J. Biol. Chem., Vol. 267, Issue 31, 22171-22177, Nov, 1992
Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat
F Folli, MJ Saad, JM Backer and CR Kahn
Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Growth factors stimulate the enzyme phosphatidylinositol (PI) 3-kinase in
cells in culture. Insulin rapidly stimulates tyrosine phosphorylation of
its endogenous substrate, insulin receptor substrate 1 (IRS-1), and in
vitro IRS-1 associates with PI 3-kinase, thus activating the enzyme. We
have examined whether insulin is capable of stimulating the PI 3-kinase
pathway in two physiological target tissues for the actions of insulin in
vivo, liver and skeletal muscle. After intraportal injection of insulin
into anesthetized rats, there was a 2- fold stimulation of total hepatic PI
3-kinase activity in liver and muscle extracts and a 10- to 20-fold
increase in PI 3-kinase activity immunoprecipitated with anti-IRS-1
antibodies. Stimulation of PI 3- kinase was accompanied by an association
between this enzyme and IRS-1 as detected by immunoprecipitation of liver
and muscle extracts with anti-IRS-1 antibodies and Western blotting with
antibodies to the 85- kDa subunit of PI 3-kinase. Immunoprecipitation with
anti-p85 antibodies and phosphotyrosine immunoblotting revealed no tyrosine
phosphorylation of PI 3-kinase, but demonstrated co-precipitation of
tyrosine-phosphorylated IRS-1, as well as another phosphotyrosine protein
of approximately 135-140 kDa. Thus, IRS-1 phosphorylation plays a
significant role in the activation of PI 3-kinase in vivo by insulin.
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