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Insulin-Like Growth Factor Binding Protein-2 Binds to Cell Surface Proteoglycans in the Rat Brain Olfactory Bulb¹

From The Centre for Hormone Research (V.C.R., N.L.B., G.A.W.), Royal Children’s Hospital, Parkville 3052, Victoria, Australia; University of Melbourne Department of Medicine (L.A.B.), Austin and Repatriation Medical Centre, Heidelberg 3084 and Department of Paediatrics (A.J.F.), Orthopaedic Molecular Biology Research Unit, Royal Children’s Hospital, Parkville 3052, Victoria, Australia

Address all correspondence and requests for reprints to: Assoc. Prof. George A. Werther, Centre for Hormone Research, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia. E-mail: Werther{at}cryptic.rch.unimelb.edu.au

A family of six insulin-like growth factor binding proteins (IGFBPs) bind IGF-I and modulate its biological activity. IGFBPs may bind to macromolecules on the cell surface or pericellular extracellular matrix, and this interaction may modulate their effect on IGF activity. To date, little is known about the specificity of IGFBPs in the regulation of IGF action in the brain. We therefore explored whether IGFBPs were associated with cell membrane or extracellular matrix components in the rat brain. IGF-I binding sites with the characteristics of an IGFBP were found in the olfactory bulb mitral cell layer. This IGFBP was identified as IGFBP-2 by immunoprecipitation of both solubilized membrane preparations and cross-linked ¹²⁵I-IGF:IGFBP complexes. While binding of IGFBP-2 to cell membranes was unaffected by RGD-containing peptide, it was inhibited by high salt concentration, suggesting interaction with proteoglycans. IGFBP-2 bound in vitro to the glycosaminoglycans chondroitin-4 and -6-sulfate, keratan sulfate, and heparin. IGFBP-2 also bound the proteoglycan aggrecan, an effect reduced by digestion of its glycosaminoglycans. Binding of IGFBP-2 to chondroitin-6-sulfate decreased the binding affinity of IGFBP-2 for IGF-I approximately 3-fold. Finally, an IGFBP-2 antibody coimmunoprecipitated IGFBP-2 and an approximately 200 kDa proteoglycan containing chondroitin-sulfate side chains from the rat olfactory bulb, providing definitive evidence for IGFBP-2 binding to olfactory bulb proteoglycans. These findings indicate that IGFBP-2 binds to proteoglycans in cell membranes of the rat olfactory bulb. Because we have previously shown that IGFs are highly expressed in the rat olfactory bulb, cell associated IGFBP-2 may have an important role in directing IGFs to specific sites in this brain region.

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