The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition by Wortmannin.
Phosphatidylinositol 3-kinase (PI 3-kinase) is a heterodimer composed of an 85-kDa subunit that binds tyrosyl-phosphorylated proteins via its SH2 domains and a 110-kDa catalytic subunit. Expression and mutagenesis experiments have shown that the 110-kDa subunit is a dual specificity kinase that possesses both lipid and serine kinase activities. Except for the 85- and 110-kDa subunits of PI 3-kinase, however, no endogenous substrates for the serine kinase have been identified. The results of the present study show that another target of this kinase is the insulin receptor substrate, IRS-1. Serine phosphorylation of IRS-1 as well as the 85-kDa subunit of PI 3-kinase was demonstrated in immunoprecipitates of PI 3-kinase and IRS-1 isolated from rat adipocytes incubated with insulin. In adipocytes incubated in the absence of insulin, only the serine phosphorylation of p85 was observed in immunoprecipitates of PI 3-kinase. Both the serine and lipid kinase activities of PI 3-kinase were abolished by the fungal metabolite Wortmannin. Wortmannin also partially inhibited the ability of insulin to stimulate glucose transport and inhibit lipolysis in fat cells. These data raise the possibility that the serine kinase activity of PI 3-kinase is involved in insulin signaling. They also suggest that inhibition of the lipid or serine kinase activities of PI 3-kinase could explain the effect of Wortmannin to diminish insulin action.
Lam
K
K
Evans Department of Medicine, Boston University Medical Center, Massachusetts 02118.
Carpenter
C L
CL
Ruderman
N B
NB
Friel
J C
JC
Kelly
K L
KL
D017667:Adipocytes / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000077191:Wortmannin
D000730:Androstadienes; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077191:Wortmannin