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)

Our polymerase chain reaction cloning of novel tyrosine kinases expressed in the K562 chronic myeloid leukemia cells has revealed a novel fibroblast growth factor receptor, FGFR4. We have here mapped the FGFR4 gene by analysis of somatic cell hybrids and in situ hybridization to the 5q33-qter chromosomal region. This finding is of interest in that the FGFR4 gene is expressed in several leukemia cell lines and the 5q33-qter region is involved in nonrandom chromosomal translocations in acute myelogenous leukemias and Ki-I lymphomas.
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PMID:Localization of the fibroblast growth factor receptor-4 gene to chromosome region 5q33-qter. 137 18

Fibroblast growth factors (FGFs) and their receptors play an important role in cell growth, angiogenesis and embryonal development. Four distinct genes encoding fibroblast growth factor receptors (FGFRs) were identified: flg, encoding FGFR1, bek encoding FGFR2, and the genes for FGFR3 and FGFR4. Both FGFR2 and keratinocyte growth factor receptor (KGFR) are encoded by the same gene, bek. To study the regulation of expression of the FGF receptors we analysed the DNA sequence flanking the 5' region of the cDNA of murine FGFR2 to seek elements that control its transcription. A 5-kbp fragment containing the 5' end of the cDNA was isolated from mouse genomic library and used to map the promoter region. We found that the sequence encoding the 5' non-translated region of the FGFR2/KGFR cDNA contains an intron located 210 bp upstream from the translation start site. Using RNAase protection and primer extension, we identified the mRNA start 37 bp upstream from the beginning of the bek cDNA. The promoter activity was found to reside in a 1.3-kbp fragment upstream from the cDNA, and deletion mapping further localized the promoter to a 0.7-kbp fragment. The sequence of this region shows high G+C content (62%), which is particularly emphasized in the 200 bp upstream from the mRNA start (80% G+C). This region contains the CCGCCC, GGGCGG AND GGAGG motifs also found in promoters of other growth factor receptors. Neither TATA nor CAAT boxes were found near the RNA start site. The characterization of this promoter will allow studies of the regulation of expression of the FGFR2 during development and in pathophysiological states. The differences between the promoter sequence of the gene for FGFR2 (bek) and FGFR1 (flg) may explain their differential expression during development.
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PMID:Promoter region of the murine fibroblast growth factor receptor 2 (bek/KGFR) gene. 140 37

The consistency of the breakpoint on chromosome 5 at band 5q35 occurring in Ki-1 non-Hodgkin's lymphomas is highly suggestive of the involvement of a locally altered gene in this disease. In this study, we analyzed the potential involvement, in the translocation, of two receptor tyrosine kinase genes and putative oncogenes, FLT4 and FGFR4, previously localized near this breakpoint. Fluorescence in situ chromosomal hybridization allowed us to refine their localization to sub-band 5q35.3 and to show that both genes are translocated to the derivative chromosomes in Ki-1 cell lines containing either a t(2;5) or a t(3;5). Pulsed-field gel electrophoresis showed that the FLT4 and FGFR4 genes are not physically linked, nor are they altered by the translocation. Finally, Northern blot analysis showed that neither FLT4 nor FGFR4 is expressed in the Ki-1 cell lines, suggesting that they are not implicated in the genesis of Ki-1 lymphomas.
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PMID:Localization of two tyrosine kinase receptor genes with respect to the 5q35 chromosomal breakpoint of Ki-1 lymphoma cell lines. 750 15

Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV.
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PMID:Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection. 752 91

Receptor tyrosine kinases (RTK) with five, three, or seven immunoglobulinlike domains in their extracellular regions are classified as subclasses III, IV, and V, respectively. Conservation of the exon/intron structure of the downstream part of the human KIT, FMS, and FLT3 genes that encode RTK of subclass III together with the particular chromosomal localization of these genes suggests that RTKIII genes have evolved from a common ancestor by cis and trans duplications. To strengthen this model of evolution and to determine if it can be extended to RTKIV and V genes, we constructed a phylogenetic tree of RTKIII, IV, and V on the basis of a multiple alignment of their catalytic tyrosine kinase domain sequences and determined the exon/intron structure of PDGFRA (subclass III), FGFR4 (subclass IV), and FLT4 (subclass V) genes in their downstream part. Phylogenetic analyses with amino acid or nucleotide sequences both resulted in one most parsimonious tree. The phylogenetic trees obtained indicate that all three subclasses are well individuated and that RTKIII and RTKV are closer to each other than RTKIV. Furthermore, RTKIII and FLT4 (subclass V) genes possess the same exon/intron structure in their downstream part while the structure of the RTKIV genes is very similar to that of RTKIII and FLT4. Both approaches are in complete agreement and indicate that RTKIII, IV, and V genes most probably evolved from a common ancestor already "in pieces" by successive duplications involving entire genes.
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PMID:Molecular evolution of the genes encoding receptor tyrosine kinase with immunoglobulinlike domains. 756 29

