Identification of Fibroblast Growth Factor 9 (FGF9) as a High Affinity, Heparin Dependent Ligand for FGF Receptors 3 and 2 but not for FGF Receptors 1 and 4

Hecht, Dalit; Zimmerman, Nives; Bedford, Mark T.; Avivi, Aaron; Yayon, Avner

doi:10.3109/08977199509036882

Cited by 101 publications

(71 citation statements)

References 31 publications

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“…For example, in these studies, the FGF-8, FGF-17, FGF-18 subfamily was most selective for FGFR3 (Xu et al, 2000), whereas FGF-9 activated both FGFR3 and FGFR2 (Hecht et al, 1995;Ornitz et al, 1996). Nevertheless, these selectivities were observed in transfected overexpressing cell lines that do not normally express FGFRs, and only the mitogenic response was measured.…”

Section: Fgf/fgfr Specificitymentioning

confidence: 97%

“…Much of the information on FGF signaling in OLs has evolved from the application of FGF-2, which activates all FGF receptors (FGFR1-FGFR4). However, structural and functional studies of ligandreceptor interactions suggest that other FGF family members are more selective in their receptor activation (Miki et al, 1992;Hecht et al, 1995;Ornitz et al, 1996). Whether the observed pleiotrophic effects of FGF-2 on OL lineage cells provides a true reflection of the complexity of FGF signaling remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Fortin¹,

Rom²,

Sun³

et al. 2005

J. Neurosci.

144

166

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Fibroblast growth factors (FGFs) have been implicated in numerous cellular processes, including proliferation, migration, differentiation, and survival. Whereas FGF-2, the prototypic ligand in a family of 22 members, activates all four tyrosine kinase FGF receptors (FGFR1-FGFR4), other members demonstrate a higher degree of selectivity. Oligodendrocytes (OLs), the myelin-producing cells of the CNS, are highly influenced by FGF-2 at all stages of their development. However, how other FGFs and their cognate receptors orchestrate the development of OLs is essentially undefined. Using a combination of specific FGF ligands and receptor blocking antibodies, we now show that FGF-8 and FGF-17 target OL progenitors, inhibiting their terminal differentiation via the activation of FGFR3, whereas FGF-9 specifically targets differentiated OLs, triggering increases in process growth via FGFR2 signaling; FGF-18 targets both OL progenitors and OLs via activation of both FGFR2 and FGFR3. These events are highly correlated with changes in FGF receptor expression from FGFR3 to FGFR2 as OL progenitors differentiate into mature OLs. In addition, we demonstrate that, although activation of FGFR1 by FGF-2 leads to proliferation of OL progenitors, it produces deleterious effects on differentiated OLs (i.e., aberrant reentry into cell cycle and downregulation of myelin proteins with a loss of myelin membrane). These data suggest that ligand availability, coupled with changes in FGF receptor expression, yield a changing repertoire of ligand-receptor signaling complexes that contribute critically to the regulation of both normal OL development and potential OL/myelin pathogenesis.

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Section: Fgf/fgfr Specificitymentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Fortin¹,

Rom²,

Sun³

et al. 2005

J. Neurosci.

144

166

View full text Add to dashboard Cite

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“…The basis for such cell selectivity resides in its differential capacity to bind the different FGF receptors. Recombinant FGF9 binds with high af®nity and in a heparin-dependent manner to FGFR3, with somewhat less af®nity to FGFR2 and with considerably less af®nity to FGFR1 (Hecht et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

Hecht¹,

Adar

Hofmann³

et al. 2001

Acta Crystallogr D Biol Cryst

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Fibroblast growth factors (FGFs) constitute a family of at least 20 structurally related heparin-binding polypeptides active in regulating cell growth, survival, differentiation and migration. FGF9, originally discovered as a glia-activating factor, shares 30% sequence identity with other FGFs and has a unique spectrum of target-cell speci®city. FGF9 crystallized in the tetragonal space group I4 1 , with unit-cell parameters a = b = 151.9, c = 117.2 A Ê . The structure of the glycosylated protein has been re®ned to an R value of 21.0% with R free = 24.8%) at 2.6 A Ê resolution. The four molecules in the asymmetric unit are arranged in two non-crystallographic dimers, with the dimer interface composed partly of residues from N-and C-terminal extensions from the FGF core structure. Most of the receptor-binding residues identi®ed in FGF1± and FGF2±receptor complexes are buried in the dimer interface, with the 8± 9 loop stabilized in a particular conformation by an intramolecular hydrogen-bonding network. The potential heparin-binding sites are in a pattern distinct from FGF1 and FGF2. The carbohydrate moiety attached at Asn79 has no structural in¯uence.

