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Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the ¹⁷⁷CYDMKTTC¹⁸⁴ Sequence of the ß3-Subunit of Vß3

Division of Endocrinology University of North Carolina, Chapel Hill, North Carolina 27599-7170

Address all correspondence and requests for reprints to: Laura A. Maile, 6111 Thurston Bowles, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: laura_maile{at}med.unc.edu.

The response of smooth muscle cells to IGF-I requires ligand occupancy of the Vß3 integrin. We have shown that vitronectin (Vn) is required for IGF-I-stimulated migration or proliferation, whereas the anti-Vß3 monoclonal antibody, LM609, which inhibits ligand binding, blocks responsiveness of these cells to IGF-I. The amino acids 177–184 (¹⁷⁷CYDMKTTC¹⁸⁴) within the extracellular domain of ß3 have been proposed to confer the ligand specificity of Vß3; therefore, we hypothesized that ligand binding to the 177–184 cysteine loop of ß3 may be an important regulator of the cross talk between Vß3 and IGF-I in SMCs. Here we demonstrate that blocking ligand binding to a specific amino acid sequence within the ß3 subunit of Vß3 (i.e. amino acids 177–184) blocked Vn binding to the ß3 subunit of Vß3 and correspondingly ß3 phosphorylation was decreased. In the presence of this antibody, IGF-I-stimulated Shc phosphorylation and ERK 1/2 activation were impaired, and this was associated with an inhibition in the ability of IGF-I to stimulate an increase in migration or proliferation. Furthermore, in cells expressing a mutated form of ß3 in which three critical residues within the 177–184 sequence were altered ß3 phosphorylation was decreased. This was associated with a loss of IGF-I-stimulated Shc phosphorylation and impaired smooth muscle cell proliferation in response to IGF-I. In conclusion, we have demonstrated that the 177–184 sequence of ß3 is necessary for Vn binding to Vß3 and that ligand occupancy of this site is necessary for an optimal response of smooth muscle cells to IGF-I.

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