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 actions of fibroblast growth factors (FGFs) are mediated via a family of four closely related FGF receptor genes (FGFRs 1-4). FGFR1, FGFR2, and FGFR4 have unique patterns of expression during embryogenesis suggesting that these receptors mediate different functions of FGFs during development. In the present study, we used in situ hybridization analysis to show that FGFR3 also has a unique pattern of expression during organogenesis. Like FGFR1 and FGFR2, FGFR3 was expressed in the germinal epithelium of the neural tube (9.5-16.5 days pc). However, at 1 day postpartum and in the adult brain, FGFR3 was expressed diffusely and localized in cells with morphologic characteristics of glia, a pattern distinctly different from the discrete neuronal expression of FGFR1. FGFR3 was also expressed at high levels in differentiating hair cells of the cochlear duct, but was not detected in other sensory epithelia. Outside the nervous system, the highest level of FGFR3 expression was found in the cartilage rudiments of developing bone. During endochondral ossification, FGFR3 was expressed exclusively in resting cartilage, a pattern distinct from FGFR1 and FGFR2 which are also expressed during this process. Unlike FGFR1 and FGFR2, FGFR3 was not detected in most other epithelial or mesenchymal tissues during these stages of organogenesis. The unique expression pattern of FGFR3 compared with the other FGF receptors strongly suggests that FGFR3 performs specific functions during organogenesis.
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PMID:Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. 843 97

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

The entorhinal cortex is a major relay between the hippocampus and other cortical and subcortical regions. Glutamatergic axons from layer II neurons form the entorhinal cortical projection to the hippocampus via the perforant pathway. We have demonstrated previously that lesion of the perforant pathway causes the death of approximately 30% of entorhinal layer II (ECL2) neurons. To elucidate mechanisms contributing to neuronal death and to investigate strategies preventing it, we identified the phenotype of the vulnerable neuronal population. Sections were immunolabeled with antibodies to the neuronal markers NeuN, glutamate, and calbindin-D28k, and to receptors for fibroblast growth factor-2 (FGFR1) and NMDA (NMDAR1) and were examined using confocal microscopy. Calbindin immunoreactivity was strikingly lamina-specific to ECL2, where one-third of all ECL2 neurons were calbindin-positive. Localization of glutamate revealed that half of the glutamatergic ECL2 neurons coexpressed calbindin. Quantification using unbiased stereology at 9 weeks after lesion of the perforant pathway revealed that the only ECL2 neuronal population that experienced a significant (70%) loss (20% of the total) was the population of glutamatergic ECL2 neurons that did not coexpress calbindin. All ECL2 neurons expressed FGFR1; therefore, we tested the role of FGF-2 in the survival of glutamatergic ECL2 neurons. We grafted fibroblasts genetically engineered to express nerve growth factor or FGF-2 and found that only FGF-2 grafts prevented loss of the vulnerable glutamatergic/calbindin-negative neurons. We present a hypothesis for the selective vulnerability of these glutamatergic/calbindin-negative ECL2 neurons and address the role of FGF-2 in neuronal rescue.
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PMID:Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death. 855 57

The locus for Werner syndrome (WRN) has been localized to human chromosome 8p21 --> p12, close to the anonymous marker D8S339. A 3.1-Mb contig of yeast artificial chromosomes (YACs) was assembled around D8S339. Results from analyses of somatic cell hybrids, FISH, and physical mapping suggest the following loci order: tel-NEFL-D8S131-D8S339-[D8S540/GSR]-D8S124 -D8S259-D8S87-FGFR1-cen. Close physical linkage between D8S540 and GSR was established within a DNA fragment of 200 kb. These two loci are not more than 400 kb from D8S339. In addition, D8S339, D8S540, D8S124, and GSR are within 1.1 Mb. These data establish a primary physical map of the Werner syndrome region and identify useful YAC clones for the isolation of new markers and of the corresponding gene.
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PMID:A 3.1-Mb YAC contig within the Werner syndrome region, on the short arm of human chromosome 8. 856 38

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

The Fgf8 gene is expressed in developing limb and craniofacial structures, regions known to be important for growth and patterning of the mouse embryo. Although Fgf8 is alternatively spliced to generate at least 7 secreted isoforms that differ only at their mature amino terminus, the biological significance of these multiple isoforms is not known. In this report, we demonstrate that multiple FGF-8 isoforms are present at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alternatively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c activate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also efficiently activates 'c' splice form of FGFR2. No activity could be detected for recombinant or cell expressed FGF-8a. Furthermore, none of the isoforms tested interact efficiently with 'b' splice forms of FGFR1-3, or the 'c' splice form of FGFR1. These results indicate that the FGF-8b and FGF-8c isoforms, produced by ectodermally derived epithelial cells, interact with mesenchymally expressed fibroblast growth factor receptors. FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.
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PMID:FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. 858 74

Fibroblast-growth-factor receptors (FGFRs), members of the tyrosine-kinase receptor family, play a crucial role in signal transduction and development. Recently, unique mutations in three human FGFR-encoding genes (FGFR1-3) have been identified as the cause of a variety of skeletal disorders. Comparison of these specific mutations with the resulting phenotypes is now providing new insight into the role of these receptors in normal and abnormal bone development.
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PMID:Fibroblast-growth-factor receptor mutations in human skeletal disorders. 858 28

Fibroblast growth factors (FGF) are multifunctional, heparin binding polypeptides that share structural similarity, but differ in their target cell specificity and expression pattern. Here we describe the cloning and expression of the mouse homologue of FGF9, and the use of a panel of soluble FGF receptors and genetically engineered cells to study its receptor binding specificity. FGF9 is found to bind with high affinity (kd: 0.25 nM) to FGFR3, for which a specific ligand has not yet been identified. FGF9 can also bind, albeit with a lower affinity, to FGFR2 but does not bind FGFR1 or FGFR4. There is no significant binding to either FGFR3 or FGFR2, expressed either as soluble receptors or in heparin sulfate deficient cells, in the absence of heparin. Moreover, receptor binding of FGF9 requires heparin in a manner specific to the receptor type. In conclusion FGF9 presents a unique case of ligand-receptor specificity and fulfills the criteria as a high affinity, heparin-dependent ligand for FGFR3.
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PMID:Identification of fibroblast growth factor 9 (FGF9) as a high affinity, heparin dependent ligand for FGF receptors 3 and 2 but not for FGF receptors 1 and 4. 861 28

Fibroblast growth factor receptor (FGFR) activation leads to receptor autophosphorylation and increased tyrosine phosphorylation of several intra cellular proteins. We have previously shown that autophosphorylated tyrosine 766 in FGFR1 serves as a binding site for one of the SH2 domains of phospholipase Cy and couples FGFR1 to phosphatidylinositol hydrolysis in several cell types. In this report, we describe the identification of six additional autophosphorylation sites (Y-463, Y-583, Y-585, Y-653, Y-654 and Y-730) on FGFR1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of FGFR1 and is therefore essential for FGFR1-mediated biological responses. In contrast, autophosphorylation of the remaining four tyrosines is dispensable for FGFR1-mediated mitogen-activated protein kinase activation and mitogenic signaling in L-6 cells as well as neuronal differentiation of PC12 cells. Interestingly, both the wild-type and a mutant FGFR1 (FGFR1-4F) are able to phosphorylate Shc and an unidentified Grb2-associated phosphoprotein of 90 kDa (pp90). Binding of the Grb2/Sos complex to phosphorylated Shc and pp90 may therefore be the key link between FGFR1 and the Ras signaling pathway, mito-genesis, and neuronal differentiation.
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PMID:Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. 862 1

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


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