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“…For example, specific mutations in this region in FGFR2 can decrease the binding of FGF2 without affecting the binding of FGF1 or FGF7 (42). The b splice form of FGFR3 (FGFR3b) also has unique properties in that it can only be activated by FGF1, which shows little specificity toward any receptor, and FGF9, which shows no activity toward FGFR1b and FGFR2b (21,43,44). Alternative splicing of Ig domain III can also lead to truncation of the transmembrane and intracellular regions ("a" splice form) creating a secreted FGF-binding protein (45).…”

mentioning

confidence: 99%

Mapping Ligand Binding Domains in Chimeric Fibroblast Growth Factor Receptor Molecules

Chellaiah¹,

Yuan²,

Chellaiah³

et al. 1999

Journal of Biological Chemistry

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Fibroblast growth factors (FGFs) 1 are essential signaling molecules that regulate embryonic growth, development, cell proliferation, differentiation, and angiogenesis (1). At least 19 related members of the FGF family have been identified thus far, and all but four are known to activate one of four high affinity cell surface FGF receptors (FGFR) (2-9).2 The FGFRs consist of an extracellular region containing three immunoglobulin-like (Ig) domains, a stretch of seven conserved acidic amino acids, and a heparin binding domain (10, 11). The FGFRs share an overall 48 -69% amino acid identity (pairwise comparison of the "c" splice form of mouse FGFRs); however, certain sub-regions are nearly 100% conserved. Individual FGFRs are activated by a subset of ligands, and alternative splicing in Ig domain III can dramatically change the specificity for certain .FGFs range in molecular mass from 18 to 29 kDa and show 13-71% amino acid identity (pairwise comparisons of mouse or rat FGFs). Most members of the family share 28 highly conserved amino acid residues, and all FGFs have six identical positions. All members of the FGF family have a high affinity for heparin. Significantly, heparin or heparan sulfate can enhance the high affinity binding of FGFs to their receptors by forming a trimolecular complex with FGF and the FGFR and by decreasing the rate of ligand dissociation (22-28). The formation of this complex results in receptor dimerization, transphosphorylation, and downstream signaling.During development, FGFs are involved in several and sometimes opposing functions requiring tight regulation of their activity and specificity. This may be achieved by regulating spatial and temporal expression of FGFs and FGFRs and by regulating binding specificity (21, 29 -34). A major determinant of ligand binding specificity is alternative splicing in the C terminus of Ig domain III of FGFRs 1-3. This splicing event is tissue-specific and is likely to regulate important signaling events across epithelial/mesenchymal boundaries (35-38). The "b" (epithelial) splice form of FGFR2 (FGFR2b) can be activated by FGF7 and FGF10, ligands produced in mesenchymal tissue. These ligands show no activity toward c (mesenchymal) spliced receptors. Conversely, FGF8 activates c-spliced FGFR2 (FGFR2c) but shows no activity toward FGFR2b (21, 39).2 Notably, FGF8 expression is often restricted to epithelial tissue such as the apical ectodermal ridge of the developing limb bud (40, 41).The C-terminal region of Ig domain III is clearly important for ligand binding and shows specificity toward different ligands. For example, specific mutations in this region in FGFR2 can decrease the binding of FGF2 without affecting the binding of FGF1 or FGF7 (42). The b splice form of FGFR3 (FGFR3b) also has unique properties in that it can only be activated by FGF1, which shows little specificity toward any receptor, and FGF9, which shows no activity toward FGFR1b and FGFR2b (21,43,44). Alternative splicing of Ig domain III can also lead to truncation of the transme...

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Identification of Fibroblast Growth Factor 9 (FGF9) as a High Affinity, Heparin Dependent Ligand for FGF Receptors 3 and 2 but not for FGF Receptors 1 and 4

Cited by 101 publications

References 31 publications

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces

Mapping Ligand Binding Domains in Chimeric Fibroblast Growth Factor Receptor Molecules

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