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Molecular and Cellular Biology, January 2000, p. 126-138, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

IRS-4 Mediates Protein Kinase B Signaling during Insulin Stimulation without Promoting Antiapoptosis

Tohru Uchida, Martin G. Myers Jr., and Morris F. White*

Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Received 15 March 1999/Returned for modification 21 May 1999/Accepted 27 September 1999

Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32DIR). Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha /beta , which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70s6k, and promoted the phosphorylation of BAD. IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70s6k. Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32DIR cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. Consequently, 32DIR cells expressing IRS-4 proliferated slowly during insulin stimulation. Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32DIR cells unless p85-associated PI 3-kinase or p70s6k are strongly activated.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Joslin Diabetes Center, 1 Joslin Pl., Boston, MA 02215. Phone: (617) 732-2578. Fax: (617) 732-2593. E-mail: whitemor{at}joslab.harvard.edu.

Molecular and Cellular Biology, January 2000, p. 126-138, Vol. 20, No. 1
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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