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)

We reported previously that the potency of heparin-binding fibroblast growth factor-1 (FGF-1) as a mitogen for rat hepatocytes in primary culture is as high as that of epidermal growth factor (EGF) and hepatocyte growth factor. To gain insight into the pathophysiological significance of FGF-1 in hepatocyte growth, we analyzed the cooperative mitogenicity of FGF-1 and EGF. Results from a nuclear labeling assay using [3H]thymidine suggest that most hepatocytes in primary culture consist of two cell populations that differ in response to FGF-1; one is an FGF-1-responsive cell population, and the other is an EGF-responsive (but not FGF-1-responsive) cell population. On the other hand, autoradiographic analysis of 125I-FGF-1 binding demonstrated that high affinity FGF receptors were homogeneously distributed on the surface of all hepatocytes. Cross-linking 125I-FGF-1 to the nonstimulated hepatocyte surface indicated that the high affinity FGF receptors comprise two FGF receptors that differ in molecular mass (128 and 79 kDa). Furthermore, the 79-kDa receptor was preferentially down-regulated when the hepatocytes were stimulated with EGF or hepatocyte growth factor. These data suggest that the abundant expression of the 79-kDa FGF receptor on some populations of hepatocytes is involved in their lack of response to FGF-1. The 128- and 79-kDa FGF receptors were assigned as FGFR2 using an antibody specific to the ectodomain of FGFR2, whereas the 79-kDa receptor was not reactive to the antibody against the carboxyl terminus of FGFR2. This 79-kDa FGF receptor was not tyrosine-phosphorylated in response to FGF-1 stimulation, while the 128-kDa FGF receptor was recognized by anti-phosphotyrosine antibody under the same conditions. Also, the heterodimer of 79- and 128-kDa FGF receptors was less tyrosine-phosphorylated than the homodimer of 128-kDa FGF receptors. These data suggest that the 79-kDa FGF receptor inhibits the function of the 128-kDa FGF receptor through their heterodimerization. Thus, we surmise that the difference in response to FGF-1 between the cell populations of normal rat hepatocytes was caused by the different levels of the 79-kDa FGF receptor in each cell population.
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PMID:Identification of a 79-kDa heparin-binding fibroblast growth factor (FGF) receptor in rat hepatocytes and its correlation with the different growth responses to FGF-1 between hepatocyte subpopulations. 862 15

Basic fibroblast growth factor (bFGF) is known to be a mesoderm inducer of the Xenopas embryo, although the role of this factor in mammalian preimplantation embryos is not known. This study was performed to examine possible roles of bFGF in murine preimplantation development. To determine the expression of bFGF and FGF receptor 1 (FGFR 1) mRNA in mouse embryos and uterine endometrial epithelial cells, a reverse transcription-polymerase chain reaction (RT-PCR) technique was used. In the mouse embryos, bFGF mRNA was not detected but FGFR 1 mRNA was expressed in the blastocyst stage. Long and short forms of FGFR1 mRNA generated by alternative splicing were expressed. Both bFGF and two forms of FGFR 1 mRNA were detected in mouse endometrial epithelial cells. Immunoblot analysis indicated that bFGF protein was present in the uterine luminal fluid during the preimplantation period, and the level of expression of the protein was relatively constant. The addition of bFGF to the culture medium had no effects on the rate of blastocyst formation of 2 cell stage embryos, but it significantly increased the protein synthesis in blastocysts. These results suggest that bFGF derived from the mouse uterine endometrium affects the development of preimplantation embryos in a paracrine fashion.
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PMID:[Effects of basic fibroblast growth factor on the development of mouse preimplantation embryos]. 872 Oct 50

Thymocytes not only receive signals from thymic epithelial cells but can also activate the latter, at least in the medulla. We have previously reported tyrosine phosphorylation of medullary epithelial cell substrates, after co-culture with thymocytes, and identified a number of protein tyrosine kinases in a line of thymic epithelial cells. We report here the in situ localisation by immunohistochemistry of JAK2 in medullary epithelial cells, of PDGF-R in medullary vascular endothelium, of FGF-R in Hassall's corpuscles, and the weak expression of JAK1 and RYK throughout the thymus.
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PMID:Expression of protein tyrosine kinases in the murine thymus stroma. 879 61

