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)

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

Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) play major roles in vertebrate embryogenesis, including control of skeletal muscle growth and differentiation. Understanding their roles requires delineating the specific FGF and FGFR isoforms involved. This study analyzes the FGFR transcripts found in a model mouse skeletal myoblast cell line (MM14) during growth and terminal differentiation. MM14 cells express transcripts for FGFR1 (flg) but not FGFR2 (bek). The predominate FGFR1 transcript contains three immunoglobulin (Ig)-like domains in the extracellular ligand binding region. Approximately one-fourth of the three Ig-like domain transcripts possess a 6-nt deletion between the first and second Ig-like domains which after translation would result in deletion of an Arg-Arg pair. Cloning of mouse genomic DNA surrounding the region of the FGFR1 6-nt deletion indicates that the deletion is derived by alternative splicing of FGFR1 transcripts. Transcripts containing two Ig-like domains account for less than 5% of total FGFR1 mRNA in MM14 cells. A survey of RNA from mouse tissues indicated that two Ig-like domain FGFR1 transcripts are rare in all tissues except in lung, in which the two Ig-like domain form accounts for roughly 70% of the lung FGFR1 mRNA. PCR RACE cloning studies disclosed 162 nt of additional FGFR1 5'-flanking RNA which was highly GC-rich. FGFR1 transcripts decline 8- to 10-fold during low serum, (-)FGF-mediated differentiation of MM14 cultures. The kinetics of the FGFR1 mRNA decline is similar to the previously described differentiation-dependent decrease in cell surface FGF receptors.
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PMID:FGF-mediated aspects of skeletal muscle growth and differentiation are controlled by a high affinity receptor, FGFR1. 142 24

We have previously shown that only adult brain contained a detectable amount of high affinity receptors for basic Fibroblast growth factor (bFGF) whereas adult liver, kidney, lung, intestine or stomach showed only low affinity binding sites. We now have studied and compared the distribution of the receptors for acidic Fibroblast growth factor (aFGF) with that of bFGF receptors in the same tissues. Membrane binding of 125I-aFGF was time dependent, reversible and displaced by an excess of unlabeled aFGF. Scatchard analyses of binding data obtained with all tissue membrane preparations revealed the presence of at least one class of low affinity/high capacity interaction sites characterized by apparent Kd values ranging from 3.9 to 6.9 x 10(-8) M. Interestingly and as for bFGF, high affinity receptors for aFGF could be detected only in adult brain membranes. Cross-linking and Scatchard analyses indicate that this family of interaction was characterized by four molecular species of 175, 125, 95 and 70 kDa and by an apparent Kd value of 1.8 x 10(-10) M. Moreover, cross-competition binding assay revealed that these brain high affinity receptors were common for both acidic and basic FGF. These results suggest that these growth factors may share identical functions mediated by the same receptors highly expressed in the brain. Using a cDNA probe for the Bek form of FGF receptors, we were able to show that all the tissues studied expressed this mRNA (4.5 kb transcript) but probably not in sufficient amounts to account for the number of high affinity receptors that we detected only in the brain.
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PMID:High affinity receptors to acidic and basic fibroblast growth factor (FGF) are detected mainly in adult brain membrane preparations but not in liver, kidney, intestine, lung or stomach. 172 86

Fibroblast growth factor-2 (FGF-2) is expressed in human fetal tissues and placenta. We, therefore, determined whether FGF-2 appeared in either fetal or maternal circulations during normal pregnancies [fetuses appropriate for gestational age (AGA)] or those complicated by fetal growth restriction (small for gestational age). Cordocentesis was performed, and matched maternal blood was collected between 19-39 weeks gestation, whereas maternal and cord blood and amniotic fluid (AF) were collected at term. FGF-2 was extracted from maternal serum (MS), cord serum (CS), and AF by heparin-Sepharose affinity chromatography and subjected to Western blot analysis or quantified by specific RIA. Western blot analysis of MS, CS, and AF revealed, in each case, a single immunoreactive FGF-2 species of 18 kilodaltons (kDa), although this was not present in nonpregnant serum. In AGA pregnancies, immunoreactive FGF-2 was present in MS from at least 18 weeks gestation and rose to maximum values at the end of second trimester (weeks 28-31; mean +/- SEM, 342 +/- 62 pmol/L), but by term had declined (weeks 40-42; 104 +/- 24 pmol/L). In CS, FGF-2 immunoreactivity was highest at weeks 18-20 of gestation (662 +/- 144 pmol/L), but thereafter, slowly declined to term (weeks 40-42; 119 +/- 28 pmol/L). Immunoreactive FGF-2 levels in MS and CS of small for gestational age pregnancies in the second trimester tended to be lower than those in AGA pregnancies, but differences were not statistically significant. AF also contained immunoreactive FGF-2 at term (91 +/- 35 pmol/L). Neutral gel chromatography on Sephadex G-200 revealed that FGF-2 immunoreactivity eluted as a broad peak with an apparent molecular size of 55-160 kDa. These same fractions contained peptides of 55-60, 90-95, and 120-130 kDa, which were recognized by antisera against the extracellular domain of the high affinity FGF receptor, FGFR1, after Western blot. Ligand blot analysis of the same nitrocellulose filters using 125I-labeled FGF-2 revealed that the 55- to 60-kDa species specifically bound FGF-2. This binding species was not recognized during Western blot analysis using an antiserum raised against the intracellular tyrosine kinase domain of FGFR1, suggesting that it represents a truncated receptor form. Similar FGFR1 immunoreactive species were present in nonpregnant female and male sera, but were barely detectable in term CS or AF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibroblast growth factor-2 (FGF-2) is present in maternal and cord serum, and in the mother is associated with a binding protein immunologically related to the FGF receptor-1. 753 16

Fibroblast growth factor receptors (FGFRs) are encoded by at least four distinct highly conserved genes, and alternative splicing generates multiple gene products. The close relationship among different FGFRs has greatly increased the difficulty in generating specific immunochemical probes. As an alternative strategy, we constructed a fusion protein comprising keratinocyte growth factor (KGF) and an IgG1 Fc domain (HFc). The chimeric molecule was efficiently secreted from transfectants as a disulfide-linked dimer that bound KGFRs with high affinity. Moreover, the KGF-HFc, like native KGF, induced DNA synthesis by epithelial cells implying normal functional receptor activation. Because it retained the convenient detection properties of an immunoglobulin, it was possible to use the KGF-HFc in ligand-mediated histochemical analysis of KGFRs. Flow cytometry revealed KGF-HFc chimera detection of the KGFR, an alternative FGFR2 product, but not FGFR1 (flg) or FGFR2 (bek). Histochemical analysis of normal skin demonstrated the specific localization of KGFRs within the spinous layer, a zone of epithelial cell differentiation. KGFRs were also localized to epithelial cells within a specific region of the hair follicle, and they were not detectable in cells of the sweat gland. Tissue sections of soft palate and tonsil, two examples of nonkeratinizing epithelium, revealed staining of stratum spinosum and some staining of the basal cell layer as well. Neither salivary gland epithelium nor lymphoid cells were positive. The ciliated epithelium of the trachea exhibited KGFR expression in intermediate and basal cell layers. In striking contrast to the normal pattern of staining in the adjacent epithelium, a squamous cell carcinoma of skin lacked detectable KGFRs. Our present findings suggest that growth factor-Ig fusion proteins may be generally applicable in ligand-mediated histochemical detection and localization of growth factor receptors.
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PMID:Specific receptor detection by a functional keratinocyte growth factor-immunoglobulin chimera. 772 40

Fibroblast growth factor receptors (FGFRs) have recently been isolated and shown to be transmembrane tyrosine kinase receptors. The FGFR1 gene has previously been assigned to human chromosome 8 and the FGFR4 gene to human chromosome 5. Here we demonstrate, by using somatic cell hybrids, that the FGFR3 gene localizes to human chromosome 4, showing that it, too, resides on a chromosome distinct from those on which other FGFRs have been localized.
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PMID:The fibroblast growth factor receptor 3 gene (FGFR3) is assigned to human chromosome 4. 842 19

