A Rapamycin-Sensitive Pathway Down-Regulates Insulin Signaling via Phosphorylation and Proteasomal Degradation of Insulin Receptor Substrate-1
Autor: | Junko Kawahara, Tatsuhito Uno, Prem M. Sharma, Tetsuro Haruta, Katsuya Egawa, Atsuko Takano, Masashi Kobayashi, Jerrold M. Olefsky |
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Rok vydání: | 2000 |
Předmět: |
Proteasome Endopeptidase Complex
medicine.medical_treatment Lactacystin Gene Expression Deoxyglucose Biology Kidney Transfection Adenoviridae Cell Line Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Endocrinology Multienzyme Complexes Insulin receptor substrate Adipocytes medicine Animals Humans Insulin Enzyme Inhibitors Phosphorylation Molecular Biology Phosphoinositide-3 Kinase Inhibitors Sirolimus GRB10 3T3 Cells General Medicine Embryo Mammalian Phosphoproteins IRS2 Acetylcysteine IRS1 Cysteine Endopeptidases Insulin receptor Biochemistry chemistry Insulin Receptor Substrate Proteins biology.protein Signal Transduction |
Zdroj: | Molecular Endocrinology. 14:783-794 |
ISSN: | 1944-9917 0888-8809 |
Popis: | Insulin receptor substrate-1 (IRS-1) is a major substrate of the insulin receptor and acts as a docking protein for Src homology 2 domain containing signaling molecules that mediate many of the pleiotropic actions of insulin. Insulin stimulation elicits serine/threonine phosphorylation of IRS-1, which produces a mobility shift on SDS-PAGE, followed by degradation of IRS-1 after prolonged stimulation. We investigated the molecular mechanisms and the functional consequences of these phenomena in 3T3-L1 adipocytes. PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor, blocked both the insulin-induced electrophoretic mobility shift and degradation of IRS-1. Adenovirus-mediated expression of a membrane-targeted form of the p110 subunit of phosphatidylinositol (PI) 3-kinase (p110CAAX) induced a mobility shift and degradation of IRS-1, both of which were inhibited by rapamycin. Lactacystin, a specific proteasome inhibitor, inhibited insulin-induced degradation of IRS-1 without any effect on its electrophoretic mobility. Inhibition of the mobility shift did not significantly affect tyrosine phosphorylation of IRS-1 or downstream insulin signaling. In contrast, blockade of IRS-1 degradation resulted in sustained activation of Akt, p70 S6 kinase, and mitogen-activated protein (MAP) kinase during prolonged insulin treatment. These results indicate that insulin-induced serine/threonine phosphorylation and degradation of IRS-1 are mediated by a rapamycin-sensitive pathway, which is downstream of PI 3-kinase and independent of ras/MAP kinase. The pathway leads to degradation of IRS-1 by the proteasome, which plays a major role in down-regulation of certain insulin actions during prolonged stimulation. |
Databáze: | OpenAIRE |
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