Clinical review 125: The insulin receptor and its cellular targets.
The pleiotropic actions of insulin are mediated by a single receptor tyrosine kinase. Structure/function relationships of the insulin receptor have been conclusively established, and the early steps of insulin signaling are known in some detail. A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. The rapid rise in Tris-phosphorylated inositol (PIP(3)) that ensues triggers a cascade of PIP(3)-dependent serine/threonine kinases. Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. The presence of multiple insulin-regulated, PIP(3)-dependent kinases is consistent with the possibility that different pathways are required to regulate different biological actions of insulin. Additional work remains to be performed to understand the distal components of insulin signaling. Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. The ultimate goal of these investigations is to provide clues to the pathogenesis and treatment of the insulin resistant state that is characteristic of type 2 diabetes.
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins / Q000502:physiology; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495692:SLC2A4 protein, human; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin