UPSTREAM MECHANISMS OF GLYCOGEN-SYNTHASE ACTIVATION BY INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I - GLYCOGEN-SYNTHASE ACTIVATION IS ANTAGONIZED BY WORTMANNIN OR LY294002 BUT NOT BY RAPAMYCIN OR BY INHIBITING P21(RAS)

This study was undertaken to define intracellular signaling pathways u pstream to glycogen synthase activation, First, we examined the role o f the two pathways of insulin signaling, Ras-dependent and wortmannin/ LY294002-sensitive, in glycogen synthase activation, Although negative dominant Ras (Ras17N) induction in PC12 cells markedly decreased acti vities of mitogen-activated protein kinase (MAP) and pp90 S6 kinase in response to insulin or insulin-like growth factor I (IGF-I), activati on of glycogen synthase by these agents was unaffected by negative dom inant Ras induction. In contrast, wortmannin and 2-(4-morpholinyl)-8-p henyl-4H-1-benzopyran-4-one (LY294002), inhibitors of phosphatidylinos itol 3-kinase, antagonized glycogen synthase activation in response to insulin or IGF-I. Next, we examined the contribution of pp70 S6 kinas e, one of the wortmannin/LY294002-sensitive signaling molecules on gly cogen synthase activation, Immunosuppressant rapamycin completely bloc ked activation of pp70 S6 kinase by insulin or IGF-I, but rapamycin al one or in combination with induction of negative dominant Ras failed t o antagonize glycogen synthase activation by these hormones, These dat a suggest that 1) activation of Ras-MAP kinase is not necessary for st imulation of glycogen synthase and 2) activation of wortmannin/LY29400 2-sensitive pathway, independent of pp70 S6 kinase, plays a key role i n glycogen synthase regulation in PC12 cells.