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J Biol Chem, Vol. 274, Issue 12, 7741-7747, March 19, 1999

Glycosaminoglycans Differentially Bind HARP and Modulate Its Biological Activity

Francis Vacherot, Jean Delbé, Mélanie Heroult, Denis Barritault, David G. Fernig^¶, and José Courty

From the  Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires (CRRET), Unité Propre de Recherche de l'Enseignement Supérieur Associées an CNRS (UPRES-A) CNRS 7053, Université Paris XII-Val de Marne, avenue du Général de Gaulle, 94010 Créteil, France and the ^¶ School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom

Heparin affin regulatory peptide (HARP) is a polypeptide belonging to a family of heparin binding growth/differentiation factors. The high affinity of HARP for heparin suggests that this secreted polypeptide should also bind to heparan sulfate proteoglycans derived from cell surface and extracellular matrix defined as extracellular compartments. Using Western blot analysis, we detected HARP bound to heparan sulfate proteoglycans in the extracellular compartments of MDA-MB 231 and MC 3T3-E1 as well as NIH3T3 cells overexpressing HARP protein. Heparitinase treatment of BEL cells inhibited HARP-induced cell proliferation, and the biological activity of HARP in this system was restored by the addition of heparin. We report that heparan sulfate, dermatan sulfate, and to a lesser extent, chondroitin sulfate A, displaced HARP bound to the extracellular compartment. Binding analyses with a biosensor showed that HARP bound heparin with fast association and dissociation kinetics (k_ass = 1.6 × 10⁶ M¹ s¹; k_diss = 0.02 s¹), yielding a K_d value of 13 nM; the interaction between HARP and dermatan sulfate was characterized by slower association kinetics (k_ass = 0.68 × 10⁶ M¹ s¹) and a lower affinity (K_d = 51 nM). Exogenous heparin, heparan sulfate, and dermatan sulfate potentiated the growth-stimulatory activity of HARP, suggesting that corresponding proteoglycans could be involved in the regulation of the mitogenic activity of HARP.

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