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Vol. 13, Issue 11, 3943-3954, November 2002

pp60Src Mediates Insulin-stimulated Sequestration of the ₂-Adrenergic Receptor: Insulin Stimulates pp60Src Phosphorylation and Activation

Elena Shumay,^* Xiaosong Song,^* Hsien-yu Wang, and Craig C. Malbon^*

Departments of  ^*Pharmacology and  Physiology and Biophysics, Diabetes and Metabolic Diseases Research Center-Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794-8651

Insulin stimulates a rapid phosphorylation and sequestration of the ₂-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 [2-(4-morpholynyl)-8-phenyl-4H-1-benzopyran-4-one], blocked the activation of Src as well as insulin-stimulated sequestration of the ₂-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 ₂-adrenergic receptors and the translocation of the GLUT4 glucose transporters. Insulin stimulates Src to associate with the ₂-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 ₂-adrenergic receptor trafficking.

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Corresponding author: E-mail address: craig{at}pharm.sunysb.edu.

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Molecular Biology of the Cell
Vol. 13, 3943-3954, November 2002
Copyright © 2002 by The American Society for Cell Biology

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