RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms.
Cell
; 153(5): 1050-63, 2013 May 23.
Article
em En
| MEDLINE
| ID: mdl-23706742
ABSTRACT
RAS proteins are important direct activators of p110α, p110γ, and p110δ type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino-terminal RAS-binding domain (RBD). Here, we investigate the regulation of the ubiquitous p110ß isoform of PI3K, implicated in G-protein-coupled receptor (GPCR) signaling, PTEN-loss-driven cancers, and thrombocyte function. Unexpectedly, RAS is unable to interact with p110ß, but instead RAC1 and CDC42 from the RHO subfamily of small GTPases bind and activate p110ß via its RBD. In fibroblasts, GPCRs couple to PI3K through Dock180/Elmo1-mediated RAC activation and subsequent interaction with p110ß. Cells from mice carrying mutations in the p110ß RBD show reduced PI3K activity and defective chemotaxis, and these mice are resistant to experimental lung fibrosis. These findings revise our understanding of the regulation of type I PI3K by showing that both RAS and RHO family GTPases directly regulate distinct ubiquitous PI3K isoforms and that RAC activates p110ß downstream of GPCRs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas ras
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Classe I de Fosfatidilinositol 3-Quinases
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Fibroblastos
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article