The internalization of basic fibroblast growth factor (FGF-2) was studied in Chinese hamster lung fibroblasts (CCL39). Recombinant FGF-2 was derivatized with a photoactivable agent, N-hydroxysuccinimidyl-4-azidobenzoate (HSAB), iodinated, and used to visualize intracellular FGF-2-affinity-labeled molecules after internalization at 37 degrees C. Iodinated HSAB-FGF-2 maintained the properties of natural FGF-2 such as affinity for heparin, binding to Bek and Fig receptors, interaction with high- and low-affinity binding sites, and reinitiating of DNA synthesis in CCL39 cells. Affinity-labeling experiments at 4 degrees C with 125I-HSAB-FGF-2 led to the detection of several FGF-cell surface complexes with apparent molecular mass of 80, 100, 125, 150, 170-180, 220, 260, and about 320 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whereas two specific bands at 80 and 130-160 kDa were obtained using the homobifunctional cross-linking reagent, disuccinimidyl suberate. When the cells, preincubated with 125I-HSAB-FGF-2 at 4 degrees C and then washed, were shifted to 37 degrees C, irradiation of the internalized labeled FGF-2 led to detection of a similar but fainted profile with one major specific band at 80 kDa. Heparitinase II treatment of the cells reduced binding of 125I-HSAB-FGF-2 to its cell surface sites by 80% and internalization by 55%, indicating the involvement of heparan sulfate proteoglycans in these processes. Among the heparitinase-sensitive bands was the 80-kDa complex.
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PMID:Visualization of several binding sites for basic fibroblast growth factor (FGF-2) on fibroblasts by photoaffinity labeling: evidence for intracellular complexes. 884 4

The membrane proximal, immunoglobulin- (Ig-) like domain 3 of KGFR shows significant sequence similarity to the Ig light chain variable (V) domain. According to our model, based on this similarity, the F-G loop in KGFR corresponds to the complementarity determining region (CDR) 3 of the Ig V domain. The F-G loop in the membrane proximal domain of the keratinocyte growth factor receptor has previously been shown to participate in determining the FGF ligand binding specificity of KGFR [Gray, T. E., Eisenstein, M., Shimon, T., Givol, D., & Yayon, A. (1995) Biochemistry 34, 10325-10333]. Here, we report the effects of additional mutations in this F-G loop. Both a single mutant KGFR Q348-->I and a double mutant KGFR Q348-->I, Q351-->H are found to have relatively mild effects on ligand binding, as was previously found for three other F-G loop mutant receptors. In contrast, a single mutation N344-->A in the F-G loop of KGFR is sufficient to abolish essentially all affinity of this receptor for its primary ligand KGF, while some affinity for aFGF is retained. Asparagine-344 is, therefore, essential for ligand binding by KGFR. We discuss the likelihood of this effect being due to global or local structural changes or to the removal of a specific interaction with the ligand, in relation to various known and model structures. Taking into account the mild effects of other mutations in the region and various other considerations, we tend to favor the idea that asparagine-344 is a key residue in determining the local conformation of the F-G loop.
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PMID:Asparagine-344 is a key residue for ligand binding in keratinocyte growth factor receptor. 896 26

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.
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PMID:Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. 897 28

The FGFs constitute a family of, at least, 12 polypeptides (FGF1 to FGF12) implicated in a number of physiological and pathological processes throughout embryogenesis and adult life. They bind to at least three types of cell surface molecules, including four high affinity transmembrane tyrosine kinase receptors (FGFR1 to FGFR4). In addition to important roles during development, FGF involvement in pathological conditions, including tumour formation, has been suspected, and overexpression of FGFR in tumour specimens is well documented. Diphtheria Toxin/FGF6 (DT/FGF6) mitotoxin has been shown to selectively and effectively target FGFR1-expressing cells. We show here that DT/FGF6 targets myoblasts engineered to express either one of the four FGFR, as well as FGFR-expressing tumour cells.
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PMID:Cytotoxic activity of a diptheria toxin/FGF6 mitotoxin on human tumour cell lines. 901 Feb 26