Fibroblast growth factors (FGFs) are involved in the transmission of signals between the epithelia and connective tissue, and influence epidermal growth and differentiation. They are thought to be important in the restoration of normal tissues after injury and aberrant expression may also play a role in tumorigenesis. However, no information is available on the nature of cells within oral mucosa which synthesise and/or respond to FGFs. We have screened normal oral mucosa and oral squamous cell carcinoma (SCC) for expression of bFGF by immunohistology and northern analysis and used RT-PCR to look for transcripts for KGF and the high-affinity FGF receptors FGFR1 and FGFR2. Transcripts for bFGF were detected in normal and malignant oral mucosa and KGF within connective tissue elements. The predominant FGF receptor detected in the epidermis and oral mucosa was FGFR2 which binds KGF with greater affinity than bFGF. Production of KGF by connective tissue components and synthesis of the high-affinity KGF receptor, FGFR2, by oral keratinocytes provides circumstantial evidence for a paracrine growth control loop with KGF synthesised within the lamina propria or tumour stroma influencing the proliferation and maturation of both normal oral epithelium and SCC.
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PMID:Expression of bFGF, KGF and FGF receptors on normal oral mucosa and SCC. 873 68

Fibroblast growth factor 2 (FGF2) has been implicated in the pathogenesis of malignant melanoma (MM), but the role of other FGFs and their receptors (FGFRs) is not elucidated. To determine whether FGF1 and FGFR1 may be involved in MM growth in vivo, we have studied the expression of the FGF1 and FGFR1 genes in 77 fresh MM biopsy samples, using RT-PCR analysis. Samples of benign nevi, normal skin and carcinoma cell lines were included as controls. Using RT-PCR analysis, expression of FGF1 and FGFR1 was observed in 69/77 and 68/77 cases, respectively. Immunohistochemical detection of the FGFR1 protein was positive in reactive stromal cells and at a much lower level in neoplastic cells. In situ hybridization experiments demonstrated FGFR1 mRNA mainly located in the stromal component. Southern blot analysis of genomic DNA prepared from MM tumors did not show any structural alteration of the FGFR1 gene. There was no correlation between FGF1/FGFR1 expression and the usual clinicopathological parameters of MM. We conclude that FGF1 and FGFR1 are frequently co-expressed in MM, a situation that may contribute to aberrant autocrine and paracrine pathways. Due to the absence of correlation with clinico-pathological parameters, this expression cannot be used as a marker of prognosis in the management of MM patients.
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PMID:Expression of FGF1 and FGFR1 in human melanoma tissues. 881 25

Fibroblast growth factors (FGFs) and receptors (FGFRs) are expressed in the developing lung and appear to be major regulators of lung growth and differentiation. By using mesenchyme-free lung epithelial cultures we show that FGF-1 (aFGF) and FGF-7 (KGF) produce different effects in the developing lung. FGF-1 stimulates epithelial proliferation that results in bud formation (branching), while FGF-7 promotes epithelial proliferation that leads to formation of cyst-like structures. In addition, FGF-7 stimulates epithelial differentiation, stimulating expression of SP-A and SP-B mRNA throughout the explant, and inducing formation of focal areas of highly differentiated cells. The FGF-1 effects on differentiation are limited to induction of surfactant protein SP-B mRNA at the tips of the explant. The FGF-induced patterns of growth appear to correlate with the distribution of epithelial FGFRs mRNAs; FGFR-2 IIIb (KGFR) is diffusely expressed in the day 11 lung epithelium, while FGFR-4 appears in distal but not in proximal sites. We propose that cyst-like structures may result from FGF-7 binding to the uniformly distributed FGFR-2-IIIb. Lung bud formation may be regulated by FGF-1 and/or other ligands binding to FGFR-2 and a distally located FGFR, such as FGFR-4, leading to an increasing binding and activation of FGFRs at the tips of the explant. Thus, in the embryonic lung epithelium, growth effects of FGFs appear to be dependent on location of FGFRs, while effects on differentiation are ligand-dependent.
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PMID:FGF-1 and FGF-7 induce distinct patterns of growth and differentiation in embryonic lung epithelium. 905 43

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


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