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)

To investigate the molecular mechanisms of cholinergic sprouting in the hippocampus after removal of entorhinal cortical inputs, we evaluated trophic factor gene expression in the denervated hippocampus. Despite the proposed role for nerve growth factor (NGF) in this sprouting, we observed no change in NGF mRNA or protein at several postlesion time points. In contrast, FGF-2 mRNA was increased within 16 hr. FGF-2 immunoreactivity was localized within GFAP-positive hypertrophic astrocytes distributed specifically within the denervated outer molecular layer after the lesion. To address the functional significance of this increase in FGF-2, we assessed the magnitude of cholinergic sprouting in animals receiving chronic intracerebroventricular infusions of neutralizing antibodies specific for FGF-2 and compared it with that observed in lesioned animals receiving infusate controls. Animals given FGF-2 antibodies displayed a marked reduction in cholinergic sprouting as compared with controls. In fact, many of these animals exhibited virtually no sprouting at all despite histological verification of complete lesions. These results suggest that endogenous FGF-2 promotes cholinergic axonal sprouting in the injured adult brain. Furthermore, immunocytochemical localization of receptors for FGF-2 (i.e., FGFR1) on projecting basal forebrain cholinergic neurons suggests that FGF-2 acts directly on these neurons to induce the lesion-induced sprouting response.
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PMID:Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus. 906 10

In this study we describe the presence of high affinity FGF-2 binding sites in the nuclei of U251MG glioma cells (K(d)=7 pM). Immunoprecipitation of total cell extracts with FGF receptor (FGFR) 1-4 antibodies showed that U251MG glioma cells express only FGFR1. [125I]FGF-2 cross linking to nuclear extracts followed by FGFR1 immunoprecipitation showed that FGFR1 may account for the nuclear FGF-2 binding sites. Western blot analysis demonstrated the presence of 103, 118 kDa and small amounts of 145 kDa FGFR1 isoforms in the nuclei of glioma cells. All isoforms contain both the C- and N-terminal domains. Nuclear FGFR1 retains kinase activity. Immunocytochemistry using confocal microscopy showed specific FGFR1 immunoreactivity within the nuclear interior. In continuously proliferating glioma cells, nuclear FGFR1 is constitutively expressed, independent of cell density. In contrast, in nontransformed human astrocytes, nuclear FGFR1 levels fluctuate with the proliferative state of the cell. In quiescent, confluent astrocytes nuclear FGFR1 protein was depleted. An accumulation of nuclear FGFR1 was observed following the transition to a subconfluent, proliferating state. Transfection of a pcDNA3.1-FGFR1 expression vector into glioma cells that do not express FGFR1 resulted in the nuclear accumulation of FGFR1, increased cell proliferation, and stimulated transition from the G0/G1 to the S-phase of the cell cycle. The increased proliferative rate was resistant to inhibition by the cell-impermeable FGF binding antagonist, myoinositol hexakis [dihydrogen phosphate]. Our results suggest that the constitutive nuclear presence of FGFR1 contributes to the increased proliferation of glioma cells while the transient nuclear accumulation of FGFR1 in normal astrocytes may play a role in the transition to a reactive state.
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PMID:Nuclear accumulation of fibroblast growth factor receptors in human glial cells--association with cell proliferation. 917 56

Heparin and related molecules have been identified as important participants in fibroblast growth factor (FGF) signaling although the mechanisms of action remain unclear. We have used heparin oligosaccharides to examine steps in the signaling process which could be affected by the polysaccharide. Immobilized FGF-1 and FGF-2 bound all sizes of oligosaccharides tested, ranging from tetrasaccharide to decasaccharide, at physiological salt concentration. Each group of oligosaccharide was eluted from the FGF affinity columns in several peaks, and larger oligosaccharides showed higher apparent affinity for the immobilized growth factors compared to the shorter ones. Heparin hexasaccharides were the smallest fragments providing complete protection of FGF-1 and FGF-2 against trypsin digestion. Tetrasaccharides, however, were able to provide partial protection. The requirement of heparin for ligand-receptor interaction was evaluated in receptor binding assays using Sf9 insect cells engineered to overexpress different recombinant FGF receptor (FGFR) species including FGFR1 beta, FGFR1 alpha or FGFR4 at the cell surface. In these assays hexasaccharides were the smallest fragments capable of stimulating FGF-receptor interaction. Over the range of concentrations examined, neither hexasaccharides nor octasaccharides were able to stimulate receptor binding to the level attained by intact heparin. In fact, these oligosaccharides interfered with the ability of intact heparin in promoting FGF-receptor binding. The presence of both stimulatory and inhibitory activities in hexasaccharide and octasaccharide populations could be attributed to structural heterogeneity within the oligosaccharide preparations. However, similar observations were obtained with "highly-sulfated" structurally homogeneous preparations of hexasaccharide and octasaccharide, although these molecules generally had greater stimulatory and less inhibitory activity than their structurally heterogeneous counterparts. Hexasaccharides were found to be the smallest fragments able to potentiate the FGF-1-induced 3T3 cell proliferation while their effect on FGF-2 signaling was less clear. These observations suggest that heparin can modulate FGF-signaling at several stages with different end results.
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PMID:Heparin-dependent fibroblast growth factor activities: effects of defined heparin oligosaccharides. 917 73

