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)

Mutations have been reported for several craniosynostotic disorders in exon IIIa (exon U or 7) or IIIc (exon B or 9) of the fibroblast growth factor receptor 2 gene (FGFR2). Among the conditions with FGFR2 mutations are two autosomal dominant syndromes, Crouzon and Jackson-Weiss. In this study, 24 Crouzon and one Jackson-Weiss syndrome patients were screened for mutations in the two exons by direct sequencing, and mutations were detected in 28% (7/25) of all cases. Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R). The W290G mutation was found in exon IIIa which is common to both alternatively spliced forms of FGFR2, BEK (expressed predominantly in primordial bones) and KGFR (expressed preferentially in epithelia). Atypical Crouzon syndrome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation. This phenotype possibly reflects the expression of both mutant BEK and KGFR. In addition, the Jackson-Weiss syndrome mutation, C342R, in exon IIIc was observed previously in other craniosynostotic syndromes, Crouzon and Pfeiffer. These results underscore the allelic heterogeneity of these conditions and the complexity of the phenotypic consequences of FGFR2 mutations.
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PMID:Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. 852 14

Basic fibroblast growth factor (FGF) and keratinocyte growth factor (KGF) are structurally related fibroblast growth factors, yet they exhibit distinct receptor binding specificity. Basic FGF binds with high affinity to FGFR1, FGFR2, and FGFR4, whereas KGF does not interact with these receptors and can only bind an isoform of FGFR2 known as the KGFR. Basic GFG binds KGFR but with lower affinity than KGF. In order to identify domains that confer this specificity, four reciprocal chimeras were generated between the two growth factors and were analyzed for receptor recognition and biological activity. The chimeras are designated BK1 (bFGF1-54:KGF91-194), BK2 (bFGF1-74:KGF111-194), KB1 (KGF31-90:bFGF55-155), and KB2 (KGF31-110:bFGF75-155). The two BK chimera similarly interacted with FGFR1 and FGFR4 but differed from each other with respect to KGFR recognition. BK1 displayed a slightly better affinity for KGFR than BK2 and induced a higher level of DNA synthesis in keratinocytes compared with bFGF and BK2. A neutralizing monoclonal antibody directed against bFGF specifically neutralized the biological activity of the BK chimeras. The reciprocal chimeras, KB1 and KB2, exhibited KGF-like receptor binding and activation properties. However, KB2 displayed higher affinity for KGFR and was significantly more potent mitogen that KB1. Altogether, our results suggest that the amino-terminal part of KGF and bFGF plays an important role in determining their receptor binding specificity. In addition, the results point to the contribution of a segment from the middle part of KGF (residues 91-110) for recognition and activation of the KGFR, as the two chimeras containing these residues (BK1 and KB2) displayed an enhanced interaction with the KGFR.
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PMID:Chimeric molecules between keratinocyte growth factor and basic fibroblast growth factor define domains that confer receptor binding specificities. 853 Mar 75

Members of the fibroblast growth factor (FGF) family are thought to initiate biological responses through the activation of cell surface receptors which must dimerize to transmit an intracellular signal. Mammalian lens epithelial cells respond to exogenous extracellular FGF, either in tissue culture or in transgenic mice, by initiating fiber cell differentiation. The role of FGF signalling in normal lens development was evaluated by lens-specific synthesis of a kinase-deficient FGF receptor type I (FGFR1) in transgenic mice. This truncated FGF receptor is thought to act as a dominant negative protein by heterodimerization with endogenous FGF receptors. The presence of transgenic mRNA in the lens was confirmed by in situ hybridization and by polymerase chain reaction amplification of reverse transcribed lens RNA (RT-PCR). The presence of transgenic protein was determined by Western blotting with antibodies to an extracellular domain of FGFR1. Three of four transgenic families expressing the truncated FGF receptor exhibited lens defects ranging from cataracts to severe microphthalmia. While the microphthalmic lenses displayed a normal pattern of differentiation-specific crystallin expression, the lens epithelial cells were reduced in number and the lens fiber cells displayed characteristics consistent with the induction of apoptosis. Our results support the view that FGF receptor signalling plays an essential role in normal lens biology.
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PMID:Expression of a truncated FGF receptor results in defective lens development in transgenic mice. 857 96

