Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein.
Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typically stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a chaperone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is up-regulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we focused on FGF-1 and -2 and investigated interactions with recombinant human FGF-BP1 protein as well as effects on signal transduction, cell proliferation, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FGF-2 and that this binding is inhibited by FGF-1, heparan sulfate, and heparinoids. Furthermore, FGF-BP1 enhances FGF-1- and FGF-2-dependent proliferation of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We conclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modulates the biological activities of these growth factors.
Tassi
E
E
Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington, D.C. 20007, USA.
Al-Attar
A
A
Aigner
A
A
Swift
M R
MR
McDonnell
K
K
Karavanov
A
A
Wellstein
A
A
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
D002352:Carrier Proteins; C489453:Fgfbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C070699:FGFBP1 protein, human; D005346:Fibroblast Growth Factors; D019950:Mitogen-Activated Protein Kinase 1