Fibroblast growth factors (FGFs) regulate cell proliferation and differentiation, and are also important regulators of extracellular matrix. They are among the most potent angiogenic factors known. Evidence suggests the FGFs play a role in glomerular development and pathology. The aim of the present study was to determine whether FGF-1 (acidic FGF) and FGF-2 (basic FGF) and their receptors (FGFRs) were expressed in normal adult rat glomeruli, using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. For RT-PCR studies, the kidneys of 200 g female Sprague-Dawley rats were perfused with buffer and glomeruli isolated using conventional sieving techniques followed by micropipetting. FGF-1 and FGF-2 were expressed in cortex and in glomeruli. All seven receptor isoforms assayed (FGFR1, 2 and 3 IIIb and IIIc splice variants, and FGFR4) were expressed in whole cortex. However, only the IIIc variants and FGFR4 were expressed in glomeruli. The relative levels of glomerular expression of these isoforms were determined using a semiquantitative RT-PCR assay using primers designed against three transmembrane regions; FGFR1 (100%); FGFR2 (0.1%); and FGFR4 (6%). Immunohistochemistry revealed specific immunostaining for all four FGFRs within glomeruli. The differential expression pattern of FGFR isoforms between glomeruli and whole cortex, and the mutually exclusive nature of the expression of IIIc but not IIIb isoforms within glomeruli, indicates that FGFR expression and thereby FGF activity is tightly regulated in glomeruli. These findings have important implications for the roles of the FGFs in glomerular health and disease.
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PMID:Expression of fibroblast growth factors and their receptors in rat glomeruli. 918 60

This report describes a systematic analysis of the expression of the fibroblast growth factor receptor (FGFR) multigene family (FGFR1, FGFR2, FGFR3, and FGFR4) in archival serial sections of normal human adult tissues representing the major organ systems, using immunohistochemical techniques. Polyclonal antisera specific for FGFR1, FGFR2, FGFR3, and FGFR4 and a three-stage immunoperoxidase technique were employed to determine the cellular distribution of these receptors at the protein level. The expression profiles for the tissue-specific cellular localization of the FGFR multigene family demonstrated wide-spread and striking differential patterns of expression of individual receptors in the epithelia and mesenchyme of multiple tissues (stomach, salivary glands, pancreas, thymus, ureter, and cornea) and co-expression of FGFR1-4 in the same cell types of other tissues. The wide-spread expression of FGFR1-4 in multiple organ systems suggests an important functional role in normal tissue homeostasis. Differences in the spatial patterns of FGFR gene expression may generate functional diversity in response to FGF-1 and FGF-2, both of which bind with equally high affinity to more than one receptor subtype. In vivo, this may lead to functional differences that are crucial for the regulation of normal physiological processes and are responsible for the pathological mechanisms that orchestrate various disease processes.
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PMID:Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. 921 26

U46619, a thromboxane A2 analogue, and basic fibroblast growth factor (FGF-2) both induced the expression of the inducible cyclo-oxygenase (Cox)-2 in porcine aortic smooth-muscle cells. This induction was dose-dependent (submaximal at 300 nM for U46619 and 1 ng/ml for FGF-2) and time-dependent, with similar intensity and maximal expression at 2 h. Under these conditions, both inducers stimulated rapid activation of extracellular signal-regulated kinase (ERK2) at 5-10 min, a transient and lower intensity being induced by U46619 whereas that induced by FGF-2 was sustained (>1 h). PD98059, an inhibitor of the ERK pathway, inhibited the expression of Cox-2. In contrast, activation of Jun-N-terminal kinase (JNK1) was sustained with U46619 but poorly induced by FGF-2. Cox-2 expression induced by U46619 or FGF-2 was similarly reduced by prostaglandin (PGE2), forskolin or dibutyryl-cAMP, suggesting a regulatory effect of adenylate cyclase on Cox-2 expression. However, activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited, suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2. The effects of PGE2 and forskolin on Cox-2 and phosphorylation of JNK1 were reversed with the protein kinase A inhibitor H89. In addition, endogenous PGE2 down-regulated the expression of Cox-2 by the two inducers, as stimulation of the cells in the presence of different Cox inhibitors increased the expression of the protein. Overall, these results suggest that exogenous and endogenous PGE2 exert negative inhibitory effects on Cox-2 expression mediated by stimulation of protein kinase A.
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PMID:Regulatory role of prostaglandin E2 in induction of cyclo-oxygenase-2 by a thromboxane A2 analogue (U46619) and basic fibroblast growth factor in porcine aortic smooth-muscle cells. 929 Nov 37

