Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.
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PMID:Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome. 915 Jul 25

Mutations in the fibroblast growth factor receptor (FGFR) gene family recently have been shown to underlie several hereditary disorders of bone development, with specific FGFR3 mutations causing achondroplasia (Ach) and thanatophoric dysplasia (TD). However, for none of these mutations has the defect in receptor function been demonstrated directly and, therefore, for none has the pathophysiological mechanism of the disease been defined. Using our established techniques for single-cell ratiometric real-time calcium image analysis, we defined the nature of the basic fibroblast growth factor (bFGF)-induced calcium signal in human diploid fibroblasts, and, in blinded studies, have analyzed the bFGF-induced signals from 18 independent fibroblast cell lines, including multiple lines from patients with known mutant alleles of FGFR3 and syndromes of Ach or TD. Control cells responded with transient increases in intracellular calcium, with many cells showing oscillatory calcium waves. Homozygous Ach cell lines failed to signal, whereas heterozygous Ach lines responded nearly normally. We observed heterogeneous signals in TD heterozygotes: the unresponsive lines all turned out to carry TD1 alleles, whereas all responsive lines had TD2 alleles. Since FGFR1, 2 and 3 receptors are known to be expressed in fibroblasts, our results suggest that specific mutant FGFR3 alleles can function in a dosage-dependent dominant-negative fashion to inactivate FGFR signaling.
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PMID:Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF-induced calcium signals in human diploid fibroblasts. 915 42

In this study we describe the presence of high affinity FGF-2 binding sites in the nuclei of U251MG glioma cells (K(d)=7 pM). Immunoprecipitation of total cell extracts with FGF receptor (FGFR) 1-4 antibodies showed that U251MG glioma cells express only FGFR1. [125I]FGF-2 cross linking to nuclear extracts followed by FGFR1 immunoprecipitation showed that FGFR1 may account for the nuclear FGF-2 binding sites. Western blot analysis demonstrated the presence of 103, 118 kDa and small amounts of 145 kDa FGFR1 isoforms in the nuclei of glioma cells. All isoforms contain both the C- and N-terminal domains. Nuclear FGFR1 retains kinase activity. Immunocytochemistry using confocal microscopy showed specific FGFR1 immunoreactivity within the nuclear interior. In continuously proliferating glioma cells, nuclear FGFR1 is constitutively expressed, independent of cell density. In contrast, in nontransformed human astrocytes, nuclear FGFR1 levels fluctuate with the proliferative state of the cell. In quiescent, confluent astrocytes nuclear FGFR1 protein was depleted. An accumulation of nuclear FGFR1 was observed following the transition to a subconfluent, proliferating state. Transfection of a pcDNA3.1-FGFR1 expression vector into glioma cells that do not express FGFR1 resulted in the nuclear accumulation of FGFR1, increased cell proliferation, and stimulated transition from the G0/G1 to the S-phase of the cell cycle. The increased proliferative rate was resistant to inhibition by the cell-impermeable FGF binding antagonist, myoinositol hexakis [dihydrogen phosphate]. Our results suggest that the constitutive nuclear presence of FGFR1 contributes to the increased proliferation of glioma cells while the transient nuclear accumulation of FGFR1 in normal astrocytes may play a role in the transition to a reactive state.
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PMID:Nuclear accumulation of fibroblast growth factor receptors in human glial cells--association with cell proliferation. 917 56

Heparin and related molecules have been identified as important participants in fibroblast growth factor (FGF) signaling although the mechanisms of action remain unclear. We have used heparin oligosaccharides to examine steps in the signaling process which could be affected by the polysaccharide. Immobilized FGF-1 and FGF-2 bound all sizes of oligosaccharides tested, ranging from tetrasaccharide to decasaccharide, at physiological salt concentration. Each group of oligosaccharide was eluted from the FGF affinity columns in several peaks, and larger oligosaccharides showed higher apparent affinity for the immobilized growth factors compared to the shorter ones. Heparin hexasaccharides were the smallest fragments providing complete protection of FGF-1 and FGF-2 against trypsin digestion. Tetrasaccharides, however, were able to provide partial protection. The requirement of heparin for ligand-receptor interaction was evaluated in receptor binding assays using Sf9 insect cells engineered to overexpress different recombinant FGF receptor (FGFR) species including FGFR1 beta, FGFR1 alpha or FGFR4 at the cell surface. In these assays hexasaccharides were the smallest fragments capable of stimulating FGF-receptor interaction. Over the range of concentrations examined, neither hexasaccharides nor octasaccharides were able to stimulate receptor binding to the level attained by intact heparin. In fact, these oligosaccharides interfered with the ability of intact heparin in promoting FGF-receptor binding. The presence of both stimulatory and inhibitory activities in hexasaccharide and octasaccharide populations could be attributed to structural heterogeneity within the oligosaccharide preparations. However, similar observations were obtained with "highly-sulfated" structurally homogeneous preparations of hexasaccharide and octasaccharide, although these molecules generally had greater stimulatory and less inhibitory activity than their structurally heterogeneous counterparts. Hexasaccharides were found to be the smallest fragments able to potentiate the FGF-1-induced 3T3 cell proliferation while their effect on FGF-2 signaling was less clear. These observations suggest that heparin can modulate FGF-signaling at several stages with different end results.
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PMID:Heparin-dependent fibroblast growth factor activities: effects of defined heparin oligosaccharides. 917 73