Receptor specificity is an essential mechanism governing the activity of fibroblast growth factors (FGF). To begin to understand the developmental role of FGF-9/glial activating factor, we have cloned and sequenced the murine FGF-9 cDNA and expressed the protein in mammalian cells and in Escherichia coli. We demonstrate that the FGF-9 protein is highly conserved between mouse and human. Receptor specificity was determined by direct binding to soluble and cell surface forms of FGF receptor (FGFR) splice variants and by the mitogenic activity on cells, which express unique FGF receptor splice variants. Our data demonstrate that FGF-9 efficiently activates the "c" splice forms of FGFR2 and FGFR3, receptors expressed in potential target cells for FGF-9. Significantly, FGF-9 also binds to and activates the "b" splice form of FGFR3, thus becoming the first FGF ligand besides FGF-1 to activate this highly specific member of the FGF receptor family.
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PMID:Expression and biological activity of mouse fibroblast growth factor-9. 857 75

We have identified a novel FGF receptor, Z-FGFR4, in zebrafish embryos. Z-FGFR4 is closely related to both chicken FREK (Marcelle et al. [1994] Development 120:683-694) and the Pleurodeles cDNA clone Pw-FGFR4 (also named PFR4). The Z-FGFR4 cDNA clones contain consensus sequences for two groups of two Ig-like domains, separated by eight acidic residues referred to as the "acid box." Z-FGFR4, therefore, is the first FGFR molecule yet described in vertebrates that contains four Ig domains in its amino-terminal region. Whole-mount in situ hybridization of staged zebrafish embryos, using probes prepared from a variety of domains of the Z-FGFR4 cDNA, reveal complex temporal and spatial expression patterns. Expression of Z-FGFR4 mRNA is first detected in embryos prior to gastrulation and then appears in prechordal plate mesendoderm. At this time, Z-FGFR mRNA is expressed in the epiblast in two distinct stripes which ultimately contribute to the brain. Eventually Z-FGFR4 transcripts are observed in forebrain, anterior hindbrain (rhombomeres 1, 3), and caudal hindbrain (rhombomere 7), as well as in the dorsal-most portion of the rostral spinal cord. Expression in axial mesendoderm appears transiently in notochord and segmental plate mesoderm. Eventually, Z-FGFR4 mRNA becomes restricted to the posterior somites and is absent in differentiated notochord. These detailed expression studies provide the basis for understanding FGFR function through an analysis, currently in progress, of the developmental consequences of Z-FGFR4 misexpression.
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PMID:Novel FGF receptor (Z-FGFR4) is dynamically expressed in mesoderm and neurectoderm during early zebrafish embryogenesis. 858 34

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

To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200-300% of the normal level 3-5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-alpha (TGF-alpha), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-beta1, TGF-beta type II receptor, hepatocyte growth factor (HGF), and c-MET/HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3-5 days after androgen replacement. The second increase was evident in TGF-alpha, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates.
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PMID:Changes in gene expression of growth factors and their receptors during castration-induced involution and androgen-induced regrowth of rat prostates. 862 17

The fibroblast growth factor receptor-2 gene contains a pair of alternative exons, K-SAM and BEK, which are spliced in a cell type specific manner. We have shown previously that a 10 nucleotide sequence within the K-SAM exon exerts a negative effect on K-SAM exon splicing independent of cell type. We demonstrate here that this sequence works autonomously, as it can repress splicing of a heterologous exon, the EIIIb alternative exon of the rat fibronectin gene. By introducing point mutations into the 10 nucleotide sequence, we have shown that the functional portion is limited to 4 nucleotides, TAGG, the dinucleotide AG of which is particularly important. This short sequence may participate in the control of splicing of exons carrying it, provided that they carry weak splice sites.
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PMID:The exon sequence TAGG can inhibit splicing. 866 31

Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in the circulation and in vascular basement membranes. However, the process of FGFR1 ectodomain release from the plasma membrane is not known. Here we report that the 72-kDa gelatinase A (matrix metalloproteinase type 2, MMP2) can hydrolyze the Val368-Met369 peptide bond of the FGFR1 ectodomain, eight amino acids upstream of the transmembrane domain, thus releasing the entire extracellular domain. Similar results were obtained regardless of whether FGF was first bound to the receptor or not. The action of MMP2 abolished binding of FGF to an immobilized recombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovary cells overexpressing FGFR1 The released recombinant FGFR1 ectodomain was able to bind FGF after MMP2 cleavage, suggesting that the cleaved soluble receptor maintained its FGF binding capacity. The activity of MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and was inhibited by tissue inhibitor of metalloproteinase type 2. These studies demonstrate that FGFR1 may be a specific target for MMP2 on the cell surface, yielding a soluble FGF receptor that may modulate the mitogenic and angiogenic activities of FGF.
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PMID:Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. 869 46

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


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