Basic fibroblast growth factor (FGF-2) is one of the mitogens that facilitate epithelial proliferation and angiogenesis. We analysed the expression of FGF-2 and type I fibroblast growth factor receptor (FGFR1) in 20 selected cases of human pancreatic carcinoma (PC) in connection with proliferation of tumour cells and intratumour endothelial cells (ECs), using immunohistochemistry and in situ hybridization (ISH). By FGF-2 immunostaining, tumour cells were strongly positive in 10 cases (50%). By FGFR1 immunostaining, stromal fibroblasts and ECs occasionally showed positive staining. Tumour cells in 12 cases (60%) were strongly positive. Expression of FGF-2 mRNA, as examined by ISH, was detected in 12 cases (60%) of PC, and its distribution pattern was similar to that of FGF-2 immunostaining. We divided these cases into two groups according to the result of FGF-2 immunostaining, and examined the Ki67 labelling indices of tumour cells and ECs between these two groups. These two proliferative indices were significantly higher in FGF-2-positive than in FGF-2-negative cases (P<0.05, P<0.05, respectively). These findings suggest that the expression of FGF-2 in PC is strongly associated with the proliferation of tumour cells and ECs and its increased expression may give tumour a growth advantage.
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PMID:Expression of basic fibroblast growth factor (FGF-2)-associated with tumour proliferation in human pancreatic carcinoma. 929 90

Progressive loss of the differentiated phenotype and communication with stroma accompanies the transition of nonmalignant rat prostate epithelial cells to anaplastic, malignant tumors. Here we show that cell surface expression of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase is reduced in malignant tumor cell populations (type II) and undetectable at the mRNA level in 30% of cells. This is in addition to the irreversible loss by splice switching of the FGFR2 ectodomain that abrogates response to FGF-7 and homologues from the stroma. One hundred % of type II malignant cells express FGFR1, which is normally expressed in the stroma. Expression of the FGFR1 kinase in premalignant type I tumor epithelial cells by transfection accelerated progression to the malignant phenotype. In contrast to the FGFR2 kinase fused to the ectodomain of FGFR1, the FGFR1 kinase failed initially to support a mitogenic response to FGF-2 in type I tumor cells. However, the FGFR1-transfected cells acquired a mitogenic response after extensive proliferation of the cell population. Resident FGFR2 and ectopic FGFR1 appeared to be partitioned in the type I cells, because neither full-length nor truncated isoforms of FGFR1 affected the mitogenic response of the other. Restoration of the FGFR2IIIb kinase to malignant cells expressing FGFR1 depressed tumor growth rates, restored responsiveness to stromal cells, and restored epithelial cell differentiation. These observations reveal that homologous FGFR1 and FGFR2 kinases play very different roles in cell growth and differentiation and in development and support of the malignant phenotype.
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PMID:Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. 939 62

Binding of fibroblast growth factors (FGFs) to receptor tyrosine kinases (FGFRs) and signaling is facilitated by binding of FGF to heparan sulfate proteoglycans (HSPGs). There are multiple families of HSPGs, including extracellular and cell surface forms. An important and potentially controversial question is whether cell surface forms of HSPGs act as positive or negative regulators of FGF signaling. This study examines the ability of the cell surface HSPG syndecan-1 to regulate FGF binding and signaling. HSPG-deficient Raji lymphoma cells, expressing a transfected syndecan-1 cDNA (Raji S1 cells), were used as HSPG "donor" cells. BaF3 cells, expressing an FGFR1 cDNA (FR1C-11 cells), were used as FGFR "reporter" cells. Using Raji S1 cells preincubated with FGF, it was found that they formed heterotypic aggregates with FR1C-11 cells in the presence of FGF-2, but not FGF-1. In addition, the FR1C-11 cells demonstrated FGF-2, but not FGF-1, dependent survival when cultured on fixed Raji S1 cells. Thus, Raji syndecan-1 1) differentially regulates the binding and signaling of FGFs 1 and 2 and 2) acts as a positive regulator of FGF-2 signaling.
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PMID:The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity. 946 93

We recently demonstrated the activation of extracellular signal- regulated protein kinase 1 and 2 (ERK1 and ERK2) by IGF-1, FGF-2, and PDGF-BB in normal human osteoblastic (HOB) cells as well as in rat and mouse osteoblastic cells. In this report, we have examined whether c-Jun NH2-Terminal Kinase (JNK) pathway is activated by growth factors and interleukin-1 beta (IL-1 beta) in normal HOB and rat UMR-106 cells using immune-complex kinase assay and anti-active JNK antibody, which recognizes activated forms of both JNK1 and JNK2. Results have demonstrated the presence of JNK1 and JNK2 proteins in normal HOB and UMR-106 cells. Both JNK1 and JNK2 were activated by IL-1 beta. IL-1 beta preferentially activated JNK pathway in a dose- and time-dependent manner and had little effect on ERK pathway. On the other hand, FGF-2 did not activate JNK but most strongly activated ERK pathway. The activation of JNK was maximal at 20 min whereas maximal activation of ERK1 and ERK2 was observed within 10 min. Results have clearly demonstrated that IL-1 beta preferentially activates JNK pathway whereas FGF-2 activates ERK pathway in normal human and rat UMR-106 osteoblastic cells.
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PMID:Activation of c-Jun NH2-terminal kinases by interleukin-1 beta in normal human osteoblastic and rat UMR-106 cells. 951 50


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