© 2000 American Heart Association, Inc.
Molecular Medicine |
Phosphatidylinositol 3-Kinase Is Required for Insulin-Like Growth Factor-I–Induced Vascular Smooth Muscle Cell Proliferation and Migration
From the Department of Biology, University of Michigan, Ann Arbor, Mich.
Correspondence to Cunming Duan, PhD, Department of Biology, The University of Michigan, Natural Science Building, Ann Arbor, MI 48109-1048. E-mail cduan{at}umich.edu
Abstract—Insulin-like growth
factor–I (IGF-I) plays an important role in regulating vascular smooth
muscle cell (VSMC) proliferation and directed migration. The
mitogenic and chemotactic actions of IGF-I are mediated
through the IGF-I receptor, but how the activation of the IGF-I
receptor leads to these biological responses is poorly understood. In
this study, we examined the role of phosphatidylinositol 3-kinase (PI3
kinase) in mediating the mitogenic and chemotactic signals
of IGF-I. IGF-I treatment resulted in a significant increase in
phosphotyrosine-associated PI3 kinase activity in cultured primary
VSMCs. To determine whether insulin receptor substrate (IRS)–1, -2, or
both are involved in IGF-I signaling in VSMCs, cell lysates were
immunoprecipitated with either an anti-IRS-1 or an anti-IRS-2 antibody,
and the associated PI3 kinase activity was determined. IGF-I
stimulation resulted in a significant increase in IRS-1– but not
IRS-2–associated PI3 kinase activity, suggesting that IGF-I primarily
utilizes IRS-1 to transmit its signal in VSMCs. The IGF-I–induced
increase in IRS-I–associated PI3 kinase activity was concentration
dependent. At the maximum concentration (50 ng/mL), IGF-I induced a
60-fold increase. This activation occurred within 5 minutes and was
sustained at high levels for at least 6 hours. IGF-I also caused a
concentration-dependent and long-lasting activation of protein kinase B
(PKB/Akt). Inhibition of PI3 kinase activation by LY294002 or
wortmannin abolished IGF-I–stimulated VSMC proliferation and reduced
IGF-I–directed VSMC migration by 
60%. These results indicate that
activation of PI3 kinase is required for both IGF-I–induced VSMC
proliferation and migration.
Key Words: insulin-like growth factor-I • phosphatidylinositol 3-kinase • proliferation • migration • vascular smooth muscle cell
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