PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes.
Mol Cell
; 65(3): 416-431.e6, 2017 Feb 02.
Article
em En
| MEDLINE
| ID: mdl-28157504
ABSTRACT
Protein kinase B/Akt regulates cellular metabolism, survival, and proliferation in response to hormones and growth factors. Hyperactivation of Akt is frequently observed in cancer, while Akt inactivation is associated with severe diabetes. Here, we investigated the molecular and cellular mechanisms that maintain Akt activity proportional to the activating stimulus. We show that binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3) or PI(3,4)P2 to the PH domain allosterically activates Akt by promoting high-affinity substrate binding. Conversely, dissociation from PIP3 was rate limiting for Akt dephosphorylation, dependent on the presence of the PH domain. In cells, active Akt associated primarily with cellular membranes. In contrast, a transforming mutation that uncouples kinase activation from PIP3 resulted in the accumulation of hyperphosphorylated, active Akt in the cytosol. Our results suggest that intramolecular allosteric and cellular mechanisms cooperate to restrict Akt activity to cellular membranes, thereby enhancing the fidelity of Akt signaling and the specificity of downstream substrate phosphorylation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilinositóis
/
Membrana Celular
/
Proteínas Proto-Oncogênicas c-akt
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article