Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FGFR2 is a membrane-spanning tyrosine kinase that serves as a high affinity receptor for several members of the fibroblast growth factor (FGF) family. To explore functions of FGF/FGFR2 signals in development, we have mutated FGFR2 by deleting the entire immunoglobin-like domain III of the receptor. We showed that murine FGFR2 is essential for chorioallantoic fusion and placenta trophoblast cell proliferation. Fgfr2(DeltaIgIII/DeltaIgIII) embryos displayed two distinct defects that resulted in failures in formation of a functional placenta. About one third of the mutants failed to form the chorioallantoic fusion junction and the remaining mutants did not have the labyrinthine portion of the placenta. Consequently, all mutants died at 10-11 days of gestation. Interestingly, Fgfr2(DeltaIgIII/DeltaIgIII) embryos do not form limb buds. Consistent with this defect, the expression of Fgf8, an apical ectodermal factor, is absent in the mutant presumptive limb ectoderm, and the expression of Fgf10, a mesenchymally expressed limb bud initiator, is down regulated in the underlying mesoderm. These findings provide direct genetic evidence that FGF/FGFR2 signals are absolutely required for vertebrate limb induction and that an FGFR2 signal is essential for the reciprocal regulation loop between FGF8 and FGF10 during limb induction.
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PMID:Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. 943 95

A newly identified member of the fibroblast growth factor (FGF) family, designated FGF-10, is expressed during development and preferentially in adult lung. The predicted FGF-10 protein is most related to keratinocyte growth factor (KGF, or FGF-7). The latter is unique among FGFs in that it binds and signals only through the FGF receptor (FGFR2b) isoform KGF receptor (KGFR) expressed specifically by epithelial cells. In order to examine the biological and biochemical properties of human FGF-10, we isolated the cDNA and expressed its encoded protein in bacteria. The recombinant protein (rFGF-10) was a potent mitogen for Balb/MK mouse epidermal keratinocytes with activity detectable at 0.1 nM and maximal at around 5 nM. Within this concentration range, FGF-10 did not stimulate DNA synthesis in NIH/3T3 mouse fibroblasts. rFGF-10 bound the KGFR with high affinity comparable to that of KGF, and did not bind detectably to either the FGFR1c (Flg) or FGFR2c (Bek) receptor isoforms. The mitogenic activity of FGF-10 could be distinguished from that of KGF by its different sensitivity to heparin and lack of neutralization by a KGF monoclonal antibody. These results indicate that FGF-10 and KGF have similar receptor binding properties and target cell specificities, but are differentially regulated by components of the extracellular matrix.
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PMID:Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7). 958 67

Acidic fibroblast growth factor (FGF-1), keratinocyte growth factor (FGF-7), and FGF-10 are homologues with distinct specificity. In the presence of heparin, FGF-1 binds and activates in vitro all FGFR subtypes, while FGF-7 exhibits absolute specificity for the IIIb splice variant of FGFR2. FGF-10 exhibits a similar specificity but also binds the FGFR1IIIb isoform. Neither FGF-7 nor FGF-10 will bind to IIIc isoforms of FGFR. Molecular models of FGF, heparin, and the FGFR ectodomain suggested that sequences between beta-strands 10 and 12 of FGF may be important for the interaction of FGF with the heparin-FGFR ectodomain duplex. Site-directed mutants of FGF-7 and FGF-10 were prepared to test whether this domain might underlie failure of FGF-7 and FGF-10 to bind to the FGFRIIIc isoforms. Constructions with substitution of FGF-1 sequences spanning the entire C-terminus encoded in exon 3 or only C-terminal sequences spanning beta-strands 10 through 12 conferred ability on FGF-7 to bind to and activate FGFRIIIc without a significant loss in binding to or activation of FGFR2IIIb. A series of twelve different substitutions of shorter segments of FGF-1 sequences into the C-terminal portion of FGF-7 or FGF-10 revealed that substitution of GSCKRG for GIPVRG or the tri-peptide sequence KKN for NQK just N-terminal to it conferred dual activities on both the FGF-7 and FGF-10 backbones. The results suggest that the combined sequence domain, which we call the FGF glycine box (G-box), is a major determinant for the specificity of the binding of FGF to heparan sulfate-FGFR duplexes.
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PMID:The glycine box: a determinant of specificity for fibroblast growth factor. 984 17

