PubMed1999
Heparan sulphate proteoglycans on cell surfaces have been shown to mediate the degradation or recycling of several ligands. Since the interaction with ligand may affect proteoglycan catabolism once the complex is internalized, this could alter the cellular pool of heparan sulphate chains, with possible consequences for heparan sulphate-mediated cellular processes. We have recently demonstrated that the specific binding of basic fibroblast growth factor (bFGF) to heparan sulphate chains prevents the glycosaminoglycan from being degraded by partially purified heparanases from Chinese hamster ovary (CHO) cells [Tumova and Bame (1997) J. Biol. Chem. 272, 9078-9085]. The present study examines the effect of bFGF on heparan sulphate catabolism in intact cells. The distribution and size of the heparan sulphate degradation products in CHO cells was analysed in the presence and absence of bFGF using pulse-chase protocols. Although heparan sulphate molecules and bFGF are internalized through the same pathway, even relatively high concentrations of the growth factor do not have any inhibitory effects on glycosaminoglycan degradation. However, the interaction with the growth factor alters the distribution of heparan sulphate-degradation products, presumably by preventing secretion of the short heparanase-derived species. Our findings show that most of the free and bFGF-bound heparan sulphate chains are destined for lysosomes, which would be consistent with a recent hypothesis that the primary role of proteoglycan-mediated internalization of the growth factor is to remove bFGF from its site of action at the cell surface. However, in the presence of bFGF, a fraction of intracellular, heparanase-degraded heparan sulphate chains is delivered to the nucleus, suggesting that the glycosaminoglycan accompanies the growth factor to the organelle. It may be important for bFGF activity that the growth factor is protected from proteolytic degradation by its interaction with heparan sulphate. This work demonstrates that the internalization of a ligand along with the proteoglycan can affect the sorting of heparan sulphate-degradation products in endosomes, and the ultimate destination of the short glycosaminoglycan. It also provides evidence that formation of heparan sulphate-ligand complexes may regulate the recycling and degradation of both ligands and heparan sulphate chains and, consequently, affect their biological activities.