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The Heparin Binding Domain of Vitronectin Is the Region that Is Required to Enhance Insulin-Like Growth Factor-I Signaling

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.

We have shown that vitronectin (Vn) binding to a cysteine loop sequence within the extracellular domain of the ß3-subunit (amino acids 177–184) of Vß3 is required for the positive effects of Vn on IGF-I signaling. When Vn binding to this sequence is blocked, IGF-I signaling in smooth muscle cells is impaired. Because this binding site is distinct from the site on ß3 to which the Arg-Gly-Asp sequence of extracellular matrix ligands bind (amino acids 107–171), we hypothesized that the region of Vn that binds to the cysteine loop on ß3 is distinct from the region that contains the Arg-Gly-Asp sequence. The results presented in this study demonstrate that this heparin binding domain (HBD) is the region of Vn that binds to the cysteine loop region of ß3 and that this region is sufficient to mediate the positive effects of Vn on IGF-I signaling. We provide evidence that binding of the HBD of Vn to Vß3 has direct effects on the activation state of ß3 as measured by ß3 phosphorylation. The increase in ß3 phosphorylation associated with exposure of cells to this HBD is associated with enhanced phosphorylation of the adaptor protein Src homology 2 domain-containing transforming protein C and enhanced activation MAPK, a downstream mediator of IGF-I signaling. We conclude that the interaction of the HBD of Vn binding to the cysteine loop sequence of ß3 is necessary and sufficient for the positive effects of Vn on IGF-I-mediated effects in smooth muscle cells.

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