Acidic fibroblast growth factor (FGF1) and two of its receptors, FGFR1 and FGFR4, were localized in cryostat sections of normal, benign and malignant human breast tissue by immunohistochemistry. Without pretreatment, FGF1 staining was mainly seen in normal epithelial cells. However, polymerase chain reaction (PCR) analysis and immunoblotting of isolated normal epithelial and myoepithelial cells showed FGF1 mRNA and protein to be present in both cell types. Following incubation of frozen sections at 37 degrees C in phosphate-buffered saline, FGF1 staining was also revealed in myoepithelial cells and basement membrane adjacent to carcinoma cells. Treatment with protease inhibitors demonstrated that this effect was due to the activity of an endogenous protease. In contrast, FGF1 staining was found to be associated with the stroma adjacent to malignant cells only in the presence of protease inhibitors. FGFR1 and FGFR4 immunostaining was localized to both normal and malignant epithelial cells and to a lesser extent to myoepithelial cells. There was no difference in the staining intensity for the FGF receptors between normal and cancer samples. The change in location of FGF1 between normal and malignant tissues and the sensitivity of stored FGF1 to the action of endogenous proteases raises the possibility of both autocrine and paracrine roles for FGF1 in the normal and malignant human breast.
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PMID:The location of acidic fibroblast growth factor in the breast is dependent on the activity of proteases present in breast cancer tissue. 918 78

Fibroblast growth factors (FGFs) regulate cell proliferation and differentiation, and are also important regulators of extracellular matrix. They are among the most potent angiogenic factors known. Evidence suggests the FGFs play a role in glomerular development and pathology. The aim of the present study was to determine whether FGF-1 (acidic FGF) and FGF-2 (basic FGF) and their receptors (FGFRs) were expressed in normal adult rat glomeruli, using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. For RT-PCR studies, the kidneys of 200 g female Sprague-Dawley rats were perfused with buffer and glomeruli isolated using conventional sieving techniques followed by micropipetting. FGF-1 and FGF-2 were expressed in cortex and in glomeruli. All seven receptor isoforms assayed (FGFR1, 2 and 3 IIIb and IIIc splice variants, and FGFR4) were expressed in whole cortex. However, only the IIIc variants and FGFR4 were expressed in glomeruli. The relative levels of glomerular expression of these isoforms were determined using a semiquantitative RT-PCR assay using primers designed against three transmembrane regions; FGFR1 (100%); FGFR2 (0.1%); and FGFR4 (6%). Immunohistochemistry revealed specific immunostaining for all four FGFRs within glomeruli. The differential expression pattern of FGFR isoforms between glomeruli and whole cortex, and the mutually exclusive nature of the expression of IIIc but not IIIb isoforms within glomeruli, indicates that FGFR expression and thereby FGF activity is tightly regulated in glomeruli. These findings have important implications for the roles of the FGFs in glomerular health and disease.
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PMID:Expression of fibroblast growth factors and their receptors in rat glomeruli. 918 60

Mutations in the gene for human fibroblast growth factor receptor 3 (hFGFR3) cause a variety of skeletal dysplasias, including the most common genetic form of dwarfism, achondroplasia (ACH). Evidence indicates that these phenotypes are not due to simple haploinsufficiency of FGFR3 but are more likely related to a role in negatively regulating skeletal growth. The effects of one of these mutations on FGFR3 signaling were examined by constructing chimeric receptors composed of the extracellular domain of human platelet-derived growth factor receptor beta (hPDGFR beta) and the transmembrane and intracellular domains of hFGFR3 or of an ACH (G375C) mutant. Following stable transfection in PC12 cells, which lack platelet-derived growth factor (PDGF) receptors, all clonal cell lines, with either type of chimera, showed strong neurite outgrowth in the presence of PDGF but not in its absence. Antiphosphotyrosine immunoblots showed ligand-dependent autophosphorylation, and both receptor types stimulated strong phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, an event associated with the differentiative response of these cells. In addition, ligand-dependent phosphorylation of phospholipase Cgamma and Shc was also observed. All of these responses were comparable to those observed from ligand activation, such as by nerve growth factor, of the native PC12 cells used to prepare the stable transfectants. The cells with the chimera bearing the ACH mutation were more rapidly responsive to ligand with less sustained MAPK activation, indicative of a preactivated or primed condition and consistent with the view that these mutations weaken ligand control of FGFR3 function. However, the full effect of the mutation likely depends in part on structural features of the extracellular domain. Although FGFR3 has been suggested to act as a negative regulator of long-bone growth in chrondrocytes, it produces differentiative signals similar to those of FGFR1, to which only positive effects have been ascribed, in PC12 cells. Therefore, its regulatory effects on bone growth likely result from cellular contexts and not the induction of a unique FGFR3 signaling pathway.
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PMID:Chimeras of the native form or achondroplasia mutant (G375C) of human fibroblast growth factor receptor 3 induce ligand-dependent differentiation of PC12 cells. 919 52

We have used the mouse mammary tumor virus promoter to express two dominant negative (DN) fibroblast growth factor receptor (FGFR) isoforms in the mammary epithelium of transgenic mice. While expression of DN-FGFR1(IIIc) showed no discernible phenotype, a similar kinase negative form of FGFR2(IIIb) caused a marked impairment of lobuloalveolar development. The growth retardation was apparent by mid-pregnancy and persisted in the post-partum glands. Despite the substantial underdevelopment of the mammary gland there was a measurable lactational response, but it was insufficient to properly sustain the new-born pups. These findings demonstrate that fibroblast growth factor signalling is necessary for pregnancy dependent lobuloalveolar development of the mammary gland.
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PMID:Fibroblast growth factor receptor signalling has a role in lobuloalveolar development of the mammary gland. 920 86

Receptor tyrosine kinases with five, seven, and three Ig-like domains in their extracellular region are grouped in subclasses IIIa, IIIb, and IIIc, respectively. Here, we describe the genomic organization of the extracellular coding region of the human FGFR4 (IIIc) and FLT4 (IIIb) genes and compare it to that of the human FGFR1(IIIc), KIT, and FMS (IIIa). The results show that while genes belonging to the same subclass have an identical exon/intron structure in their extracellular coding region-as they do in their intracellular coding region-genes of related subclasses only have a similar exon/intron structure. These results strongly support the hypothesis that the genes of the three subclasses evolved from a common ancestor by duplications involving entire genes, already in pieces. Hypotheses on the origin of introns and on the difference in the number of extracellular Ig-like domains in the three gene subclasses are discussed.
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PMID:Genomic organization of the extracellular coding region of the human FGFR4 and FLT4 genes: evolution of the genes encoding receptor tyrosine kinases with immunoglobulin-like domains. 921 33

This report describes a systematic analysis of the expression of the fibroblast growth factor receptor (FGFR) multigene family (FGFR1, FGFR2, FGFR3, and FGFR4) in archival serial sections of normal human adult tissues representing the major organ systems, using immunohistochemical techniques. Polyclonal antisera specific for FGFR1, FGFR2, FGFR3, and FGFR4 and a three-stage immunoperoxidase technique were employed to determine the cellular distribution of these receptors at the protein level. The expression profiles for the tissue-specific cellular localization of the FGFR multigene family demonstrated wide-spread and striking differential patterns of expression of individual receptors in the epithelia and mesenchyme of multiple tissues (stomach, salivary glands, pancreas, thymus, ureter, and cornea) and co-expression of FGFR1-4 in the same cell types of other tissues. The wide-spread expression of FGFR1-4 in multiple organ systems suggests an important functional role in normal tissue homeostasis. Differences in the spatial patterns of FGFR gene expression may generate functional diversity in response to FGF-1 and FGF-2, both of which bind with equally high affinity to more than one receptor subtype. In vivo, this may lead to functional differences that are crucial for the regulation of normal physiological processes and are responsible for the pathological mechanisms that orchestrate various disease processes.
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PMID:Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. 921 26


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