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Endocrinology, Vol 137, 4571-4575, Copyright © 1996 by Endocrine Society
ARTICLES |
T Arai, W Busby Jr and DR Clemmons
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) is secreted by several cell types that also secrete IGF-I or IGF-II. The binding of IGF-I or IGF-II to IGFBP-2 has been shown to alter their actions. Although IGFBP-2 is not an abundant component of the extracellular matrix (ECM), it is easily localized by immunohistochemical staining in basement membranes of several epithelial cell types. We have previously shown that IGFBP-5 associates with glycosaminoglycans and binds to proteoglycans that are contained in ECM and basement membranes. In those studies we were unable to demonstrate an association of IGFBP-2 with glycosaminoglycans. In this study we report that IGFBP-2 binds to heparin if IGF-I or IGF-II is also included in the incubation buffer. IGFBP-1, -3, -4, or -5 did not have increased heparin binding in the presence of IGF-I or IGF-II. The binding of IGFBP-2 to heparin was detectable using an IGF-I to IGFBP-2 molar ratio of 2:1. Binding to heparin-Sepharose could be inhibited by soluble heparin or heparan sulfate, but not by glycosaminoglycans that do not contain O-linked sulfate groups in the 2 or 3 position of the iduronic acid ring. Binding was also inhibited by a synthetic IGFBP-5 peptide that contained a heparin-binding domain, but not by a peptide with an identical charge to mass ratio that does not bind to heparin. Binding appeared to be physiologically significant, as IGFBP-2 bound to human fibroblast ECM if IGF-I or IGF-II was added. IGF-II was more potent than IGF-I in facilitating the binding interaction, and des(1-3)- IGF-I or insulin had no effect, suggesting that IGF binding to IGFBP-2 is required for this effect to be detected. In summary, IGFBP-2 binding to glycosaminoglycans is dependent upon binding of IGF-I and IGF-II to IGFBP-2. This suggests that IGFBP-2 undergoes a conformational change that exposes a glycosaminoglycan-binding domain. This could provide a mechanism for focally concentrating IGFBP-2 in the pericellular environment.
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