FGF binding and FGF receptor activation by synthetic heparan-derived di- and trisaccharides

Science ◽  
1995 ◽  
Vol 268 (5209) ◽  
pp. 432-436 ◽  
Author(s):  
D. Ornitz ◽  
A. Herr ◽  
M Nilsson ◽  
J Westman ◽  
C. Svahn ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Fgf Receptor

scholarly journals The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

2009 ◽  
Vol 187 (7) ◽  
pp. 1101-1116 ◽  
Author(s):  
Chiara Francavilla ◽  
Paola Cattaneo ◽  
Vladimir Berezin ◽  
Elisabeth Bock ◽  
Diletta Ami ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cellular Response ◽  
Critical Role ◽  
Biological Significance ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Fgf Receptor ◽  
Neural Cell Adhesion ◽  
Sustained Activation

Neural cell adhesion molecule (NCAM) associates with fibroblast growth factor (FGF) receptor-1 (FGFR1). However, the biological significance of this interaction remains largely elusive. In this study, we show that NCAM induces a specific, FGFR1-mediated cellular response that is remarkably different from that elicited by FGF-2. In contrast to FGF-induced degradation of endocytic FGFR1, NCAM promotes the stabilization of the receptor, which is recycled to the cell surface in a Rab11- and Src-dependent manner. In turn, FGFR1 recycling is required for NCAM-induced sustained activation of various effectors. Furthermore, NCAM, but not FGF-2, promotes cell migration, and this response depends on FGFR1 recycling and sustained Src activation. Our results implicate NCAM as a nonconventional ligand for FGFR1 that exerts a peculiar control on the intracellular trafficking of the receptor, resulting in a specific cellular response. Besides introducing a further level of complexity in the regulation of FGFR1 function, our findings highlight the link of FGFR recycling with sustained signaling and cell migration and the critical role of these events in dictating the cellular response evoked by receptor activation.

The development of the pattern of retinal ganglion cells in the chick retina: mechanisms that control differentiation

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5713-5724 ◽  
Author(s):  
K.L. McCabe ◽  
E.C. Gunther ◽  
T.A. Reh
Keyword(s):  
Cell Differentiation ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Receptor Activation ◽  
Peripheral Retina ◽  
Retinal Ganglion ◽  
Fgf Receptor ◽  
Chick Retina ◽  
Regular Arrays

Neurons in both vertebrate and invertebrate eyes are organized in regular arrays. Although much is known about the mechanisms involved in the formation of the regular arrays of neurons found in invertebrate eyes, much less is known about the mechanisms of formation of neuronal mosaics in the vertebrate eye. The purpose of these studies was to determine the cellular mechanisms that pattern the first neurons in vertebrate retina, the retinal ganglion cells. We have found that the ganglion cells in the chick retina develop as a patterned array that spreads from the central to peripheral retina as a wave front of differentiation. The onset of ganglion cell differentiation keeps pace with overall retinal growth; however, there is no clear cell cycle synchronization at the front of differentiation of the first ganglion cells. The differentiation of ganglion cells is not dependent on signals from previously formed ganglion cells, since isolation of the peripheral retina by as much as 400 μm from the front of ganglion cell differentiation does not prevent new ganglion cells from developing. Consistent with previous studies, blocking FGF receptor activation with a specific inhibitor to the FGFRs retards the movement of the front of ganglion cell differentiation, while application of exogenous FGF1 causes the precocious development of ganglion cells in peripheral retina. Our observations, taken together with those of previous studies, support a role for FGFs and FGF receptor activation in the initial development of retinal ganglion cells from the undifferentiated neuroepithelium peripheral to the expanding wave front of differentiation.

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

1999 ◽  
Vol 342 (3) ◽  
pp. 677-682 ◽  
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.

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

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Katja Thümmler ◽  
Eran Rom ◽  
Thomas Zeis ◽  
Maren Lindner ◽  
Sarah Brunner ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Neurological Diseases ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Neuroprotective Signaling ◽  
Mechanistic Basis ◽  
Novel Strategy

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.

scholarly journals A requirement for fibroblast growth factor in regulation of skeletal muscle growth and differentiation cannot be replaced by activation of platelet-derived growth factor signaling pathways.

1995 ◽  
Vol 15 (6) ◽  
pp. 3238-3246 ◽  
Author(s):  
A J Kudla ◽  
M L John ◽  
D F Bowen-Pope ◽  
B Rainish ◽  
B B Olwin
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Map Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Muscle Differentiation ◽  
Receptor Activation ◽  
Skeletal Muscle Differentiation ◽  
Fgf Receptor ◽  
Beta Receptor

The distinct effects of cytokines on cellular growth and differentiation suggest that specific signaling pathways mediate these diverse biological activities. Fibroblast growth factors (FGFs) are well-established inhibitors of skeletal muscle differentiation and may operate via activation of specific signaling pathways distinct from recently identified mitogen signaling pathways. We examined whether platelet-derived growth factor (PDGF)-activated signaling pathways are sufficient to mediate FGF-dependent repression of myogenesis by introducing the PDGF beta receptor into a mouse skeletal muscle cell line. Addition of PDGF-BB to cells expressing the PDGF beta receptor activated the PDGF beta receptor tyrosine kinase, stimulated mitogen-activated protein (MAP) kinase, and increased the steady-state levels of junB and c-fos mRNAs. Despite the activation of these intracellular signaling molecules, PDGF beta receptor activation elicited no detectable effect on cell proliferation or differentiation. In contrast to PDGF-BB, addition of FGF-2 to myoblasts activated signaling pathways that resulted in DNA synthesis and repression of differentiation. Because of the low number of endogenous FGF receptors expressed, FGF-stimulated signaling events, including tyrosine phosphorylation and activation of MAP kinase, could be detected only in cells expressing higher levels of a transfected FGF receptor cDNA. As the PDGF beta receptor- and FGF receptor-stimulated signaling pathways yield different biological responses in these skeletal muscle cells, we hypothesize that FGF-mediated repression of skeletal muscle differentiation activates signaling pathways distinct from those activated by the PDGF beta receptor. Activation of PDGF beta receptor tyrosine kinase activity, stimulation of MAP kinase, and upregulation of immediate-early gene expression are not sufficient to repress skeletal muscle differentiation.

scholarly journals A Lipid-Anchored Grb2-Binding Protein That Links FGF-Receptor Activation to the Ras/MAPK Signaling Pathway

Cell ◽  
1997 ◽  
Vol 89 (5) ◽  
pp. 693-702 ◽  
Author(s):  
H Kouhara ◽  
Y.R Hadari ◽  
T Spivak-Kroizman ◽  
J Schilling ◽  
D Bar-Sagi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Binding Protein ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Fgf Receptor

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

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.

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

2004 ◽  
Vol 24 (9) ◽  
pp. 3769-3781 ◽  
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.

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

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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