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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2011-4-27
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pubmed:abstractText |
The identity of specific serine phosphorylation residues of insulin receptor substrate (IRS)-2 and their impact on insulin signal transduction are largely unknown. Ser(675) and Ser(907) of mouse IRS-2 are adjacent to PI 3-kinase or Grb2 binding domains, respectively. Using monoclonal phosphosite-specific antibodies, we demonstrated the phosphorylation of both serines after stimulation of Fao hepatoma cells with insulin, anisomycin, or phorbol esters. Phosphorylation of both sites was a late and prolonged event during insulin treatment and was also detected in liver tissue of insulin-treated as well as refed mice. Inhibition and siRNA-mediated knockdown of ERK1/2 indicated that the insulin-induced phosphorylation of Ser(907) was ERK dependent. Phosphorylation of Ser(907) did not prevent the insulin-induced association of IRS-2 with Grb2, but phosphorylation of the adjacent Tyr(911) was proved to be crucial in HEK 293 cells expressing IRS-2 Ala mutants. The insulin-induced phosphorylation of Ser(675) was prevented by inhibition and siRNA-mediated knockdown of mTOR but not of p70(S6K1). Mutation of Ser(675) to Ala did not affect downstream insulin signaling but increased the half-life of the protein, suggesting an involvement of phospho-Ser(675) in an accelerated degradation of IRS-2. Moreover, the insulin-induced degradation of IRS-2 was blocked by inhibition of mTOR. We conclude that the two novel insulin-dependent serine phosphorylation sites of IRS-2 were not involved in the regulation of the adjacent PI 3-kinase and Grb2 binding domains but might be implicated in the ERK- and mTOR-mediated negative feedback control.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoglycemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/IRS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1522-1555
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
300
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
E824-36
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21098738-Animals,
pubmed-meshheading:21098738-Antibodies, Monoclonal,
pubmed-meshheading:21098738-Blotting, Western,
pubmed-meshheading:21098738-Computational Biology,
pubmed-meshheading:21098738-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:21098738-HEK293 Cells,
pubmed-meshheading:21098738-Hepatocytes,
pubmed-meshheading:21098738-Humans,
pubmed-meshheading:21098738-Hypoglycemic Agents,
pubmed-meshheading:21098738-Immunoprecipitation,
pubmed-meshheading:21098738-Insulin,
pubmed-meshheading:21098738-Insulin Receptor Substrate Proteins,
pubmed-meshheading:21098738-Mice,
pubmed-meshheading:21098738-Mutagenesis, Site-Directed,
pubmed-meshheading:21098738-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:21098738-Phosphorylation,
pubmed-meshheading:21098738-RNA,
pubmed-meshheading:21098738-RNA, Small Interfering,
pubmed-meshheading:21098738-Rats,
pubmed-meshheading:21098738-Serine,
pubmed-meshheading:21098738-TOR Serine-Threonine Kinases,
pubmed-meshheading:21098738-Transfection
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pubmed:year |
2011
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pubmed:articleTitle |
Insulin-induced serine phosphorylation of IRS-2 via ERK1/2 and mTOR: studies on the function of Ser675 and Ser907.
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pubmed:affiliation |
Dept. of Internal Medicine, Div. of Pathobiochemistry and Clinical Chemistry, Univ. of Tuebingen, Otfried-Mueller-Straße 10, 72076 Tuebingen, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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