90-kDa S6 kinase is insufficient or not involved in the activation of glycogen synthase induced by insulin.
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.
Yasui
K
K
Department of Pharmacology, Nagoya University School of Medicine, Japan.
Niki
I
I
Hidaka
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006006:Glycogen Synthase / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D019893:Ribosomal Protein S6 Kinases
D007328:Insulin; D004815:Epidermal Growth Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D006006:Glycogen Synthase; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; C049347:fasudil