Fibroblast growth factor (FGF)-10, a homologue of FGF-7, is expressed significantly in normal rat prostate tissue, well differentiated rat prostate tumors with an epithelial and stromal compartment and only in derived prostate stromal cells in culture. Similar to FGF-7, recombinant rat FGF-10 was a specific mitogen for prostate epithelial cells. In contrast to FGF-7 which is widely expressed among stromal cells in tissues, the expression of FGF-10 correlated with the presence of stromal cells of muscle origin. Radioreceptor binding assays and covalent cross-linking analysis revealed that FGF-10 binds with an affinity equal to FGF-7 to resident epithelial cell receptor, FGFR2IIIb, but unlike FGF-7 also binds the IIIb splice variant of FGFR1. Analysis of mRNA expression by RNase protection revealed that, similar to FGF-7, the expression of FGF-10 was responsive to androgen in stromal cells from normal prostate and non-malignant differentiated tumors. Although FGF-10 cDNA exhibits a signal sequence for secretion, cultured stromal cells exhibit strictly a cell-associated FGF-10 antigen that correlates with an alternately translated intracellular isoform. FGF-10 requires 1.4 times higher NaCl for elution from immobilized heparin than does FGF-7 and binds to four times the number of sites on the pericellular matrix of epithelial cells. The results show that prostate stromal cell-derived FGF-10, like FGF-7, exhibits the properties of an andromedin which may indirectly mediate control of epithelial cell growth and function by androgen. Although FGF-10 and FGF-7 bind and activate the same resident epithelial cell receptor (FGFR2IIIb), differences in cell type of origin, compartmentation by alternate translation, the affinity for FGFR1IIIb, and access to FGFR by differential interaction with pericellular matrix heparan sulfate suggest they may play both independent and compensatory roles in prostate homeostasis.
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PMID:Fibroblast growth factor-10. A second candidate stromal to epithelial cell andromedin in prostate. 1021 69

Fibroblast growth factors (FGFs) transmit their signals through four transmembrane receptors that are designated FGFR1-4. Alternative splicing in the extracellular region of FGFR1-3 generates receptor variants with different ligand binding affinities. Thus two types of transmembrane receptors (IIIb and IIIc isoforms) have been identified for FGFR2 and FGFR3, and the existence of analogous variants has been postulated for FGFR1 based on its genomic structure. However, only a single full-length transmembrane FGFR1 variant (FGFR1-IIIc) has been identified so far. Here we describe the cloning of a full-length cDNA encoding FGFR1-IIIb from a mouse skin wound cDNA library. This receptor isoform was expressed at the highest levels in a subset of sebaceous glands of the skin and in neurons of the hippocampus and the cerebellum. FGFR1-IIIb was expressed in L6 rat skeletal muscle myoblasts and used in cross-linking and receptor binding studies. FGF-1 was found to bind the receptor with high affinity, whereas FGF-2, -10, and -7 bound with significantly lower affinities. Despite their apparently similar but low affinities, FGF-10 but not FGF-7 induced the activation of p44/42 mitogen-activated protein kinase in FGFR1-IIIb-expressing L6 myoblasts and stimulated mitogenesis in these cells, demonstrating that this new receptor variant is a functional transmembrane receptor for FGF-10.
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PMID:Fibroblast growth factor (FGF) receptor 1-IIIb is a naturally occurring functional receptor for FGFs that is preferentially expressed in the skin and the brain. 1082 61

Epithelial cells, which express FGFR2IIIb, bind and respond to FGF-1, FGF-7 and FGF-10, but not FGF-2. Stromal cells, which bind and respond to FGF-1 and FGF-2, but not FGF-7 and FGF-10, express FGFR2IIIc or FGFR1IIIc. Here we show that when both isolated FGFR2betaIIIb and FGFR2betaIIIc or their common Ig module II are allowed to affinity select heparin from a mixture, the resultant binary complexes bound FGF-1, FGF-2, and FGF-7 with nearly equal affinity. In addition, FGF-2 and FGF-7 bound to both heparin-Ig module IIIb and IIIc complexes, but FGF-1 bound to neither Ig module III. The results show that in isolation both Ig modules II and III of FGFR2 can interact with heparin and that each exhibits a binding site for FGF. We suggest that the specificity of FGFR2IIIb and FGFR2IIIc is dependent on the cell membrane environment and heparin/heparan sulfate. Ig modules II and III cooperate both within monomers and across dimers with cellular heparan sulfates to confer cell type-dependent specificity of the FGFR complex for FGF.
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PMID:Ligand binding properties of binary complexes of heparin and immunoglobulin-like modules of FGF receptor 2. 1086 Aug 38

Craniosynostosis syndromes are autosomal dominant human skeletal diseases that result from various mutations in fibroblast growth factor receptor genes (Fgfrs). Apert syndrome (AS) is one of the most severe craniosynostosis syndromes and is associated with severe syndactyly of the hands and feet and with central nervous system malformations. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking Ig-like domains II and III of FGFR2. Here we demonstrate that these mutations break one of the cardinal rules governing ligand specificity of FGFR2. We show that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 or FGF10 and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2, FGF6, and FGF9. These data demonstrate loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. These data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2.
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PMID:Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. 1112 Oct 55

