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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review describes recent progress in the field of fibroblast growth factor receptors (FGFRs) with an emphasis on the role of FGFR mutants in skeletal malformations. This family of four receptors contains the most frequent germline mutations in humans. More than 75 mutations have been recorded, which account for more than seven skeletal syndromes. The common cause for all the mutant phenotypes is gain-of-function by receptor activation through three major mechanisms: receptor dimerization, kinase activation, and increased affinity for FGF. The severity of the disease is correlated with both the extent of receptor activation and the specific tissue in which the mutant receptor form is expressed. Paradoxically, the consequence of receptor activation is inhibition of chondrocyte cell growth through signaling pathways that are cell-type specific. The structure of the FGFR-FGF complex and its possible ternary complex with heparin explain the mechanism of receptor dimerization in the ectodomain and the possible contribution by some of the mutations to this process. Analysis of FGFR3 mutant mice produced by gene targeting as models for human disease, and studies in cell lines, have begun to delineate the novel signaling pathways of FGFR3 and to define possible targets for therapy.
...
PMID:FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models. 1086 10

A series of new 3-substituted indolin-2-ones containing a tetrahydroindole moiety was developed as specific inhibitors of receptor tyrosine kinases associated with VEGF-R, FGF-R, and PDGF-R growth factor receptors. These compounds were evaluated for their inhibitory properties toward VEGF-R2 (Flk-1/KDR), FGF-R1, PDGF-Rbeta, p60(c)()(-)()(Src)(), and EGF-R tyrosine kinases and their ability to inhibit growth factor-dependent cell proliferation. Structure-activity relationships of this new pharmacophore have been determined at the level of kinase inhibition. Compounds containing a propionic acid moiety at the C-3' position of the tetrahydroindole ring represented the most potent indolin-2-ones to inactivate the VEGF, FGF, and PDGF receptor kinases. The inhibitory activities of 9d against VEGF-R2 (Flk-1), 9h against FGF-R1, and 9b against PDGF-Rbeta were 4, 80, and 4 nM, respectively. However, all of these compounds were inactive when tested against the EGF-R tyrosine kinase. Compounds 9a and 9b represented the most potent inhibitors of these classes to inhibit both biochemical kinase and growth factor-dependent cell proliferation for these three targets. In addition, compound 9a was cocrystallized with the catalytic domain of FGF-R1 providing evidence to explain the structure-activity relationship results. This study has provided evidence to support the potential of these new tyrosine kinase inhibitors for the treatment of angiogenesis and other growth factor-related diseases including human cancers.
...
PMID:Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. 1089 3

We previously reported that fibroblast growth factor-2 (FGF-2) acts not only on osteoblasts to stimulate osteoclastic bone resorption indirectly but also on mature osteoclasts directly. In this study, we investigated the mechanism of this direct action of FGF-2 on mature osteoclasts using mouse and rabbit osteoclast culture systems. FGF-2 stimulated pit formation resorbed by isolated rabbit osteoclasts moderately from low concentrations (>/=10(-12) m), whereas at high concentrations (>/=10(-9) m) it showed stimulation on pit formation resorbed by unfractionated bone cells very potently. FGF-2 (>/=10(-12) m) also increased cathepsin K and MMP-9 mRNA levels in mouse and rabbit osteoclasts. Among FGF receptors (FGFR1 to 4) only FGFR1 was detected on isolated mouse osteoclasts, whereas all FGFRs were identified on mouse osteoblasts. FGF-2 (>/=10(-12) m) up-regulated the phosphorylation of cellular proteins, including p42/p44 mitogen-activated protein (MAP) kinase, and increased the kinase activity of immunoprecipitated FGFR1 in mouse osteoclasts. The stimulation of FGF-2 on mouse and rabbit osteoclast functions was abrogated by PD-98059, a specific inhibitor of p42/p44 MAP kinase. These results strongly suggest that FGF-2 acts directly on mature osteoclasts through activation of FGFR1 and p42/p44 MAP kinase, causing the stimulation of bone resorption at physiological or pathological concentrations.
...
PMID:Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase. 1089 47

