Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.
Mol Cell Biol
; 26(1): 63-76, 2006 Jan.
Article
en En
| MEDLINE
| ID: mdl-16354680
ABSTRACT
Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Proteínas Quinasas
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Proteínas
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Fosfatidilinositol 3-Quinasas
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Diabetes Mellitus Tipo 2
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Proteínas Proto-Oncogénicas c-akt
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Glucosa
Límite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cell Biol
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos