HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inoue, G. Articles by Kahn, C. R. Search for Related Content PubMed PubMed Citation Articles by Inoue, G. Articles by Kahn, C. R. Social Bookmarking                      What's this?

Volume 271, Number 45, Issue of November 8, 1996 pp. 28206-28211
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

---

Different Pathways of Postreceptor Desensitization following Chronic Insulin Treatment and in Cells Overexpressing Constitutively Active Insulin Receptors

(Received for publication, February 15, 1996, and in revised form, July 11, 1996)

From the Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02215

We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IR^erbVE) results in constitutive activation of the insulin receptor kinase. Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IR^wt), cells overexpressing IR^erbVE displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor.

In contrast to IR^erbVE, the insulin receptor content and its tyrosine phosphorylation were significantly decreased in IR^wt cells chronically stimulated (>24 h) with insulin. With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. These data suggest that there are multiple levels of postreceptor desensitization to insulin action. These are used somewhat differently in these two different models, probably due in part to the difference in receptor down-regulation.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Kumar and C. S. Dey Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells J. Exp. Biol., December 1, 2002; 205(23): 3739 - 3746. [Abstract] [Full Text] [PDF]

				A. V. Lee, J. L. Gooch, S. Oesterreich, R. L. Guler, and D. Yee Insulin-Like Growth Factor I-Induced Degradation of Insulin Receptor Substrate 1 Is Mediated by the 26S Proteasome and Blocked by Phosphatidylinositol 3'-Kinase Inhibition Mol. Cell. Biol., March 1, 2000; 20(5): 1489 - 1496. [Abstract] [Full Text]

				T. C. Haddad and C. A. Conover Insulin and Interleukin-4 Induce Desensitization to the Mitogenic Effects of Insulin-like Growth Factor-I. PIVOTAL ROLE FOR INSULIN RECEPTOR SUBSTRATE-2 J. Biol. Chem., August 1, 1997; 272(31): 19525 - 19531. [Abstract] [Full Text] [PDF]