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Submitted on September 16, 2005
Accepted on November 22, 2005
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.
We have shown that vitronectin binding to a cysteine loop sequence within the extracellular domain of the 
3 subunit (amino acids 177-184) of 
V3 is required for the positive effects of vitronectin on IGF-I signaling. When vitronectin binding to this sequence is blocked, IGF-I signaling in SMCs is impaired. Since this binding site is distinct from the site on 3 to which the RGD sequence of extracellular matrix ligands bind (amino acids 107-171) we hypothesized that the region of vitronectin that binds to the cysteine loop on 3 is distinct from the region that contains the RGD sequence. The results presented in this study demonstrate that this heparin binding domain is the region of vitronectin that binds to the cysteine loop region of 3 and that this region is sufficient to mediate the positive effects of vitronectin on IGF-I signaling. We provide evidence that binding of the heparin binding domain of vitronectin to V3 has direct effects on the activation state of 3 as measured by 3 phosphorylation. The increase in 3 phosphorylation associated with exposure of cells to this heparin binding domain is associated with enhanced phosphorylation of the adaptor protein Shc and enhanced activation MAPK, a downstream mediator of IGF-I signaling. We conclude that the interaction of the heparin binding domain of vitronectin binding to the cysteine loop sequence of 3 is necessary and sufficient for the positive effects of vitronectin on IGF-I mediated effects in SMCs.
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