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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)

Basic fibroblast growth factor (b-FGF) appears to be an important positive modulator of the neointimal hyperplasia that occurs after prosthetic vascular graft implantation through its effects on vascular myointimal/smooth muscle cell migration and proliferation. The distribution and extent of b-FGF receptor (b-FGFR1) expression was compared using immunohistochemical techniques in normal porcine carotid arteries and at various times up to 6 weeks following implantation of small caliber prosthetic vascular grafts. At the time of graft harvest, specimens were infused with OCT medium at 100 mm Hg and rapidly frozen in liquid nitrogen. Transverse sections of the perianastomotic arterial tissues were labeled with primary mouse monoclonal antibody directed toward the extracellular domain of the receptor, followed by goat-anti mouse IgG and rabbit anti-goat IgG conjugated to horseradish peroxidase. The b-FGFR1-positive cells were identified by peroxidase activity within the Golgi complex of smooth muscle cells. Normal porcine carotid arteries showed no evidence of staining for b-FGFR1. However, at 6 weeks cells in the perianastomotic area clearly showed significant b-FGFR1 localization. Anti-muscle actin labeling confirmed these to be smooth muscle cells. The observed upregulation of b-FGFR1 expression supports the concept of positive feedback by cytokines as a contributing factor to the hyperplastic response of smooth muscle cells after prosthetic vascular graft implantation. This finding further supports a potential strategy to specifically target activated smooth muscle cells through use of mitotoxin therapy.
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PMID:Upregulation of b-FGF receptor expression after carotid bypass. 783 Apr 2

In birds and mammals, cardiac myocytes terminate mitotic activity in the neonatal period and regeneration of cardiac muscle does not occur after myocardial injury in adult hearts. Even embryonic myocytes, which actively proliferate in vivo, quickly lose mitotic activity when placed in cell culture. Several growth factors, including fibroblast growth factor (FGF), have been documented in embryonic hearts and some have been shown to influence myocyte terminal differentiation in culture. However, none of these growth factors have been shown to reactivate cell division in postmitotic myocytes nor have their in vivo functions been defined satisfactorily. To clarify the role of FGF signaling in heart growth, we prepared two retroviral vectors capable of suppressing (i) functions of FGF receptors (FGFRs) with a dominant-negative mutant of receptor type 1 (FGFR1) or (ii) the translation of endogenous FGFR1 by transcribing its antisense RNA. Both vectors inhibited myocyte proliferation and/or survival during the first week of chicken embryonic development but had much less effect after the second week. No apparent alteration of myocyte growth was observed after overexpression of full-length FGFR1. These results suggest that receptor-coupled FGF signaling regulates cardiac myocyte growth during tubular stages of cardiogenesis but that myocyte growth becomes FGF-independent after the second week of embryogenesis.
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PMID:Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development. 783 12

In the MM14 mouse myoblast cell line, fibroblast growth factor (FGF) stimulates proliferation and represses differentiation. However, the intracellular signaling pathways used by FGF to affect these cellular processes are unknown. The predominant FGF receptor present on MM14 cells, FGFR1, is a receptor tyrosine kinase capable of activating the mitogen-activated protein kinase (MAPK) cascade in fibroblast and neuronal cell lines. To determine whether the FGF signal is mediated via the MAPK cascade in myoblasts, MM14 cells were stimulated with basic FGF (bFGF) and activities of the various kinases were measured. After withdrawal from serum and bFGF for 3 hr, bFGF stimulated MAPK kinase (MAPKK) activity, but MAPK and S6 peptide kinase activities were not detected. In contrast, when serum and bFGF were withdrawn for 10 hr, the activities of MAPKK, MAPK, and S6 peptide kinase were all stimulated by bFGF treatment. The inability of bFGF to stimulate MAPK after 3 hr of withdrawal may be due, in part, to the presence of a MAPK phosphatase activity that was detected in MM14 cell extracts. This dephosphorylating activity diminishes during commitment to terminal differentiation and is inhibited by sodium orthovanadate. Thus, the ability of bFGF to stimulate MAPK in MM14 cells is correlated with the loss of a MAPK phosphatase activity. These results show that although bFGF activates MAPKK in proliferating myoblasts, the mitogenic signal does not progress to the downstream kinases, providing a physiological example of an uncoupling of the MAPK cascade.
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PMID:Differential activation of mitogen-activated protein kinase in response to basic fibroblast growth factor in skeletal muscle cells. 784 69

