The inhibitory effect of staurosporine on insulin action is prevented by okadaic acid. Evidence for an important role of serine/threonine phosphorylation in eliciting insulin-like effects.
The serine/threonine phosphatase inhibitor, okadaic acid (OA), exerted several insulin-like effects in rat adipose cells and was, in part, synergistic with insulin. OA stimulated glucose transport activity, altered the electrophoretic mobility of IRS-1, increased the phosphorylation of the MAP-kinases ERK 1 and 2 on tyrosine sites, markedly increased MAP kinase activity and also acted synergistically with insulin in activating these enzymes. However, OA did not increase PI 3-kinase activity or the tyrosine phosphorylation of key upstream proteins in insulin's signaling cascade. Staurosporine virtually completely inhibited the insulin-stimulated glucose transport and MAP kinase activation in spite of a maintained high PI 3-kinase activity. In contrast, the effects of OA alone or in the presence of insulin were less, or not at all, affected. These data suggest that OA exerts an insulin-like effect through a serine/threonine-related pathway which is distinct from, but converges with, that of insulin downstream PI 3-kinase and upon which staurosporine exerts an inhibitory effect.
Rondinone
C M
CM
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Zarnowski
M J
MJ
Londos
C
C
Smith
U P
UP
D000818:Animals; D001692:Biological Transport; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D008297:Male; D019319:Okadaic Acid / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013912:Threonine / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D007328:Insulin; D007329:Insulin Antagonists; D019319:Okadaic Acid; D013912:Threonine; D014443:Tyrosine; D012694:Serine; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011972:Receptor, Insulin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D019311:Staurosporine; D005947:Glucose