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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2133-2140.)
© 1999 American Heart Association, Inc.

Vascular Biology

Phosphatidylinositol 3-Kinase and Focal Adhesion Kinase Are Early Signals in the Growth Factor–Like Responses to Thrombospondin-1 Seen in Human Vascular Smooth Muscle

Joanne S. Lymn; Sarafina J. Rao; Gerard F. Clunn; Karen L. Gallagher; Clive O'Neil; Neil T. Thompson; Alun D. Hughes

From Clinical Pharmacology, National Heart and Lung Institute, Imperial College of Science, Technology & Medicine, St. Mary's Hospital, London (J.S.L., S.J.R., G.F.C., K.L.G., A.D.H.), and the Immunology Unit, Glaxo-Wellcome, Medicines Research Centre, Stevenage (C.N., N.T.T.), England.

Correspondence to Joanne S. Lymn, Clinical Pharmacology, National Heart and Lung Institute, Imperial College of Science, Technology & Medicine, QEQM Wing, St. Mary's Hospital, Paddington, London W2 1NY, England. E-mail j.lymn{at}ic.ac.uk

Abstract—Thrombospondin-1 (TSP-1) is a matricellular protein that is expressed in negligible amounts in normal blood vessels but is markedly upregulated in vascular injury. Although TSP-1 can act as a pleiotropic regulator for human vascular smooth muscle cells (HVSMCs), the intracellular signaling pathways stimulated by this protein remain obscure. In cultured HVSMCs derived from saphenous vein, TSP-1 induces tyrosine phosphorylation of a number of cellular proteins, with a complex temporal pattern of activation. Immunoprecipitation techniques have identified the early tyrosine-phosphorylated signals as being the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-K) and focal adhesion kinase (FAK). Tyrosine phosphorylation of the p85 subunit of PI 3-K showed a biphasic response to TSP-1 stimulation, which corresponded to a biphasic activation of the lipid kinase. Treatment with both wortmannin and LY294002 inhibited PI 3-K activity of HVSMCs but did not affect tyrosine phosphorylation of the p85 regulatory subunit. TSP-1–stimulated FAK phosphorylation, however, was substantially reduced by these inhibitors, as was the TSP-1–induced chemotaxis of these cells. These results suggest that activation of PI 3-K is an early signal induced by TSP-1 and is critical for chemotaxis. Activation of this kinase precedes and may occur upstream from FAK phosphorylation, although the nature of the interaction between these 2 enzymes remains obscure.

Key Words: thrombospondin-1 • focal adhesion kinase • phosphatidylinositol 3-kinase • human vascular smooth muscle

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