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Endocrinology Vol. 143, No. 11 4259-4264
Copyright © 2002 by The Endocrine Society

ARTICLE

The {alpha}Vß3 Integrin Regulates Insulin-Like Growth Factor I (IGF-I) Receptor Phosphorylation by Altering the Rate of Recruitment of the Src-Homology 2-Containing Phosphotyrosine Phosphatase-2 to the Activated IGF-I Receptor

Laura A. Maile and David R. Clemmons

University of North Carolina Department of Medicine, Division of Endocrinology and Metabolism, Chapel Hill, North Carolina 27599-7170

Address all correspondence and requests for reprints to: David R. Clemmons, M.D, CB 7170, 6111 Thurston-Bowles, Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: endo{at}med.unc.edu.

The {alpha}Vß3 integrin is an important determinant of IGF-I-stimulated receptor phosphorylation and biological actions. Blocking ligand occupancy of {alpha}Vß3 with the distintegrin echistatin reduces IGF-I-stimulated receptor phosphorylation, and it inhibits cellular migration and DNA synthesis responses to IGF-I. We have shown that recruitment of the tyrosine phosphatase Src-homology 2-containing phosphotyrosine phosphatase-2 (SHP-2) to the IGF-I receptor (IGF-IR) is an important determinant of the duration of IGF-IR phosphorylation. These studies were undertaken to determine whether an alteration in the recruitment of SHP-2 to the receptor in the presence of echistatin could account for the decrease in receptor phosphorylation. Following an overnight exposure of smooth muscle cell cultures to echistatin, the addition of IGF-I was accompanied by rapid dephosphorylation of IGF-IR compared with cells exposed to media alone. This was associated with an increase in the rate of SHP-2 recruitment to the IGF-IR. In cells expressing a catalytically inactive form of SHP-2, prior exposure to echistatin had no effect on the rate of receptor dephosphorylation. In contrast to the usual physiologic situation in which following IGF-I exposure SHP-2 is recruited to IGF-IR via SHP-2 substrate-1 (SHPS-1) in the presence of echistatin, SHPS-1 was not used for SHP-2 recruitment. Our findings show that IRS-1 may substitute for SHPS-1 under these conditions. These results demonstrate that the activation state of {alpha}Vß3 is an important regulator of the duration of IGF-IR phosphorylation and subsequent downstream signaling and that this regulation is mediated through changes in the subcellular localization of SHP-2.




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