A cDNA predicted to encode a transmembrane tyrosine kinase receptor with sequence features characteristic of known fibroblast growth factor (FGF) receptors was isolated from an expression library constructed from the human mammary epithelial cell line B5/589. This cDNA, designated cl44, encodes a product of 803 amino acid residues and was readily distinguishable from known FGF receptors. During the course of our studies, Partanen et al. (Partanen, J., Makela, T. P., Eerola, E., Korhonen, J., Hirvonen, H., Claesson, W. L., and Alitalo, K. (1991) EMBO J. 10, 1347-1354) isolated a new FGF receptor, designated FGFR4, from the human leukemia cell line, K562. Its amino acid sequence is identical to that of cl44 with the exception of 1 residue. The 5'-untranslated sequences of the two cDNAs diverged far upstream of the initiation codon. A myoblast line, L6E9, which lacks FGF receptors, was utilized to express high levels of FGFR4. We found, in contrast to Partenen et al., who reported only binding of acidic FGF, that FGFR4 bound both acidic and basic FGF with dissociation constants of 10-15 and 120 pM, respectively. No detectable binding of keratinocyte growth factor was observed. In studies aimed to determine whether FGF receptors contribute to the development of human tumors, we screened RNAs prepared from cell lines derived from a variety of solid tumors. High levels of the cl44 transcript were detected in 8 of 14 and 6 of 9 human mammary and kidney carcinomas, respectively, but only infrequently in other types of tumors. In contrast, FGFR1 was found to be frequently expressed in kidney, but not in breast tumor cells, suggesting a possible role for FGFR4 in human mammary cancer.
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PMID:Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. 768 Jun 45

The family of FGF growth factors is involved in several biological processes and might play an important role in tumorigenesis. We have studied the respective expression of 8 of the 9 characterized FGF genes, and of the 4 known FGF receptor genes, in a panel of 10 tumor-cell lines and 103 breast-tumor samples, using RT-PCR and Northern-blot analyses. FGF1 and FGF2 were expressed in almost all samples, while expression of FGF5, FGF6, FGF7, and FGF9 was more restricted. FGFR1, FGFR2 and FGFR4 were expressed at high levels in respectively 22%, 4% and 32% of tumors. FGFR3 expression was not detected. The transcript encoding an FGFR1 isoform with 2 immunoglobulin-like domains was the most prevalent.
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PMID:Expression of FGF and FGF receptor genes in human breast cancer. 770 43

We compared the mitogenic and signaling pathways of three Fibroblast Growth Factor Receptors (FGFRs), FGFR1, KGFR and FGFR4 in the same cell line. Each receptor was expressed in L6E9 rat myoblasts that do not normally express detectable levels of FGFRs and clones that express comparable levels of each receptor were selected. Our results show that FGFs induce an effective survival and growth of FGFR1 and KGFR expressing cells. In addition, these cells exhibit a morphology that is reminiscent of that of malignantly transformed cells and display anchorage independent growth in a ligand dependent manner. Unlike KGFR and FGFR1, FGFR4 mediates a less effective growth, and cells overexpressing this receptor do not undergo any morphological changes nor do they display an anchorage independent growth in response to FGFs. All three receptors exhibit both quantitative and qualitative differences in their ability to induce tyrosine phosphorylation of cellular substrates. Both FGFR1 and KGFR induce strong phosphorylation of phospholipase C-gamma and a 90 kDa protein, while FGFR4 induces a relatively weak phosphorylation of phospholipase C-gamma and completely fails to induce phosphorylation of the 90 kDa. The three receptors also induce phosphorylation of the mitogen activated protein kinases (MAPK) but the effect of FGFR1 is far stronger than that of the other two receptors. Since FGFR4 is expressed in myoblasts in vivo, we examined whether this receptor can function in the differentiation pathway of myoblasts. Contrary to its weak mitogenic activity, FGFR4 effectively mediates the inhibition of myogenic differentiation in L6E9 cells and also suppresses the expression of the myogenic regulatory protein myogenin. Taken together, our results suggest that the signaling mechanism of FGFR4 differs from that of FGFR1 and KGFR, and that the primary role of FGFR4 in myoblasts may be the maintenance of their non differentiated state.
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PMID:Fibroblast growth factor receptors display both common and distinct signaling pathways. 773 10

We demonstrate that purified fibroblast growth factor (FGF) 3 from Xenopus laevis (XFGF3) activates the mitogen-activated protein kinase pathway and induces DNA synthesis in quiescent cells. To characterize the high affinity cell surface receptors that mediate these responses, the ligand binding domains of different FGF receptors (FGFR) were expressed on COS-1 cells, and their affinity for XFGF3 was determined. Unlabeled XFGF3 efficiently competed with 125I-FGF1 for binding to the IIIb and IIIc isoforms of FGFR2, giving 50% displacement (ID50) at 0.3-0.8 nM. Higher XFGF3 concentrations were needed to displace 125I-FGF1 from FGFR3 and FGFR1 (ID50 approximately 4 and 21 nM, respectively), indicating that XFGF3 has a lower affinity for these receptors. No association of XFGF3 with FGFR4 was found using this assay. FGFR2 isoforms isolated from both mouse and Xenopus showed similar high affinity binding of XFGF3 as determined by direct binding assays (Kd values in the range of 0.2-0.6 nM). These results indicate that the binding specificity of XFGF3 is different from that of other FGFs, and identifies FGFR2 as its high affinity receptor.
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PMID:Fibroblast growth factor (FGF) 3 from Xenopus laevis (XFGF3) binds with high affinity to FGF receptor 2. 789 24

FGF6 is structurally very similar to the other members of the FGF gene family, and particularly to the FGF4 gene, which was instrumental in its isolation. Its longest open reading frame encodes a 208 amino acid residues long protein, both in man and in the mouse. It is expressed as a 4.8 kb transcript in skeletal muscle. In developing muscle, expression starts at the myotomal stage and culminates in differentiated fetal muscle masses. In culture, FGF6 protein is mitogenic and has a transforming capacity for fibroblasts. It represses the terminal differentiation of myoblasts. Action of FGF6 could be mediated by the FGFR4 receptor, which binds FGF6 and whose gene is also expressed in developing skeletal muscle.
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PMID:The human and mouse fibroblast growth factor 6 (FGF6) genes and their products: possible implication in muscle development. 819 50


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