HH-5709

Insulin and growth factors increase glycogen synthesis via complex pathways including protein phosphorylation/dephosphorylation processes. We investigated the involvement of 90-kDa S6 kinase in the control of insulin- or epidermal growth factor (EGF)-stimulated glycogen synthase activation using newly synthesized compounds which selectively inhibit 90-kDa S6 kinase. HH-5709 (1-(5-hydroxynaphthalenesulfonyl)-1H-hexahydro-1,4-diazepine) inhibited 90-kDa S6 kinase at lower concentrations than observed for protein kinases A or C. The inhibition by HH-5709 was competitive with respect to ATP with a Ki value of 1.3 microM. H-7, an inhibitor of protein kinases A and C, and HA-1077 (1-(5-isoquinolinesulfonyl)-homopiperazine), where the naphthalene ring of HH-5709 was replaced with isoquinoline, also inhibited 90-kDa S6 kinase to a similar extent as HH-5709. In 3Y1 fibroblasts, H-7 and HA-1077 attenuated the activation of glycogen synthase. HH-5709, however, failed to affect the glycogen synthase activation by either insulin or EGF. These findings suggest that 90-kDa S6 kinase is unrelated or insufficient to mediate activation of glycogen synthase and that unidentified pathway(s) sensitive to H-7 or HA-1077 would be involved in the activation of glycogen synthase by insulin or EGF in 3Y1 fibroblasts.