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Guanosine Triphosphatase-Activating Protein-Associated Protein, But Not src-Associated Protein p68 in Mitosis, Is a Part of Insulin Signaling Complexes¹

Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Chin K. Sung, Ph.D., Department of Physiology and Biophysics, University of Southern California School of Medicine, 1333 San Pablo Street, MMR 626, Los Angeles, California 90033. E-mail: csung{at}hsc.usc.edu

The insulin receptor, following insulin stimulation of cells, triggers formation of various signaling complexes. In rat HTC hepatoma cells overexpressing normal human insulin receptors (HTC-IR), p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K) forms signaling complexes containing the insulin receptor, insulin receptor substrate 1 (IRS-1), guanosine triphosphatase-activating protein (GAP) and 60–70 kDa phosphotyrosine proteins (p60–70). In the present study, we demonstrate that p60–70 interacts directly with the p85 subunit via src homology 2 domain of the latter. Employing antibodies specific to two p85 isoforms, p85 and p85ß, we demonstrate that HTC-IR cells express both p85 isoforms, and these isoforms induce the formation of similar signaling complexes in response to insulin. p60–70, present in both -p85 and -p85ß immunoprecipitates, is a GAP-associated protein, but is distinct from the p68 src-associated protein in mitosis (Sam68) by several criteria. These data suggest that 1) GAP-associated protein, but not Sam68, is a part of insulin signaling complexes; and 2) p85 and p85ß form similar, but distinct, insulin receptor signaling complexes.

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