Rac1-mediated membrane raft localization of PI3K/p110ß is required for its activation by GPCRs or PTEN loss.
Elife
; 52016 10 04.
Article
em En
| MEDLINE
| ID: mdl-27700986
ABSTRACT
We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110ß. We found that p110ß localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110ß to rafts alleviated the requirement for p110ß-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110ß dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110ß.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neuropeptídeos
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Membrana Celular
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Proteínas rac1 de Ligação ao GTP
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Microdomínios da Membrana
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PTEN Fosfo-Hidrolase
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Classe Ia de Fosfatidilinositol 3-Quinase
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article