Heparan sulfate proteoglycans as transducers of FGF-2 signalling.
The fibroblast growth factor-2 (FGF-2) low-affinity binding sites, heparan sulfate proteoglycans (HSPGs), function as modulators of FGF-2 activity. It is noteworthy that HSPG binding protects FGF-2 from denaturation and proteolytic degradation, provides a matrix-bound or cell-surface reservoir of this factor for the cells and is required for the activation of FGF high-affinity receptors. In our study we investigated the biological meaning of FGF-2 internalization mediated through its low-affinity binding sites, HSPGs. Using as model system L6 myoblasts lacking endogenous FGF receptors (FGFRs), we demonstrated that these cells internalize FGF-2 efficiently through an HSPG-mediated pathway. FGF-2 internalization occurring through HSPGs was paralleled by an increase in the activity of urokinase plasminogen activator (u-PA). The u-PA-inducing activity of FGF-2 was strictly correlated to its internalization, as chlorate treatment, which causes a strong inhibition of FGF-2 internalization, abrogated the u-PA-inducing activity of FGF-2. In addition, expression of functional FGF high-affinity receptors (FGFR-1) did not enhance u-PA in L6 myoblasts upon FGF-2 stimulation. According to our results we propose that FGF-2 internalization mediated through HSPGs may transduce FGF-2 signalling such as u-PA-activity stimulation. Thus, HSPGs may act as direct transducers of FGF signalling and indeed, different FGF-signalling pathways must exist.
Quarto
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Laboratoire de Biologie Moléculaire Eucaryote, CNRS, Toulouse, France.
Amalric
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D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002704:Chlorates / Q000494:pharmacology; D006224:Cricetinae; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009132:Muscles / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D002704:Chlorates; D016222:Fibroblast Growth Factor 2; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D006497:Heparan Sulfate; D011509:Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D014568:Urokinase-Type Plasminogen Activator