This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lymn, J. S. Articles by Hughes, A. D. Search for Related Content PubMed PubMed Citation Articles by Lymn, J. S. Articles by Hughes, A. D. Related Collections Cell signalling/signal transduction Growth factors/cytokines Smooth muscle proliferation and differentiation

(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

This article has been cited by other articles:

				X.-J. Wang, K. Maier, S. Fuse, A. I. Willis, E. Olson, S. Nesselroth, B. E. Sumpio, and V. Gahtan Thrombospondin-1-Induced Migration Is Functionally Dependent Upon Focal Adhesion Kinase Vascular and Endovascular Surgery, June 1, 2008; 42(3): 256 - 262. [Abstract] [PDF]

				X. Cai, D. Lietha, D. F. Ceccarelli, A. V. Karginov, Z. Rajfur, K. Jacobson, K. M. Hahn, M. J. Eck, and M. D. Schaller Spatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells Mol. Cell. Biol., January 1, 2008; 28(1): 201 - 214. [Abstract] [Full Text] [PDF]

				V. Thamilselvan, D. H. Craig, and M. D. Basson FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway FASEB J, June 1, 2007; 21(8): 1730 - 1741. [Abstract] [Full Text] [PDF]

				A. W. Orr, M. A. Pallero, W.-C. Xiong, and J. E. Murphy-Ullrich Thrombospondin Induces RhoA Inactivation through FAK-dependent Signaling to Stimulate Focal Adhesion Disassembly J. Biol. Chem., November 19, 2004; 279(47): 48983 - 48992. [Abstract] [Full Text] [PDF]

				F. G. Spinale Cell-Matrix Signaling and Thrombospondin: Another Link to Myocardial Matrix Remodeling Circ. Res., September 3, 2004; 95(5): 446 - 448. [Full Text] [PDF]

				M. Campbell, W. E. Allen, C. Sawyer, B. Vanhaesebroeck, and E. R. Trimble Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways Circ. Res., August 20, 2004; 95(4): 380 - 388. [Abstract] [Full Text] [PDF]

				A. I. Willis, D. Pierre-Paul, B. E. Sumpio, and V. Gahtan Vascular Smooth Muscle Cell Migration: Current Research and Clinical Implications Vascular and Endovascular Surgery, January 1, 2004; 38(1): 11 - 23. [Abstract] [PDF]

				E. A. Papakonstanti, M. Kampa, E. Castanas, and C. Stournaras A Rapid, Nongenomic, Signaling Pathway Regulates the Actin Reorganization Induced by Activation of Membrane Testosterone Receptors Mol. Endocrinol., May 1, 2003; 17(5): 870 - 881. [Abstract] [Full Text] [PDF]

				J. S. Lymn, M. K. Patel, G. F. Clunn, S. J. Rao, K. L. Gallagher, and A. D. Hughes Thrombospondin-1 differentially induces chemotaxis and DNA synthesis of human venous smooth muscle cells at the receptor-binding level J. Cell Sci., November 15, 2002; 115(22): 4353 - 4360. [Abstract] [Full Text] [PDF]

				J. Huang and C. D. Kontos Inhibition of Vascular Smooth Muscle Cell Proliferation, Migration, and Survival by the Tumor Suppressor Protein PTEN Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 745 - 751. [Abstract] [Full Text] [PDF]