90-KDA S6 KINASE IS INSUFFICIENT OR NOT INVOLVED IN THE ACTIVATION OFGLYCOGEN-SYNTHASE INDUCED BY INSULIN

Insulin and growth factors increase glycogen synthesis via complex pat hways including protein phosphorylation/dephosphorylation processes. W e investigated the involvement of 90-kDa S6 kinase in the control of i nsulin- or epidermal growth factor (EGF)-stimulated glycogen synthase activation using newly synthesized compounds which selectively inhibit 90-kDa S6 kinase. HH-5709 y-naphthalenesulfonyl)-1H-hexahydro-1,4-dia zepine) inhibited 90-kDa S6 kinase al lower concentrations than observ ed for protein kinases A or C. The inhibition by HH-5709 was competiti ve with respect to ATP with a K-i value of 1.3 mu M. H-7, an inhibitor of protein kinases A and C, and HA-1077 (1-(5-isoquinolinesulfonyl)-h omopiperazine), where the naphthalene ring of HH-5709 was replaced wit h isoquinoline, also inhibited 90-kDa S6 kinase to a similar extent as HH-5709. In 3Y1 fibroblasts, H-7 and HA-1077 attenuated the activatio n of glycogen synthase. HH-5709, however, failed to affect the glycoge n synthase activation by either insulin or EGF. These findings suggest that 90-kDa S6 kinase is unrelated or insufficient to mediate activat ion of glycogen synthase and that unidentified pathway(s) sensitive to H-7 or HA-1077 would be involved in the activation of glycogen syntha se by insulin or EGF in 3Y1 fibroblasts.