Satellite cells are the myogenic precursors in postnatal muscle and are situated beneath the myofiber basement membrane. We previously showed that fibroblast growth factor 2 (FGF2, basic FGF) stimulates a greater number of satellite cells to enter the cell cycle but does not modify the overall schedule of a short proliferative phase and a rapid transition to the differentiated state as the satellite cells undergo myogenesis in isolated myofibers. In this study we investigated whether other members of the FGF family can maintain the proliferative state of the satellite cells in rat myofiber cultures. We show that FGF1, FGF4, and FGF6 (as well as hepatocyte growth factor, HGF) enhance satellite cell proliferation to a similar degree as that seen with FGF2, whereas FGF5 and FGF7 are ineffective. None of the growth factors prolongs the proliferative phase or delays the transition of the satellite cells to the differentiating, myogenin(+) state. However, FGF6 retards the rapid exit of the cells from the myogenin(+) state that routinely occurs in myofiber cultures. To determine which of the above growth factors might be involved in regulating satellite cells in vivo, we examined their mRNA expression patterns in cultured rat myofibers using RT-PCR. The expression of all growth factors, excluding FGF4, was confirmed. Only FGF6 was expressed at a higher level in the isolated myofibers and not in the connective tissue cells surrounding the myofibers or in satellite cells dissociated away from the muscle. By Western blot analysis, we also demonstrated the presence of FGF6 protein in the skeletal musle tissue. Our studies therefore suggest that the myofibers serve as the main source for the muscle FGF6 in vivo. We also used RT-PCR to analyze the expression patterns of the four tyrosine kinase FGF receptors (FGFR1-FGFR4) and of the HGF receptor (c-met) in the myofiber cultures. Depending on the time in culture, expression of all receptors was detected, with FGFR2 and FGFR3 expressed only at a low level. Only FGFR4 was expressed at a higher level in the myofibers but not the connective tissue cell cultures. FGFR4 was also expressed at a higher level in satellite cells compared to the nonmyogenic cells when the two cell populations were released from the muscle tissue and fractionated by Percoll density centrifugation. The unique localization patterns of FGF6 and FGFR4 may reflect specific roles for these members of the FGF signaling complex during myogenesis in adult skeletal muscle.
...
PMID:Gene expression patterns of the fibroblast growth factors and their receptors during myogenesis of rat satellite cells. 1089 1

Basic fibroblast growth factor (bFGF) has been reported to support the survival of brain neurons. In the present study, we investigated whether the neurotrophic effect of bFGF is mediated by the mitogen-activated protein kinase (MAPK) cascade in cultured rat cerebral cortical neurons. Recombinant human bFGF (0.1-10 ng/ml) induced phosphorylation of p44/42 MAPK (ERK1/2) in a concentration- and time-dependent manner. bFGF-induced ERK1/2 phosphorylation and promotion of neuronal survival were both blocked by U0126 and PD98059, inhibitors of the MAPK-activating enzyme MEK. These results suggest that the MEK/ERK signal transduction cascade is involved in the neurotrophic effect of bFGF.
...
PMID:Neurotrophic effect of basic fibroblast growth factor is mediated by the p42/p44 mitogen-activated protein kinase cascade in cultured rat cortical neurons. 1091 7

7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4, 6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1, 8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)-ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-beta receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1, 6-Naphthyridin-2(1H)-one analogues bearing basic aliphatic side chains [7-NH(CH(2))(n)()NRR, 7-NHPhO(CH(2))(n)()NRR, or 7-NHPhN(CH(2))(4)NMe] were the most potent against c-Src (IC(50)s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR. The 1, 6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1, 8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2, 3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions.
...
PMID:Synthesis and structure-activity relationships of 7-substituted 3-(2, 6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src). 1095 22

Basic fibroblast growth factor (FGF-2) promotes survival and/or neurite outgrowth from a variety of neurons in cell culture and regenerative processes in vivo. FGFs exert their effects by activating cell surface receptor tyrosine kinases. FGF receptor (FGFR) inhibitors have not been characterized on neuronal cell behaviors to date. In the present study, we show that the FGFR1 inhibitor PD 173074 potently and selectively antagonized the neurotrophic and neurotropic actions of FGF-2. Nanomolar concentrations of PD 173074 prevented FGF-2, but not insulin-like growth factor-1, support of cerebellar granule neuron survival under conditions of serum/K(+) deprivation; another FGF-2 inhibitor, SU 5402, was effective only at a 1,000-fold greater concentration. Neither PD 173074 nor SU 5402, at 100 times their IC(50) values, interfered with the survival of dorsal root ganglion neurons promoted by nerve growth factor, ciliary neurotrophic factor, or glial cell line-derived neurotrophic factor. PD 173074 and SU 5402 displayed 1,000-fold differential IC(50) values for inhibition of FGF-2-stimulated neurite outgrowth in PC12 cells and in granule neurons, and FGF-2-induced mitogen-activated protein kinase (p44/42) phosphorylation. The two inhibitors failed to disturb downstream signalling stimuli of FGF-2. PD 173074 represents a valuable tool for dissecting the role of FGF-2 in normal and pathological nervous system function without compromising the actions of other neurotrophic factors.
...
PMID:The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects. 1098 32

