Heparin, heparan sulfate, and dermatan sulfate regulate formation of the insulin-like growth factor-I and insulin-like growth factor-binding protein complexes.
The mechanisms by which insulin-like growth factor-I (IGF-I) is released from insulin-like growth factor binding proteins (IGFBPs) and then binds to its receptor have not been defined. This study was designed to determine the role of glycosaminoglycans in altering the formation of the IGF-I.IGFBP complexes. Heparin inhibited formation of the IGF-I.IGFBP-5 complex and also separated preformed IGF-I.IGFBP-5 complexes. Heparin also inhibited formation of the IGF-I.IGFBP-3 complex; however, it did not inhibit formation of complexes between IGF-I and IGFBP-1, -2, or -4. Heparin exposure was associated with a 17-fold decrease in the affinity of IGFBP-5 for IGF-I. A synthetic peptide that contains residues from Arg221 to Arg238 of IGFBP-5, and a heparin binding domain prevented the inhibitory effects of heparin on formation of the IGF-I.IGFBP-5 complex. It did not directly compete with IGF-I for binding to IGFBP-5, suggesting that heparin binding to this region of IGFBP-5 resulted in a conformational change in IGFBP-5 which lowered its affinity for IGF-I. Other glycosaminoglycans that contained O-linked sulfates in the 2 or 3 carbon positions of iduronic acid, e.g. heparan sulfate and dermatan sulfate, also inhibited the IGF-I.IGFBP-5 complex formation, whereas those that did not, such as keratan sulfate or hyaluronic acid, had minimal effects. Anionic polysaccharides that contained O-sulfate groups in the 2 or 3 positions, such as dextran sulfate, pentosan polysulfate, and fucoidan, also had inhibitory activity. The findings suggest a role for these compounds in inhibiting IGF-I.IGFBP interactions, thus making IGF-I available to bind to its receptor.
Arai
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Department of Medicine, University of North Carolina, School of Medicine, Chapel Hill 27599.
Parker
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Busby
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Clemmons
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D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D006224:Cricetinae; D003871:Dermatan Sulfate / Q000502:physiology*; D006493:Heparin / Q000502:physiology*; D006497:Heparan Sulfate / Q000502:physiology*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008969:Molecular Sequence Data
D002352:Carrier Proteins; D003871:Dermatan Sulfate; D006493:Heparin; D006497:Heparan Sulfate; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I