DIFFERENT SIGNALING ROLES OF SHPTP2 IN INSULIN-INDUCED GLUT1 EXPRESSION AND GLUT4 TRANSLOCATION

Insulin activates hexose transport via at least two mechanisms: a p21( ras)-dependent pathway, leading to an increase in the amount of cell s urface GLUT1; and a metabolic, p21(ras)-independent pathway, leading t o translocation of the insulin-responsive transporter GLUT4 to the cel l surface. Following insulin stimulation, SHPTP2, a non-transmembrane protein-tyrosine phosphatase, associates with insulin receptor substra te 1 via its Src homology 2 (SH2) domains. Microinjection of a glutath ione S-transferase fusion protein encoding the N- and C-terminal SH2 d omains of SHPTP2 (GST-NC-SH2) or anti-SHPTP2 antibodies into NIH-3T3 f ibroblasts overexpressing the insulin receptor blocks insulin-induced DNA synthesis. Microinjection of either GST-NC-SH2 or anti-SHPTP2 anti bodies into 3T3-L1 adipocytes inhibited the insulin-stimulated increas e in expression of GLUT1. In contrast, translocation of GLUT4 to the c ell surface was unaffected by either GST-NC-SH2 or anti-SHPTP2 antibod ies. These data confirm a role for SHPTP2 in insulin-stimulated mitoge nesis and indicate that whereas SHPTP2 is necessary for insulin-stimul ated expression of GLUT1, it is not required for activation of the met abolic pathway leading to GLUT4 translocation.