The tubular epithelium of the Drosophila tracheal system forms a network with a stereotyped pattern consisting of cells and branches with distinct identity. The tracheal primordium undergoes primary branching induced by the FGF homolog Branchless, differentiates cells with specialized functions such as fusion cells, which perform target recognition and adhesion during branch fusion, and extends branches toward specific targets. Specification of a unique identity for each primary branch is essential for directed migration, as a defect in either the EGFR or the Dpp pathway leads to a loss of branch identity and the misguidance of tracheal cell migration. Here, we investigate the role of Wingless signaling in the specification of cell and branch identity in the tracheal system. Wingless and its intracellular signal transducer, Armadillo, have multiple functions, including specifying the dorsal trunk through activation of Spalt expression and inducing differentiation of fusion cells in all fusion branches. Moreover, we show that Wingless signaling regulates Notch signaling by stimulating delta expression at the tip of primary branches. These activities of Wingless signaling together specify the shape of the dorsal trunk and other fusion branches.
...
PMID:Control of tracheal tubulogenesis by Wingless signaling. 1100 42

Fibroblast growth factor 2 (FGF2) is an excellent candidate to regulate remyelination based on its proposed actions in oligodendrocyte lineage cell development in conjunction with its involvement in CNS regeneration. To assess the potential for FGF2 to play a role in remyelination, we examined the expression pattern of FGF2 and FGF receptors (FGFRs) in an experimental demyelinating disease with extensive remyelination. Adult mice were intracranially injected with murine hepatitis virus strain A-59 (MHV-A59) to induce focally demyelinated spinal cord lesions that spontaneously remyelinate, with corresponding recovery of motor function. Using kinetic RT-PCR analysis of spinal cord RNA, we found significantly increased levels of FGF2 mRNA transcripts, which peaked during the initial stage of remyelination. Analysis of tissue sections demonstrated that increased levels of FGF2 mRNA and protein were localized within demyelinated regions of white matter, including high FGF2 expression associated with astrocytes. The expression of corresponding FGF receptors was significantly increased in lesion areas during the initial stage of remyelination. In normal and lesioned white matter, oligodendrocyte lineage cells, including progenitors and mature cells, were found to express multiple FGFR types (FGFR1, FGFR2, and/or FGFR3). In addition, in lesion areas, astrocytes expressed FGFR1, FGFR2, and FGFR3. These findings indicate that, during remyelination, FGF2 may play a role in directly regulating oligodendrocyte lineage cell responses and may also act through paracrine or autocrine effects on astrocytes, which are known to synthesize other growth factors and immunoregulatory molecules that influence oligodendrocyte lineage cells.
...
PMID:Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. 1102 Feb 17

Utilizing a subtractive cDNA cloning approach we have identified a novel protein from human cartilage. This protein represents an integral membrane protein with 504 amino acids and a molecular mass of 55 kDa. It is composed of a signal peptide, three extracellular Ig-like modules, a transmembrane segment, and a short intracellular domain. The extracellular domain is closely related to the extracellular domain of FGF receptors. The intracellular domain, however, does not show any similarity to the protein tyrosine kinase domain of FGF receptors. The novel gene (FGFRL1) is located on human chromosome 4 band p16 in close proximity to the gene for FGFR3. Its mRNA is preferentially expressed in cartilaginous tissues. Owing to the structural similarity, it is conceivable that the novel protein plays a role in the modulation of FGF receptor activity.
...
PMID:Characterization of a novel protein (FGFRL1) from human cartilage related to FGF receptors. 1103 Nov 11


<< Previous 1 2 3 4 5 6 7 8 9 10

---