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A more recent version of this article appeared on November 1, 2002
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Submitted on March 29, 2002
Revised on August 14, 2002
Accepted on August 21, 2002
1 Department of Pharmacology, Diabetes and Metabolic Diseases Research Center-HSC, State University of New York at Stony Brook, Stony Brook, NY 11794-8651
2 Department of Physiology and Biophysics, Diabetes and Metabolic Diseases Research Center-HSC, State University of New York at Stony Brook, Stony Brook, NY 11794-8651
* Corresponding author. E-mail address: craig{at}pharm.sunysb.edu.
Insulin stimulates a rapid phosphorylation and sequestration of the ß2-adrenergic receptor. Analysis of the signaling downstream of the insulin receptor with enzyme inhibitors revealed roles for both phosphatidylinositol 3-kinase and pp60Src. Inhibition of Src with PP2, like the inhibition of phosphatidylinositol 3-kinase with LY294002, blocked the activation of Src as well as insulin-stimulated sequestration of the ß2-adrenergic receptor. Depletion of Src with antisense morpholinos also suppressed insulin-stimulated receptor sequestration. Src is shown to be phosphorylated/activated in response to insulin, in human epidermoid carcinoma A431 cells as well as in mouse 3T3-L1 adipocytes and their derivative 3T3-F422A cells, well-known models of insulin signaling. Inhibition of Src with PP2 blocks the ability of insulin to sequester ß2-adrenergic receptors and the translocation of the GLUT-4 glucose transporters. Insulin stimulates Src to associate with the ß2-adrenergic receptor/AKAP250/protein kinase A/protein kinase C signaling complex. We report a novel positioning of Src, mediating signals from insulin to phosphatidylinositol 3-kinase and to ß2-adrenergic receptor trafficking.
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