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
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PMID:Attenuation of FGF signalling in mouse beta-cells leads to diabetes. 1113 Jul 26

Fibroblast growth factor (FGF) -10 (keratinocyte growth factor 2, KGF 2) is a new member of the FGF family that is mainly synthesized by mesenchymal cells and acts predominantly on epithelial cells in a paracrine manner. Its actions are dependent on its binding to the iiib isoform of the cell-surface FGF receptor 2 (FGFR2 iiib). FGF-10 is known to play an important role in fetal limb and lung development, skin wound healing and prostatic epithelial cell growth. In the present study, the expression of FGF-10 and FGFR2 iiib in five cultured human colorectal adenocarcinoma cell lines (COLO 205, DLD-1, HCT-15, SW 480 and WiDr) and the localization of FGF-10 messenger RNA (mRNA) and its protein in human colorectal cancer tissues from 10 patients were determined. All five colorectal cancer cell lines expressed FGF-10 mRNA and its protein. FGFR2 iiib mRNAs were expressed in these cells and the recombinant FGF-10 (1 ng/ml) increased the growth rate of COLO 205 cells. To determine the localization of FGF-10 protein and its mRNA in normal and cancerous human colorectal tissues, immunohistochemistry and in situ hybridization were performed. In normal colorectal tissues, FGF-10 and its mRNA were not detected. In contrast, moderate immunoreactivity was present in cancer cells in 5 of 10 colorectal cancer cases and mild immunoreactivity was recognized in adjacent fibroblasts. By using in situ hybridization, FGF-10 mRNA was observed in colorectal cancer cells and fibroblasts adjacent to cancer cells. These findings indicate that FGF-10 and its receptor, FGFR2 iiib expression in colorectal adenocarcinoma cells and FGF-10 may contribute to the growth of cells of this type.
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PMID:Expression of fibroblast growth factor (FGF)-10 in human colorectal adenocarcinoma cells. 1159 23

Together with glial-derived neurotrophic factor (GDNF), soluble factors present in a metanephric mesenchyme (MM) cell conditioned medium (BSN-CM) are necessary to induce branching morphogenesis of the isolated ureteric bud (UB) in vitro (Proc. Natl. Acad. Sci. USA 96 (1999) 7330). Several lines of evidence are presented here in support of a modulating role for fibroblast growth factors (FGFs) in this process. RT-PCR revealed the expression of two FGF receptors, FGFR1(IIIc) and FGFR2(IIIb), in isolated embryonic day 13 rat UBs, which by indirect immunofluorescence displayed a uniform distribution. Rat kidney organ culture experiments in the presence of a soluble FGFR2(IIIb) chimera or a neutralizing antibody to FGF7 suggested an important contribution of FGFs other than FGF7 to the branching program. Several FGFs, including FGF1, FGF2, FGF7 and FGF10, in combination with GDNF and BSN-CM were found to affect growth and branching of the isolated UB, albeit with very different effects. FGF1 and FGF7 were at extreme ends of the spectrum, with FGF10 (more FGF1-like) and FGF2 (more FGF7-like) falling in between. FGF1 induced the formation of elongated UB branching stalks with distinct proliferative ampullary tips, whereas FGF7 induced amorphous buds displaying nonselective proliferation with little distinction between stalks and ampullae. Electron microscopic examination demonstrated that FGF1 treatment induced cytoskeletal organization, intercellular junctions and lumens along the stalk portion of the developing tubules, while the ampullary regions contained 'less differentiated' cells with an abundant secretory apparatus. In contrast, FGF7-induced UBs displayed this 'less differentiated' morphology regardless of position on the structure and were virtually indistinguishable from FGF1-induced ampullae. Consistent with this, GeneChip array analysis (employing a novel nanogram-scale assay consisting of two rounds of amplification and in vitro transcription for analyzing small quantities of RNA) revealed that FGF7-induced UBs expressed more markers of cell proliferation than FGF1, which caused the UB to express cytoskeletal proteins, extracellular matrix proteins, and at least one integrin, some of which may be important in UB branch elongation. Thus, while the various FGFs examined all support UB growth, FGF1 and FGF10 appear to be more important for branching and branch elongation, and may thus play a role in determination of nephron number and patterning in the developing kidney. These in vitro data may help to explain results from knockout and transgenic studies and suggest how different FGFs may, together with GDNF and other factor(s) secreted by MM cells, regulate branching morphogenesis of the UB by their relative effects on its growth, branching and branch elongation and differentiation, thereby affecting patterning in the developing kidney.
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PMID:Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis. 1173 Dec 27


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