Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2.
The activity of fibroblast growth factor 2 (FGF-2) is stringently controlled. Inactive in undisturbed tissues, it is activated during injury and is critical for tissue repair. We find that this control can be imposed by the soluble syndecan-1 ectodomain, a heparan sulfate proteoglycan shed from cell surfaces into wound fluids. The ectodomain potently inhibits heparin-mediated FGF-2 mitogenicity because of the poorly sulfated domains in its heparin sulfate chains. Degradation of these regions by platelet heparanase produces heparin-like heparin sulfate fragments that markedly activate FGF-2 mitogenicity and are found in wound fluids. These results establish a novel physiological control for FGF-2 and suggest new ways to modulate FGF activity.
Kato
M
M
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wang
H
H
Kainulainen
V
V
Fitzgerald
M L
ML
Ledbetter
S
S
Ornitz
D M
DM
Bernfield
M
M
D001665:Binding Sites / Q000502:physiology; D005122:Exudates and Transudates / Q000737:chemistry / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D005966:Glucuronidase; D006026:Glycoside Hydrolases / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D008934:Mitogens / Q000378:metabolism; D009844:Oligosaccharides / Q000494:pharmacology; D011485:Protein Binding; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012995:Solubility; D053668:Syndecan-1; D053667:Syndecans; D014947:Wounds and Injuries / Q000378:metabolism; D000099175:Heparanase
D005343:Fibrinolytic Agents; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D006493:Heparin; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D008934:Mitogens; D009844:Oligosaccharides; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor; D053668:Syndecan-1; D053667:Syndecans; D000099175:Heparanase; C508241:SDC1 protein, human; C496348:FGFR1 protein, human