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This version published online on September 29, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0241
A more recent version of this article appeared on February 1, 2006
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Submitted on June 20, 2005
Accepted on September 21, 2005

IGF-I signaling in smooth muscle cells is regulated by ligand binding to the 177CYDMKTTC184 sequence of the {beta}3 subunit of {alpha}V{beta}3

Laura A Maile*, Walker H Busby, Kevin Sitko, Byron E Capps, Tiffany Sergent, Jane Badley-Clarke, and David R Clemmons

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

* To whom correspondence should be addressed. E-mail: laura_maile{at}med.unc.edu.

The response of smooth muscle cells to IGF-I requires ligand occupancy of the {alpha}V{beta}3 integrin. We have shown that vitronectin is required for IGF-I stimulated migration or proliferation while the anti {alpha}V{beta}3 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 {beta}3 have been proposed to confer the ligand specificity of {alpha}V{beta}3 therefore we hypothesized that ligand binding to the 177-184 cysteine loop of {beta}3 may be an important regulator of the cross talk between {alpha}V{beta}3 and IGF-I in SMCs.

Here we demonstrate that blocking ligand binding to a specific amino acid sequence within the {beta}3 subunit of {alpha}V{beta}3 (i.e. amino acids 177-184) blocked vitronectin binding to the {beta}3 subunit of {alpha}V{beta}3 and correspondingly {beta}3 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 {beta}3 in which three critical residues within the 177-184 sequence were altered {beta}3 phosphorylation was decreased. This was associated with a loss of IGF-I stimulated Shc phosphorylation and impaired SMC proliferation in response to IGF-I. In conclusion, we have demonstrated that the 177-184 sequence of {beta}3 is necessary for vitronectin binding to {alpha}V{beta}3 and that ligand occupancy of this site is necessary for an optimal response of smooth muscle cells to IGF-I.
Key words: integrin • IGF-I • growth factor




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