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Vitronectin Binding to IGF Binding Protein-5 (IGFBP-5) Alters IGFBP-5 Modulation of IGF-I Actions

University of North Carolina, Chapel Hill, North Carolina 27599

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 275990-7170. E-mail: endo{at}med.unc.edu

IGF binding protein-5 (IGFBP-5) and vitronectin are matricellular proteins that are produced by smooth muscle cells and modulate their responsiveness to IGF-I. These studies were conducted to determine if vitronectin bound IGFBP-5 with high affinity and if this altered the ability of either protein to modify cellular responsiveness to IGF-I. Solution binding assays were used to determine that vitronectin bound to IGFBP-5 with high affinity. This binding was inhibitable with glycosaminoglycans. Synthetic peptides that contained four distinct regions of the IGFBP-5 sequence were used in competitive binding assays to determine the regions of IGFBP-5 that were necessary for vitronectin binding. The regions that mediated the interaction were determined to be between amino acids 201 and 218 and between amino acids 131 and 141. Mutation of specific basic residues within these regions resulted in significant reduction in vitronectin binding and residues R134, R136, K138, K139, R201, and K202 were shown to be the most important. When the combination of IGFBP-5 and IGF-I was added to smooth muscle cells that had been plated on a vitronectin-enriched matrix, the smooth muscle cell DNA synthesis and migration responses to IGF-I plus vitronectin were enhanced. In contrast, if mutant forms of IGFBP-5 that did not bind to vitronectin were used, the responses were decreased. These effects appeared to be due to modulation of IGF-I action because the addition of a mutant form of IGFBP-5 that did not bind to IGF-I had no additional effect over and above that noted with vitronectin alone. These findings suggest that localization of IGFBP-5 within the extracellular matrix by vitronectin results in modification of cellular responsiveness to IGF-I and that vitronectin may be an important component of the extracellular matrix that modulates IGFBP-5 actions.

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