On the regulation of fibroblast growth factor activity by heparin-like glycosaminoglycans

The activity of several angiogenic factors, like fibroblast growth factors (FGF), is modulated by heparin-like glycosaminoglycans (HLGAGs), which are acidic polysaccharides present in the extracellular matrix and at the cell surface. FGF binds to HLGAG in the matrix, where it is sequestered in a protected and inactive form, and at the cell surface, where it activates its cognate signaling receptor. Here we review recent progress in elucidating how HLGAG regulates FGF-induced signal transduction. Data from crystal structures of FGF complexed to active and inactive oligosaccharides is analyzed in the context of current models for HLGAG modulation of FGF activity. We propose that FGF can dimerize in several different modes, stabilized by HLGAGs. Individual dimer modes may represent active or inactive FGF and it is possible that different HLGAGs preferentially stabilize different FGF dimer modes. Understanding HLGAG–FGF interactions can provide leverage for new approaches to therapeutic control of angiogenesis.