Role of phosphatidylinositol-3-kinase in insulin receptor signaling: studies with inhibitor, LY294002.
In order to study the role of phosphatidylinositol-3-kinase (PI3K) in insulin action, we employed a specific inhibitor of PI3K, LY294002, and measured five biological functions of insulin in mouse 3T3 fibroblasts overexpressing human insulin receptors. LY294002 had no effect on tyrosine phosphorylation of both the insulin receptor beta-subunit and insulin receptor substrate 1 (IRS-1) and did not influence the association of the p85 subunit of PI3K with IRS-1. However, LY294002 partially inhibited insulin stimulated glucose uptake, amino acid uptake and protein synthesis, while it completely inhibited insulin stimulation of DNA synthesis and p70 S6 kinase activation. These data suggest that: 1) PI3K plays a crucial role in various functions of insulin; and 2) there exist multiple signaling pathways (both PI3K dependent and PI3K independent) for the insulin receptor.
Sanchez-Margálet
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Department of Medicine, Mount Zion Medical Center, University of California, San Francisco 94115.
Goldfine
I D
ID
Vlahos
C J
CJ
Sung
C K
CK
D016475:3T3 Cells; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D000596:Amino Acids; D002867:Chromones; D004247:DNA; D005947:Glucose; D055504:Insulin Receptor Substrate Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011972:Receptor, Insulin; D019893:Ribosomal Protein S6 Kinases; D014443:Tyrosine; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one