Members of the fibroblast growth factor (FGF) family act on a variety of mammalian cell types and play key roles in many biological processes, including cell growth, proliferation, differentiation and migration. The FGFs initiate signal transmission across the cell membrane by binding to the FGF receptors (FGFRs) and inducing changes in the oligomerization state of the receptors. The cytoplasmic domains of FGFRs possess tyrosine kinase activity. The oligomerization process brings these cytoplasmic domains into close proximity and allows phosphorylation in trans on Tyr residues, leading to receptor activation and phosphorylation of various downstream signaling molecules. While dimerization would intuitively seem to be sufficient for receptor autophosphorylation, it has yet to be demonstrated that a dimer is indeed the minimal signaling unit in this system, since receptor clusters in the cell membrane may actually be required for the activation process.

The fibroblast growth factors are monomeric proteins that are unable to induce receptor activation by themselves; rather, they function in concert with proteoglycans that contain heparin moieties to promote FGFR oligomerization. The recent crystal structure of an FGF in complex with the extracellular ligand binding domain of an FGFR (Plotnikov et al., Cell, 98 641–650; 1999) provides an important clue to the structural basis for FGFR activation by FGFs and heparins.

In the crystal structure, two FGF molecules (orange) bind on the opposite sides of the receptor dimer (green and cyan). Notably, the two FGF molecules do not directly contact each other. A positively charged canyon is formed between the top domains of the dimer of the receptor (behind the green FGFR subunit) and could accommodate a heparin molecule of various lengths. The ends of a heparin molecule of 12 sugar subunits manually docked into this canyon (ball-and-stick model, only the part of the heparin extruding from FGFR is visible) reach and interact with the FGFs.

The structure of the FGF–FGFR complex provides clues to how a heparin molecule and two FGFs stabilize the receptor dimer. The negatively charged heparin could interact with the positive charges lining both sides of the canyon, thereby facilitating dimer formation. In addition, the interactions between the heparin and the FGFs (as proposed in the model), together with the receptor–receptor interactions and the interactions between the FGF and the FGFR on opposite sides of the complex (as observed in the crystal structure), could further stabilize the dimer. The crystal structure of FGF–FGFR and the model of FGF–FGFR–heparin therefore suggest that dimerization is, in fact, sufficient for FGFR activation. Thus it is likely that an FGF–FGFR–heparin dimer is representative of the minimal structural unit required for transmembrane signaling by this family of growth factors.