HEPARAN-SULFATE PROTEOGLYCANS AS TRANSDUCERS OF FGF-2 SIGNALING

The fibroblast growth factor-2 (FGF-2) low-affinity binding sites, hep aran sulfate proteoglycans (HSPGs), function as modulators of FGF-2 ac tivity. It is noteworthy that HSPG binding protects FGF-2 from denatur ation and proteolytic degradation, provides a matrix-bound or cell-sur face reservoir of this factor for the cells and is required for the ac tivation of FGF high-affinity receptors. In our study we investigated the biological meaning of FGF-2 internalization mediated through its l ow-affinity binding sites, HSPGs. Using as model system L6 myoblasts l acking endogenous FGF receptors (FGFRs), we demonstrated that these ce lls internalize FGF-2 efficiently through an HSPG-mediated pathway. FG F-2 internalization occurring through HSPGs was paralleled by an incre ase in the activity of urokinase plasminogen activator (u-PA). The u-P A-inducing activity of FGF-2 was strictly correlated to its internaliz ation, as chlorate treatment, which causes a strong inhibition of FGF- 2 internalization, abrogated the u-PA-inducing activity of FGF-2. In a ddition, expression of functional FGF high-affinity receptors (FGFR-1) did not enhance u-PA in L6 myoblasts upon FGF-2 stimulation. Accordin g to our results we propose that FGF-2 internalization mediated throug h HSPGs may transduce FGF-2 signalling such as u-PA-activity stimulati on. Thus, HSPGs may act as direct transducers of FGF signalling and in deed, different FGF-signalling pathways must exist.