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J Biol Chem, Vol. 274, Issue 21, 14529-14532, May 21, 1999

COMMUNICATION
Insulin Activates the  Isoform of Class II Phosphoinositide 3-Kinase

Richard A. Brown, Jan Domin^§, Alexandre Arcaro^§, Michael D. Waterfield^§, and Peter R. Shepherd

From the  Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT and the ^§ Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, United Kingdom

The novel class II phosphoinositide (PI) 3-kinases are characterized by the presence of a C-terminal C2 domain, but little is known about their regulation. We find insulin causes a rapid 2-3-fold increase in the activity of PI 3-kinase C2 (PI3K-C2) in CHO-IR cells, 3T3-L1 adipocytes, and fully differentiated L5L6 myotubes. No insulin-induced activation of PI3K-C2 was observed in cell types known to have low responsiveness to insulin including HEK 293 cells, 3T3-L1 preadipocytes, and undifferentiated L5L6 myoblasts. The mechanism of activation of PI3K-C2 by insulin differs from that of class Ia PI 3-kinases in that insulin stimulation did not cause PI3K-C2 to associate with IRS-1 or insulin receptor. PI3K-C2 existed as a doublet, and insulin stimulation caused a redistribution from the lower molecular weight band to the higher molecular weight band, suggesting phosphorylation-induced bandshift. Consistent with this, in vitro phosphatase treatment reduced the intensity of the upper band back to that seen in unstimulated cells. This suggests that insulin-induced phosphorylation could play a role in regulation of the activity of PI3K-C2. The finding that insulin activates PI3K-C2 in cell types known to possess a wide range of responses to insulin suggests that PI3K-C2 is a novel component of insulin-stimulated signaling cascades.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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