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

Basic (b) fibroblast growth factor (FGF) mediates various biological responses including mitogenesis and angiogenesis by binding to specific cell surface receptors of the tyrosine kinase family. The bFGF receptor-1 FGFR1) exists in short and long isoforms due to alternate RNA splicing. Minor alterations in the amino acid sequence have also led to reports of different FGFR1 isoforms in different tissues even in the same species. In the absence of any sequence for heart FGFR1 and accumulating evidence for a role of bFGF in heart growth and differentiation, we cloned FGFR1 from embryonic mouse hearts. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to generate full-length short (2259 base pairs) and long (2526 base pairs) forms of FGFR1 cDNAs which generated 86 and 102 kDa proteins, respectively, following in vitro translation. Embryonic mouse heart FGFR1 differed by seven amino acids from the reported sequence for mouse neuroepithelial FGFR1 and appeared more similar to human placental FGFR1. A single FGFR1 transcript of approximately 4.3 kb was seen in RNA isolated from embryonic as well as adult mouse hearts. There was a decrease (approximately 8.5-fold) in FGFR1 RNA levels in the adult. The majority of FGFR1 transcripts in the adult as well as embryonic heart contained exon IIIc (FGFR1-IIIc) which is associated with isoforms that display the highest affinity for bFGF. However, the relative ratio of short versus long FGFR1 RNA expression was 0.5 in the embryonic heart compared to 5.9 in the adult heart. These results indicate that: (i) structurally distinct short and long FGFR1 isoform RNAs are expressed in the embryonic and adult heart; (ii) FGFR1-IIIc is the major form of receptor expressed in the embryonic as well as adult heart; (iii) the transition from the embryo to the adult stage is associated with a decrease but not absence of FGFR1 RNA expression; and (iv) long FGFR1-isoforms are more abundant in the embryo while short FGFR1 isoforms predominate in the adult.
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PMID:Cloning and expression of fibroblast growth factor receptor-1 isoforms in the mouse heart: evidence for isoform switching during heart development. 789 69

Although several tyrosine kinase-type growth factor receptors have been demonstrated in human colonic epithelial cells, the full spectrum of growth factor receptors has not been identified. Low stringency screening of a complementary DNA library prepared from the human colon cancer-derived cell line HT-29 with a probe containing the tyrosine kinase domain of human c-src kinase led to the identification and isolation of a clone containing a receptor class tyrosine kinase. This putative receptor was found to be identical to the human fibroblast growth factor receptor 3 (FGFR3) except for a region of 150 nucleotides (50 amino acids) encoding the presumptive ligand-binding domain, where it exhibited only 32% homology with the previously described FGFR3. The variant domain corresponded precisely to the splicing junctions of the exon encoding the carboxyl terminal half of the third immunoglobulin-like domain, suggesting that two forms of FGFR3 result from splicing of alternate exons in a manner similar to that previously found for FGFR1 and FGFR2. By prior convention, the previously reported from of FGFR3 was designated IIIc due to its high degree of homology with the IIIc domain of FGFR1 (83% homology) and the IIIc domain of FGFR2 (81% homology). However, the ligand-binding domain of FGFR3 found in the HT-29 cell line was more highly divergent from all previously reported FGFR immunoglobulin-like domain IIIs than any other two members of this receptor family. Therefore, we propose to designate the newly reported form as the FGFR3 IIIb variant. Genomic polymerase chain reaction confirmed that the IIIb-containing exon occupies a position 5' relative to the IIIc-containing exon within the FGFR3 gene. Northern blot analysis using a probe encompassing sequences unique to the FGFR3 IIIb mRNA confirmed the expression of a 4.4-kilobase transcript in two colon cancer-derived cell lines as well as normal human colonic mucosa. Using a technique combining reverse transcriptase polymerase chain reaction with restriction endonuclease digestion, cell lines, primary cells, and tissues were assessed for IIIb and IIIc transcripts; expression of the IIIb variant was associated with an epithelial lineage, while the IIIc variant was expressed predominantly in nonepithelial cells and tissues.
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PMID:Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. 792 41

The expression patterns of two distinct types of fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2, were compared during early chick eye development. In situ hybridization was performed with riboprobes synthesized from cDNA fragments of FGFRs cloned by the polymerase chain reaction method. FGFR1 was expressed in the prospective lens, neural retina, pigment epithelium and mandibular mesenchyme. In contrast, FGFR2 was expressed predominantly in the periocular mesenchyme of a 2.5 day-old embryo. In the 5.5-day-old embryo, transcripts of FGFR2 were detected in the prospective corneal epithelium. The results suggest that expression patterns of FGFR1 and FGFR2 are complementary and ligands of each FGFR might be involved differentially in early chick eye development. It is concluded that the action of FGFs on pigment epithelium and lens cells reported so far, probably occurs through FGFR1, and both types of FGFR are involved in head mesenchymal development.
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PMID:Expression patterns of two fibroblast growth factor receptor genes during early chick eye development. 792 4

