Abstract
Insulin receptor substrate-1 (IRS-1) is tyrosine-phosphorylated in response to insulin resulting in association with and activation of phosphatidylinositol 3-kinase (PI 3-kinase), thereby initiating some of the effects of insulin. We have recently shown that the insulin-like effects of growth hormone (GH) in adipocytes can be inhibited by the selective PI 3-kinase inhibitor wortmannin (Ridderstråle, M., and Tornqvist, H. (1994) Biochem. Biophys. Res. Commun. 203, 306-310), suggesting a similar role for PI 3-kinase in GH action. Here we show that IRS-1 is tyrosine-phosphorylated in a time- and dose-dependent manner in response to GH in primary rat adipocytes. This phosphorylation coincided with the extent of interaction between IRS-1 and the 85-kDa subunit of PI 3-kinase as evidenced by coimmunoprecipitation. Stimulation with 23 nM GH increased the PI 3-kinase activity associated with IRS1 4-fold. Our data suggest that GH-induced tyrosine phosphorylation of IRS-1 and the subsequent docking of PI 3-kinase are important postreceptor events in GH action. The mechanism for the phosphorylation of IRS-1 induced by GH is unknown, but involvement of JAK2, the only known GH receptor-associated tyrosine kinase, seems possible.
Highlights
From the Departments of §Pediatrics and Medical and Physiological Chemistry, University of Lund, P
We have recently shown that the insulin-like effects of growth hormone (GH) in adipocytes can be inhibited by the selective PI 3-kinase inhibitor wortmannin (Ridderstr81e, M., and Tornqvist, H. (1994) Biochem
We have recently shown that the insulin-like effects ofGH in isolated rat adipocytes can be blocked by wortmannin, a selective inhibitor of phosphatidyl inositol 3-kinase (PI 3-kinase) (7)
Summary
Growth Hormone Stimulates the Tyrosine Phosphorylation of the Insulin Receptor Substrate-l and Its Association with Phosphatidylinositol3-Kinase in Primary Adipocytes*. Insulin receptor substrate-I (IRS-I) is tyrosine-phosphorylated in response to insulin resulting in association with and activation of phosphatidylinositol 3-kinase (PI 3-kinase), thereby initiating some of the effects of insulin. We show that mS-l is tyrosine-phosphorylated in a time- and dose-dependent manner in response to GH in primary rat adipocytes. Tyrosine phosphorylation of IRS-1I4PS results in the association of several other proteins (Grb[2], SHPTP2, and Nck) through their SH2 domains (31). To further explore the possible role of PI 3-kinase in GH action, we precipitated PI 3-kinase from GH-treated rat adipocytes and looked for associated tyrosine-phosphorylated proteins. IRS-1 was tyrosine-phosphorylated and bound to the p85 subunit of PI 3-kinase in a dose- and time dependent manner in response to GH
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