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Integrin-Associated Protein Binding Domain of Thrombospondin-1 Enhances Insulin-Like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells

From the Division of Endocrinology, University of North Carolina, Chapel Hill, NC.

Correspondence to David R. Clemmons, MD, CB No. 7170, 6111 Thurston-Bowles, Division of Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7170. E-mail endo{at}med.unc.edu

Insulin-like growth factor-I (IGF-I) stimulates vascular smooth muscle cell (SMC) proliferation and migration. The response of smooth muscle cells to IGF-I is determined not only by activation of the IGF-I receptor but also by at least three other transmembrane proteins, _Vß₃, integrin-associated protein (IAP), and SHPS-1. This regulation seems to be attributable to their ability to regulate the transfer of SHP-2 phosphatase, a key component of IGF-I signaling. Ligand occupancy of SHPS-1 with IAP is required for the recruitment and transfer of SHP-2 and subsequent signaling in response to IGF-I. The extracellular matrix protein thrombospondin-1 stimulates an increase in the cell proliferation response to IGF-I. Because thrombospondin-1 is a ligand for IAP, we wished to determine whether the enhancing effect of thrombospondin-1 was mediated through IAP binding. To examine the effect of thrombospondin-1 binding to IAP, we used a peptide termed 4N1K derived from the IAP binding site of thrombospondin-1. Preincubation with 4N1K increased IGF-I–stimulated mitogen-activated protein kinase activation and DNA synthesis. This enhancement seemed to be attributable to its ability to increase the duration of IGF-I–stimulated receptor and insulin receptor substrate-1 (IRS-1) phosphorylation. Preincubation with 4N1K delayed IGF-I stimulation of SHPS-1 phosphorylation (attributable to an alteration in IAP–SHPS-1 interaction), resulting in a delay in SHP-2 recruitment. This delay in SHP-2 transfer seems to account for the increase in the duration of IGF-I receptor phosphorylation and for enhanced downstream signaling. These observations support the conclusion that thrombospondin-1 and IGF-I seem to function coordinately in stimulating smooth muscle proliferation via the thrombospondin-1 interaction with IAP.

Key Words: insulin-like growth factor-I • thrombospondin-1 • integrin-associated protein • smooth muscle cells • atherosclerosis

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