The comparative biological properties of NBT-II cells, a rat bladder carcinoma cell line constitutively expressing FGF-1 and FGF-2 were analysed in nude mice. FGF-1 is not secreted by the transfected cells unless the cDNA contains a signal sequence; conversely, NBT-II cells transfected with FGF-2 coding sequence produce and secrete the factor in a biologically active form. Bovine brain capillary endothelial cells are stimulated to proliferate upon addition of medium conditioned by the FGF-2-producing cells and this activity can be abrogated by the addition of anti-FGF-2 blocking antibodies. In addition, the FGF-2-containing medium, which cannot stimulate NBT-II cells due to absence of appropriate receptors, is able to induce scattering of NBT-II cells expressing the FGFR1. It has been reported previously that FGF-1-producing cells are highly tumorigenic in nude mice and induce carcinoma with a period of latency reduced from 6 to 5 weeks when compared to parental NBT-II cells. In contrast, NBT-II cells producing FGF-2 are no more tumorigenic than parental cells, indicating that FGF-1 and FGF-2 have different oncogenic properties in carcinoma. FGF-1 and FGF-2 are potent antiogenic factors that trigger the host endothelial cells. VEGF, another potent angiogen was found to be expressed in small amounts by NBT-II cells and to be expressed in reduced amount in the FGF-producing cells. In the NBT-II system in vivo FGF-1 and FGF-2 are highly and comparatively angiogenic in the resultant carcinoma and this occurs in the absence of production of significant amounts of VEGF by the carcinoma cells. Taken together, our results indicate that activated angiogenesis is not sufficient for rapid tumor expansion. FGF-1 behaves as a tumorigenic factor in the NBT-II bladder carcinoma cell model, whereas expression and secretion of large amounts of FGF-2 are not sufficient for increasing tumor growth.
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PMID:FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. 903 74

The present study provides a detailed comparative description in the adult rat brain of areas that express mRNAs coding for the fibroblast growth factor subtype receptors 1-3 (FGFR1-3). One observation in this analysis was a widespread expression in the brain of all three FGFR mRNAs, according to the following rank order: FGFR1, diencephalon < telencephalon < mesencephalon and metencephalon < myelencephalon; FGFR2 and FGFR3, telencephalon < diencephalon < mesencephalon and metencephalon < myelencephalon. Another observation was an apparent cellular specificity in their basal expression. Thus, the FGFR1 mRNA was expressed mainly in large and weakly stained cells, whereas FGFR2 transcripts were expressed primarily in small and strongly stained cells and in cells of brain regions devoid of neuronal cells, such as the white matter. FGFR3 mRNA was always detected in small and strongly stained cells with scattered distribution and was not expressed in the white matter. However, FGFR2 mRNA was weakly expressed also in large cells localized in some nuclei of the lower brainstem, in the diagonal band, and in the septum. Furthermore, in the medial habenula and in the nuclei of the pons, there exists a high density of cells expressing both FGFR1 and FGFR2 (60-100%). With neurotoxic lesions involving 6-hydroxydopamine microinjections in the substantia nigra, reactive glial cells in the lesioned area and surrounding the cannula tract showed an increase in the expression of both FGFR1 and FGFR2 mRNAs, whereas no increased expression was found for FGFR3 mRNA. Taken together, these findings showed that these three FGF receptors exist in all subtypes of cells of each brain region. Their apparent cellular specificity suggests that these receptor subtypes can have a differential trophic role in the brain, reflecting the various biological activities shown by the ligands of the FGF family.
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PMID:Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: in situ hybridization analysis. 905 Jul 87

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.
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PMID:Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. 905 94


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