Stimulation of IRS-1-associated Phosphatidylinositol 3-Kinase and Akt/Protein Kinase B but Not Glucose Transport by β1-Integrin Signaling in Rat Adipocytes*
- From the Program in Molecular Medicine and Department of Biochemistry and Molecular Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01605
Abstract
The signal transduction pathway by which insulin stimulates glucose transport is not understood, but a role for complexes of insulin receptor substrate (IRS) proteins and phosphatidylinositol (PI) 3-kinase as well as for Akt/protein kinase B (PKB) has been proposed. Here, we present evidence suggesting that formation of IRS-1/PI 3-kinase complexes and Akt/PKB activation are insufficient to stimulate glucose transport in rat adipocytes. Cross-linking of β1-integrin on the surface of rat adipocytes by anti-β1-integrin antibody and fibronectin was found to cause greater IRS-1 tyrosine phosphorylation, IRS-1-associated PI 3-kinase activity, and Akt/PKB activation, detected by anti-serine 473 antibody, than did 1 nm insulin. Clustering of β1-integrin also significantly potentiated stimulation of insulin receptor and IRS-1 tyrosine phosphorylation, IRS-associated PI 3-kinase activity, and Akt/PKB activation caused by submaximal concentrations of insulin. In contrast, β1-integrin clustering caused neither a change in deoxyglucose transport nor an effect on the ability of insulin to stimulate deoxyglucose uptake at any concentration along the entire dose-response relationship range. The data suggest that (i) β1-integrins can engage tyrosine kinase signaling pathways in isolated fat cells, potentially regulating fat cell functions and (ii) either formation of IRS-1/PI 3-kinase complexes and Akt/PKB activation is not necessary for regulation of glucose transport in fat cells or an additional signaling pathway is required.
Footnotes
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↵* This work was supported by Grant DK30648 (to M. P. C.) from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Tel.: 508-856-2254; Fax: 508-856-1617; E-mail: Michael.Czech{at}ummed.edu.
- Abbreviations:
- IRS
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insulin receptor substrate
- PI
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phosphatidylinositol
- PKB
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protein kinase B
- PBS
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phosphate-buffered saline
- PAGE
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polyacrylamide gel electrophoresis
- CHO-T cells
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Chinese hamster ovary cells expressing human insulin receptors.
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- Received September 1, 1998.
- Revision received October 21, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
