Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.
Nat Cell Biol
; 5(5): 427-32, 2003 May.
Article
em En
| MEDLINE
| ID: mdl-12717443
ABSTRACT
The signalling cascade including Raf, mitogen-activated protein kinase (MAPK) kinase and extracellular-signal-regulated kinase (ERK) is important in many facets of cellular regulation. Raf is activated through both Ras-dependent and Ras-independent mechanisms, but the regulatory mechanisms of Raf activation remain unclear. Two families of membrane-bound molecules, Sprouty and Sprouty-related EVH1-domain-containing protein (Spred) have been identified and characterized as negative regulators of growth-factor-induced ERK activation. But the molecular functions of mammalian Sproutys have not been clarified. Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. In addition, Sprouty4 mutants of the amino-terminal region containing the conserved tyrosine residue, which is necessary for suppressing fibroblast growth factor signalling, still inhibit the VEGF-induced ERK pathway. Our results show that receptor tyrosine kinases use distinct pathways for Raf and ERK activation and that Sprouty4 differentially regulates these pathways.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Membrana Celular
/
Substâncias de Crescimento
/
Receptores Proteína Tirosina Quinases
/
Proteínas Proto-Oncogênicas c-raf
/
Sistema de Sinalização das MAP Quinases
/
Células Eucarióticas
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article