Heparin, Heparan Sulphate and the TGF-β Cytokine Superfamily

Of the circa 40 cytokines of the TGF-beta superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-beta 1, TGF-beta 2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-beta cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-beta type cystine-knot domain. Other antagonists are more distant members of the TGF-beta superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-beta cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity.