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)

The development of specific antibody probes for characterizing the expression of the family of 4 fibroblast growth factor receptor (FGFR) types has been difficult because of their close homology to each other and high degree of evolutionary conservation. Of the existing anti-FGFR monoclonal antibodies (MAbs), there are few that are useful for staining paraffin-embedded tissues. We have raised MAbs against human FGFR1 and FGFR2 in both rats and mice using bacterial recombinant receptor fusion proteins as immunogens. We used peptide epitope mapping to characterize the immune sera and the selected MAbs. Immunized animals were selected that displayed the broadest reactivity against epitopes unique to the immunizing receptor type. We produced FGFR1 specific MAbs that bind epitopes in immunoglobulin domain I (Ig-I) and FGFR2 specific MAbs that bind epitopes in Ig-I, Ig-II, and the acid box. The specificity of the antibodies was demonstrated by ELISA and immunoblot analysis of purified recombinant FGFR1 and FGFR2 extracellular domains produced both in E. coli and in eucaryotic cells. Based on the lack of epitope homology, these MAbs would not be expected to cross-react with FGFR3 or FGFR4. We isolated MAbs that bound to paraffin embedded tissue and immunoblots of recombinant receptor. These epitope-defined MAbs can distinguish between members of the FGF receptor family and should be useful as tools for assessing FGF receptor expression in a variety of normal and diseased tissues.
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PMID:Establishment of epitope-defined monoclonal antibodies with specificity for fibroblast growth factor receptor types 1 and 2. 952 34

Signaling through the FGF receptor (FGFR) is required for mesoderm induction in Xenopus. Some of the downstream signaling molecules implicated in this developmental process include Ras, Raf and MAP kinase. In a previous report, we demonstrated that PLC gamma 1, Grb-2, SOS and Nck were associated with activated FGFR1s in a signaling complex in Xenopus blastulae. In addition, several unidentified phosphotyrosylproteins were present in the FGFR1 complex. Here we identify three of these proteins as Ras-GAP, the p85 of P13'K and SHP2, while demonstrating that c-Src and She were not associated with the FGFR1. Furthermore, we show that three additional phosphotyrosylproteins from the FGFR1 complex specifically bound to the adaptor molecule Nck.
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PMID:Identification of phosphorylated proteins associated with the fibroblast growth factor receptor type I during early Xenopus development. 953 39

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

FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV). Int-2 was later designated FGF-3 based on sequence homology with other members of the fibroblast growth factor (FGF) family. FGF-1 is the prototypical member of the FGF family, and is the only family member which activates all known FGF receptor isoforms. Transgenic mice expressing in the lens a form of FGF-1 engineered to be secreted show premature differentiation of the entire lens epithelium. In contrast, transgenic mice engineered to secrete FGF-2 in the lens do not undergo premature differentiation of the lens epithelium (C. M. Stolen et al., 1997, Development 124, 4009-4017). To further assess the roles of FGFs and FGF receptors in lens development, the alpha A-crystallin promoter was used to target expression of FGF-3 to the developing lens of transgenic mice. The expression of FGF-3 in the lens rapidly induced epithelial cells throughout the lens to elongate and to express fiber cell-specific proteins including MIP and beta-crystallins. This premature differentiation of the lens epithelium was followed by the degeneration of the entire lens. Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 IIIb) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo. Furthermore, transgenic lens cells expressing FGF-3 were able to induce the differentiation of neighboring nontransgenic lens epithelial cells in chimeric mice. Expression of FGF-3 in the lens also resulted in developmental alterations of the eyelids, cornea, and retina, and in the most severely affected transgenic lines, the postnatal appearance of intraocular glandular structures.
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PMID:Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice. 964 Mar 29

To characterize fibroblast growth factor (FGF) gene expression in the late fetal (days E18 to E22) and early postnatal lung (days P0 to P28), when the alveolar region undergoes extensive growth and reorganization, we analyzed the expression of four FGF receptors and six ligands. FGF receptor 1 (FGFR1) RNA levels were first low (E18) before rising late in the postnatal period (P28). FGFR2 RNA levels were detected early (at E18) and then increased (E20-P0) before falling (P2) to below later postnatal levels (P6 to P28). FGFR3 RNA levels were low at first (E18) and then increased, with peak levels in the days after birth (P2 to P10). FGFR4 RNA levels, barely detected in fetal lung (E18 to E22), increased at birth (P0) and remained high postnatally (P2 to P28). In fetal lung, FGF2 (basic FGF) RNA expression levels were low and FGF1 (acidic FGF) RNA levels were not detected: low RNA levels of each ligand were detected postnatally (P7 to P28). FGF3 to 5 and FGF7 RNA were not detected in fetal or postnatal lung. With in situ hybridization, predominantly the smooth muscle cells of large vessels expressed FGFR1 and 4 mRNA; the epithelial cells of large airways expressed FGFR1, 2, and 4; and alveolar cells expressed FGFR2, 3, and 4. Analysis of protein expression first identified FGF2 localized to the basement membrane of large airways and branching epithelial buds, to mesenchymal cells associated with buds, to the putative smooth muscle cells of large airways and vessels, and to pleural- and mesenchymal-associated cells (E18). Immediately before birth, this pattern of expression persisted (E20 to E22), with FGF2 also being expressed by putative smooth muscle cells of smaller airways and vessels (E22). After birth (P0 to P28), FGF2 expression remained relatively high in the smooth muscle cells of large and small vessels and in pleural cells; in airway smooth muscle cells and in most cells in the alveolar region, however, although FGF2 expression persisted in some cells, its intensity decreased with time.
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PMID:Differential expression of fibroblast growth factor receptors 1 to 4 and ligand genes in late fetal and early postnatal rat lung. 976 52

Immune reactions in the gut are associated with increased epithelial cell proliferation. Here we have studied the role of keratinocyte growth factor (KGF; FGF7) and transforming growth factor-alpha (TGF-alpha) in the epithelial cell hyperplasia seen in explants of fetal human small intestine after activation of lamina propria T cells with the superantigen Staphylococcus aureus enterotoxin B (SEB). After the addition of SEB to the explants there is a 10-fold increase in KGF mRNA by 72 h of culture. KGF transcripts were abundant in the lamina propria using in situ hybridization and the culture supernatants contained elevated amounts of KGF protein. SEB had no direct effect on KGF mRNA and protein production by cultured lamina propria mesenchymal cells, but both were upregulated by TNF-alpha. Accompanying the increase in KGF there was also an increase in TGF-alpha precursor proteins in the culture supernatants and the phosphorylated form of the EGFR receptor was also detected in the tissue. Increased TGF-alpha precursor proteins were also detected in the supernatants of control explants stimulated with KGF alone. The direct addition of KGF and TGF-alpha enhanced epithelial cell proliferation and antibodies against KGF and TGF-alpha partially inhibited SEB-induced crypt hyperplasia. These results suggest molecular cross-talk between the KGF/KGFR and the TGF-alpha/EGFR in immune-mediated crypt cell hyperplasia.
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PMID:Interactions between stromal cell--derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia. 978 59

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that induces mesenchymal cell proliferation in vivo while inhibiting growth of most cells directly via serine-threonine receptor(s) binding/activation in vitro. In this study, the ability of TGF-beta1 to regulate the receptor expression of classical mitogenic growth factors that bind receptor tyrosine kinases was examined. TGF-beta1 markedly increased the protein expression of the fibroblast growth factor (FGF) receptors FGFR-1 (Flg) and FGFR-2 (Bek) in a time- and dose-dependent manner in human lung fibroblasts. This resulted in a potentiation of the mitogenic response of multiple FGF ligands that bind to these receptors. TGF-beta1 had no effect on epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)-beta receptor expression and the mitogenic responses mediated by specific ligands for these receptors were not increased. These results demonstrate a novel action of TGF-beta1 to selectively upregulate the expression of FGF receptor family members leading to enhanced mitogenesis by FGFs.
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PMID:Upregulated expression of fibroblast growth factor (FGF) receptors by transforming growth factor-beta1 (TGF-beta1) mediates enhanced mitogenic responses to FGFs in cultured human lung fibroblasts. 979 92

