Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential

AbstractFibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.

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Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro

Biochemical Journal ◽

10.1042/bj3420677 ◽

1999 ◽

Vol 342 (3) ◽

pp. 677-682 ◽

Cited By ~ 28

Author(s):

Nicole B. WEKSLER ◽

Gregory P. LUNSTRUM ◽

Eric S. REID ◽

William A. HORTON

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Physiological Responses ◽

Terminal Differentiation ◽

Receptor Activation ◽

Fibroblast Growth ◽

Fgf Receptor ◽

Chondrocytic Differentiation ◽

Mitotic Inhibitor

Fibroblast growth factor (FGF) 9 was compared with FGF2 in its ability to influence proliferation, differentiation, terminal differentiation and apoptosis in a rat calvaria-derived cell line (RCJ 3.1C5.18) that spontaneously undergoes chondrocyte differentiation in vitro. Like FGF2, FGF9 promoted proliferation, but to a lesser extent. In contrast to FGF2, which blocked chondrocytic differentiation, FGF9 had no effect on differentiation but inhibited terminal differentiation. FGF9 also stimulated expression of the mitotic inhibitor p21 to a greater extent than FGF2. Neither ligand influenced apoptosis. The results indicate that FGF9 could account for many of the physiological responses attributed to FGF-receptor activation in the growth plate.

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Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells

Molecular and Cellular Biology ◽

10.1128/mcb.12.1.240-247.1992 ◽

1992 ◽

Vol 12 (1) ◽

pp. 240-247

Author(s):

D M Ornitz ◽

A Yayon ◽

J G Flanagan ◽

C M Svahn ◽

E Levi ◽

...

Keyword(s):

Growth Factor ◽

Cell Surface ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Receptor Binding ◽

Receptor Activation ◽

Soluble Form ◽

Placental Alkaline Phosphatase ◽

Fibroblast Growth ◽

Fgf Receptor

Heparin is required for the binding of basic fibroblast growth factor (bFGF) to high-affinity receptors on cells deficient in cell surface heparan sulfate proteoglycan. So that this heparin requirement could be evaluated in the absence of other cell surface molecules, we designed a simple assay based on a genetically engineered soluble form of murine FGF receptor 1 (mFR1) tagged with placental alkaline phosphatase. Using this assay, we showed that FGF-receptor binding has an absolute requirement for heparin. By using a cytokine-dependent lymphoid cell line engineered to express mFR1, we also showed that FGF-induced mitogenic activity is heparin dependent. Furthermore, we tested a series of small heparin oligosaccharides of defined lengths for their abilities to support bFGF-receptor binding and biologic activity. We found that a heparin oligosaccharide with as few as eight sugar residues is sufficient to support these activities. We also demonstrated that heparin facilitates FGF dimerization, a property that may be important for receptor activation.

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Downstream-of-FGFR Is a Fibroblast Growth Factor-Specific Scaffolding Protein and Recruits Corkscrew upon Receptor Activation

Molecular and Cellular Biology ◽

10.1128/mcb.24.9.3769-3781.2004 ◽

2004 ◽

Vol 24 (9) ◽

pp. 3769-3781 ◽

Cited By ~ 18

Author(s):

Valérie Petit ◽

Ute Nussbaumer ◽

Caroline Dossenbach ◽

Markus Affolter

Keyword(s):

Cell Migration ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Mapk Pathway ◽

Functional Characterization ◽

Receptor Activation ◽

Scaffolding Protein ◽

Specific Substrate ◽

Fibroblast Growth ◽

Fgf Receptor

ABSTRACT Fibroblast growth factor (FGF) receptor (FGFR) signaling controls the migration of glial, mesodermal, and tracheal cells in Drosophila melanogaster. Little is known about the molecular events linking receptor activation to cytoskeletal rearrangements during cell migration. We have performed a functional characterization of Downstream-of-FGFR (Dof), a putative adapter protein that acts specifically in FGFR signal transduction in Drosophila. By combining reverse genetic, cell culture, and biochemical approaches, we demonstrate that Dof is a specific substrate for the two Drosophila FGFRs. After defining a minimal Dof rescue protein, we identify two regions important for Dof function in mesodermal and tracheal cell migration. The N-terminal 484 amino acids are strictly required for the interaction of Dof with the FGFRs. Upon receptor activation, tyrosine residue 515 becomes phosphorylated and recruits the phosphatase Corkscrew (Csw). Csw recruitment represents an essential step in FGF-induced cell migration and in the activation of the Ras/MAPK pathway. However, our results also indicate that the activation of Ras is not sufficient to activate the migration machinery in tracheal and mesodermal cells. Additional proteins binding either to the FGFRs, to Dof, or to Csw appear to be crucial for a chemotactic response.

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