Regulation of growth factor activation by proteoglycans: What is the role of the low affinity receptors?

Many cell membrane receptors, such as the nicotinic ace-tylcholine receptor and the T cell antigen receptor, are composed of several different subunits, and their correct assembly is necessary for the generation of functional receptors. Most lymphokine receptors are composed of at least two components, and ligand-induced oligomeriza-tion is essential for receptor activation and signal transmission. In recent years, it has become clear that various growth factors and lymphokines can bind to two different classes of cell surface receptors. For example, fibroblast growth factor (FGF) and transforming growth factor p (TGFB) both bind with high affinity to signaling receptors endowed with tyrosine or serinelthreonine kinase activities. However, the same growth factors also bind with lower affinity to cell surface proteoglycans that cannot transmit signals alone, but somehow modulate the ability of the growth factor or the signaling receptor to generate a biological response Proteoglycans are proteins that are found predominantly on the cell surface and in the extracellular matrix and that contain carbohydrates called glycosaminogly-cans. Glycosaminoglycans are polymers of disaccharide repeats, which are mostly highly sulfated and negatively charged. The main glycosaminoglycans in proteoglycans are chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, and keratan sulfate (Ruoslahti, 1989). Binding of growth factors to proteoglycans is thought to have an important regulatory role (Ruoslahti and Yamaguchi, 1991). This has been particularly well explored for FGF, in which it has been shown that heparins (or heparan sulfate proteoglycans) are necessary for FGF-induced biologic&l responses (Mason, 1994). Several mechanisms have been proposed for the role of heparin. One such proposal is that proteoglycans stabilize FGF and protect it from pro-teolytic degradation, thus enhancing its efficacy. Another is that FGF bound to cell matrix proteoglycans serves as a reservoir of growth factors that can be released by enzymes that degrade the proteoglycans (Saksela and Rif-kin, 1990). Several studies have also led to the proposal that binding to proteoglycans induces a conformational change in FGF that enhances its affinity for the signaling receptors (Yayon et al., 1991). However, other studies have shown that heparins can also interfere with FGF-induced mitogenic signaling (Mali et al., 1993), which is difficult to reconcile with the model proposing a conforma-tional change induced in FGF by heparin binding. A dual receptor model has been proposed, in which binding of FGF to low affinity cell surface proteoglycan receptors is required for the presentation of FGF molecules to their high affinity signaling receptors, which …