THE INHIBITORY EFFECT OF STAUROSPORINE ON INSULIN ACTION IS PREVENTEDBY 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, s ynergistic with insulin. OA stimulated glucose transport activity, alt ered the electrophoretic mobility of IRS-1, increased the phosphorylat ion of the MAP-kinases ERK 1 and 2 on tyrosine sites, markedly increas ed MAP kinase activity and also acted synergistically with insulin in activating these enzymes. However, OA did not increase PI 3-kinase act ivity or the tyrosine phosphorylation of key upstream proteins in insu lin'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 effe cts 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 t hrough 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.