Fibroblast growth factors (FGF) constitute a family of at least 9 members which act through high-affinity tyrosine-kinase receptors encoded by 4 distinct genes. In humans, the FGFR1 gene is located in chromosomal region 8p12. Its amplification and expression were examined in a panel of 110 breast carcinoma samples by Southern- and Northern-blot analyses. FGFR1 was amplified in 9% and overexpressed in about 15% of the tumors studied. In situ hybridization experiments were performed on tissue sections of normal breast and tumors with a high level of FGFR1 expression. In both normal and tumoral tissues, FGFR1 RNA was detected in the epithelial cells. Overexpression of FGFR1 seems to be associated with small, well-differentiated diploid tumors.
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PMID:Expression of the FGFR1 gene in human breast-carcinoma cells. 792 44

We have examined phosphorylation of phospholipase C gamma 1 (PLC gamma 1) and its association with FGFR1 during mesoderm induction in animal pole explants and during early development in Xenopus embryos. In explants, PLC gamma 1 became associated with FGFR1 during mesoderm induction by FGF or by vegetal cells, the source of the natural inducer. Both PLC gamma 1 and FGFR1 were phosphorylated on tyrosine, indicating that both proteins were activated. Phosphorylation of these two proteins occurred very early during the induction process (within 0.5 hr), providing evidence that a member of the FGF family is a component of the vegetal inducing signal. PLC gamma 1 was also associated with FGFR1 in Xenopus blastulae and this association was specific to presumptive mesoderm cells. Examination of the PLC gamma 1 phosphorylation pattern during early Xenopus development and its association with FGFR1 revealed that maximum phosphorylation and association of these two proteins occurred during early- to mid-blastula stages, concurrent with mesoderm induction in vivo. This spatiotemporal pattern PLC gamma 1-FGFR1 association and phosphorylation suggests that PLC gamma 1 is involved in intracellular signaling during mesoderm induction in Xenopus. Seven additional phosphotyrosyl bands were coimmunoprecipitated with either PLC gamma 1 or FGFR1 from Xenopus blastulae; these bands may represent additional components of an FGFR1 signaling complex. One of these phosphotyrosyl bands was identified as NCK. In addition, growth factor receptor-binding protein, and son-of-sevenless two upstream regulators of RAS signaling, were co-immunoprecipitated with FGFR1.
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PMID:Phosphorylation of phospholipase C gamma 1 and its association with the FGF receptor is developmentally regulated and occurs during mesoderm induction in Xenopus laevis. 795 37

Basic fibroblast growth factor (bFGF) and other members of the FGF family share several biological properties that have the potential to mediate neoplastic cell growth. To test the hypothesis that bFGF may play a role in human ovarian cancer cell growth, three ovarian cancer cell lines, A90, A121(P), and A121(A), were investigated for their ability to respond to bFGF as a mitogen, to express endogenous bFGF protein or message for FGF proteins, and to exhibit FGF receptor or its message. Addition of bFGF to cultures of all three cell lines maintained in chemically defined media resulted in a statistically significant increase in cell number. Cell extracts from A90, A121(P), and A121(A) contained an immunoreactive protein that comigrated with hr-bFGF by Western blot analysis. Several bands of higher molecular weight were also noted. Immunohistochemical staining for bFGF demonstrated a cytoplasmic distribution of bFGF in the three cell lines. Both high- and low-affinity binding sites for human recombinant bFGF (hr-bFGF) were expressed by all three lines. High-affinity sites varied from 2700 sites per cell (Kd = 29 pM) to 13,500 sites per cell (Kd = 71 pM). All three cell lines were screened for mRNA expression for seven FGF proteins and four FGF receptors. In all three lines, mRNA for FGF2 (bFGF) was detected by PCR analysis, and in two lines, mRNA for FGF1 (aFGF) and FGF5 were also found. The FGFR1 receptor subtype (flg) was common to all of the cell lines. Finally, suramin inhibited proliferation of A90 and A121 (P and A) with IC50's of 60 and 210 micrograms/ml, respectively. This is consistent with the A90 cell line having higher levels of endogenous bFGF and flg and therefore being more responsive to suramin inhibition than the A121 cell line. The results indicate that these ovarian cancer cell lines can produce bFGF as well as other members of the FGF family of genes and have the ability to respond to bFGF.
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PMID:Basic fibroblast growth factor and receptor expression in human ovarian cancer. 795 96


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