A dual receptor system is required for basic fibroblast growth factor activity

Abstract

Michael Klagsbrun* and Andrew Bairdt *Departments of Surgery, Biological Chemistry, and Molecular Pharmacology Harvard Medical School and Children's Hospital Boston, Massachusetts 02115 tDepartment of Molecular and Cellular Growth Biology Whittier Institute at Scripps Memorial Hospitals La Jolla, California 92037 The notion that interaction with a single high affinity recep- tor is the most important step that mediates growth factor binding to the cell surface and its initiation of a mitogenic cascade is now regarded by many as simplistic. The com- plex interactions of fibroblast growth factors (FGFs) with high and low affinity receptors provide a good case for amending this view. To date four human genes have been identified that each encode a distinct high affinity receptor (Kd of -10 -11 M)(Houssaint et al., 1990; Johnson et al., 1990; Keegan et al., 1991; Partanen et al., 1991). Each of these genes (shown in Figure 1 as A-D) encodes multiple proteins de- rived from alternative mRNA splicing. Despite their struc- tural similarities, these high affinity receptors may differ in their ability to bind various members of the FGF family, for example, acidic FGF and basic FGF (Partanen et al., 1991). Basic FG F also binds to cell surface heparan sulfate proteoglycans (HSPGs) that have been determined to be low affinity receptors (K~ of -2 x 10 -9 M) (Moscatelli, 1987). Low affinity HSPG-binding sites for basic and acidic FGF exist in the extracellular matrix of cells as well. The existence of at least seven genes encoding FGF family members, at least four genes encoding high affinity recep- tors, and heterogeneous populations of HSPG low affinity receptors on cell surfaces and in the extracellular matrix suggests novel mechanisms for regulating FGF activity and determining responsiveness of target cells to FGF. The binding of basic FGF to the extracellular domain of a high affinity receptor and to heparan sulfate moieties on HSPG is shown schematically in Figure 1. Basic FGF exported into the extracellular matrix by the cell (step 1) is sequestered as a complex with HSPG but is made avail- able (through unkown processes) to cell surface HSPG' low affinity receptors (step 2). This cell-associated HSPG can deliver the growth factor to one or several high affinity receptors (step 3) that internalize basic FGF and initiate the cellular response (step 4). The law of mass action pre- dicts that the relative concentration of low and high affinity sites on the cell surface determines which type of binding site is available to a ligand. In the absence of high affinity receptors, all ligands will be inactive; in the absence of low affinity binding, insufficient ligand accumulates at the cell surface. There presumably exists a low affinity receptor number that may concentrate the ligand at the cell surface and optimally mediate its transfer to the high affinity site. It is of paramount importance to study the characteristics