEK1/2, and Raf-1 at Ser-338 in rat chondrosarcoma cells, pretreatment with a cell-permeable cGMP analog strongly inhibited their phosphorylation. On the other hand, Ser-43 of Raf-1 was phosphorylated by cGMP in a dose-dependent manner. Therefore, we examined the direct phosphorylation of Raf-1 by PKGII. Wild-type PKGII phosphorylated Raf-1 at Ser-43 in a cGMP-dependent manner, but a PKGII D412A/R415A mutant, which has a low affinity for cGMP, did not. Finally, we found that a phospho-mimic mutant, Raf-1 S43D, suppressed FGF2-induced MAPK pathway. These results suggest that PKGII counters FGF-induced MEK/ERK activation through the phosphorylation of Raf-1 at Ser-43 in chondrocytes.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Condrosarcoma
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Factor 2 de Crecimiento de Fibroblastos
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Proteínas Proto-Oncogénicas c-raf
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Proteína Quinasa Dependiente de GMP Cíclico Tipo II
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2017
Tipo del documento:
Article