Basic fibroblast growth factor (bFGF, FGF-2) is progressively lost from mammary epithelial cells as they become malignant. To investigate the effects of restoring the expression of bFGF in breast cancer cells, we constructed MCF-7 cells that permanently overexpress 18-kD cytoplasm-localizing bFGF (MCF-7/deltaA(FGF)(18) cells) and cells that express both the 18-kD along with the 22- and 24-kD nucleus-localizing bFGF peptides (MCF-7/NCF(FGF)(18,22,24) cells), using retroviral transduction. These stable cell constructs grew more slowly and had a larger fraction of their populations in the G0/G1 phase of the cell cycle than control cells. All forms of bFGF were eluted from MCF-7/NCF(FGF)(18,22,24) cell monolayers with 2 M NaCl, in contrast to fibroblasts that were demonstrated to secrete only the 18-kD bFGF isoform. High-affinity binding of 18-kD 125I-bFGF to these cells was significantly decreased, probably because of competitive binding by the autocrine-secreted bFGF. Recombinant 18-kD bFGF that was previously demonstrated in our laboratory to inhibit proliferation, activate MAP kinase, and induce the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in MCF-7 cells, further inhibited MCF-7/deltaA(FGF)(18) cells but had no effect on MCF-7/NCF(FGF)(18,22,24) cells. The total cellular content of the high-affinity FGF receptors 1-3 was unchanged, but FGF receptor 4 was decreased in MCF-7/NCF(FGF)(18,22,24) cells. Both cell types overexpressing bFGF isoforms had elevated levels of the cyclin-dependent kinase inhibitor p27Kip1 but not that of p21WAF1/CIP1. In MCF-7/deltaA(FGF)(18) cells, FGFR1 and MAP kinase were constitutively phosphorylated. Exogenous recombinant 18-kD bFGF did not accentuate these effects but did induce an increase in the levels of p21WAF1/CIP1 corresponding to the further inhibition induced by exogenous bFGF in these cells. In MCF-7/NCF(FGF)(18,22,24) cells, FGFR1 and MAP kinase were not phosphorylated at baseline nor upon stimulation with recombinant bFGF, and exogenous bFGF only had a minimal effect on low steady-state p21WAF1/CIP1 levels. However, stimulation of these cells with phorbol ester or insulin did result in MAP kinase phosphorylation. While growth-inhibited in the G1 phase of the cell cycle, MCF-7/NCF(FGF)(18,22,24) cells retained active isoforms of cdk2 and the hyperphosphorylated form of Rb. These data suggest that high molecular weight forms of bFGF overexpressed in MCF-7 cells do not activate the receptor-mediated MAP kinase pathway, and do not induce p21WAF1/CIP1 in an autocrine manner, but inhibit proliferation through other, possibly direct nuclear signalling mechanisms.
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PMID:Overexpression of basic fibroblast growth factor in MCF-7 human breast cancer cells: lack of correlation between inhibition of cell growth and MAP kinase activation. 980 50

Keratinocyte growth factor (KGF) is a fibroblast growth factor which acts specifically on epithelial cells, regulating their proliferation and differentiation. KGF elicits its activity through binding to and activation of KGF receptor, a splicing transcript variant of fibroblast growth factor receptor 2 (FGFR2). Here we analyzed the pathway of internalization of KGF and its receptor using several approaches, including the utilization in immunofluorescence and in immunoelectron microscopy of a functional KGF-HFc chimeric protein as a specific tool to follow the endocytosis of the growth factor and of its receptor. Western blot analysis with anti-FGFR2 and anti-phosphotyrosine antibodies, as well as parallel double immunofluorescence and confocal analysis of NIH3T3 KGFR transfectants treated with KGF at 4 degrees C, followed by incubations at 37 degrees C for different time points, showed that KGF induced endocytosis of tyrosine activated KGFRs. The use of KGF-HFc in immunofluorescence and in immunogold electron microscopy on KGFR transfectants, A253 epithelial tumor cells and human cultured keratinocytes allowed us to follow the early steps of KGF internalization and revealed that this process occurred through clathrin-coated pits. A quantitative ELISA assay confirmed that KGF-HFc binding on the cell surface rapidly decreased because of internalization. Our results demonstrate that KGF is internalized by receptor-mediated endocytosis and illustrate the involvement of clathrin-coated pits in this process.
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PMID:Receptor-mediated endocytosis of keratinocyte growth factor. 981 66

The K-sam gene, originally isolated as an amplified gene from the stomach cancer cell line KATO-III, is characterized by its preferential amplification in the undifferentiated type (diffuse type) of stomach cancer and encodes one of the receptors for heparin-binding growth factors or fibroblast growth factors. The K-sam gene has been isolated by different methods and has been designated BEK, TK14, and Cek2. The receptor for keratinocyte growth factor was also found to be encoded by the same gene. To examine the expression of the K-sam protein in stomach cancer, polyclonal antibody pK1-2 was raised against the extracellular domain of the gene product. This antibody detected K-sam proteins by Western blot and flow cytometry analyses in stomach cancer cell lines KATO-III and HSC39, in which the K-sam gene is amplified and overexpressed. By immunohistochemical analysis, 20 of 38 cases of the undifferentiated type of advanced stomach cancer were K-sam positive, whereas none of 11 cases of the differentiated or intestinal type revealed K-sam staining. The K-sam product was observed predominantly in diffusely infiltrative lesions. In one autopsy case, the K-sam protein was detected only focally in the primary tumor, whereas markedly increased staining for the K-sam product was detected diffusely in the metastasized tumor in the lymph node and liver. These results suggest that K-sam overexpression is associated with the malignant phenotype of the undifferentiated type of stomach cancer, such as infiltrative growth and metastasis.
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PMID:Immunohistochemical detection of K-sam protein in stomach cancer. 981 10


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