Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factor 2 (FGF-2) is produced as CUG-initiated, 22-34 kDa or AUG-initiated 18 kDa isoforms (hi- and lo-FGF-2, respectively), with potentially distinct functions. We report that expression of hi-FGF-2 in HEK293 cells elicited chromatin compaction preceding cell death with apoptotic features. Nuclear localization of the intact protein was required as expression of a non-nuclear hi-FGF-2 mutant failed to elicit chromatin compaction. Equally ineffective, despite nuclear localization, was the over-expression of the 18 kDa core sequence (lo-FGF-2). Chromatin compaction by hi-FGF-2 was accompanied by increased cytosolic cytochrome C, and was attenuated either by over-expression of Bcl-2 or by a peptide inhibitor of the pro-apoptotic protein Bax. In addition hi-FGF-2 elicited sustained activation of total and nuclear extracellular signal regulated kinase (ERK1/2) by an intracrine route, as it was not prevented by neutralizing anti-FGF-2 antibodies. Inhibition of the ERK1/2 activating pathway by dominant negative upstream activating kinase, or by PD 98059, prevented chromatin compaction by hi-FGF-2. ERK1/2 activation was not affected by the Bax-inhibiting peptide suggesting that it occurred upstream of mitochondrial involvement. We conclude that the hi-FGF-2-induced chromatin compaction and cell death requires its nuclear localization, intracrine ERK1/2 activation and mitochondrial engagement.
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PMID:Chromatin compaction and cell death by high molecular weight FGF-2 depend on its nuclear localization, intracrine ERK activation, and engagement of mitochondria. 1750 59

Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase (MAPK). Here, we show that FGF receptor 1 (FGFR1), which is expressed mainly in neoplastic thyroid cells, propagates MAPK activation and promotes tumor progression. In contrast, FGFR2 is down-regulated in neoplastic thyroid cells through DNA promoter methylation. Reexpression of FGFR2 competes with FGFR1 for the immediate substrate FGFR substrate 2 to impede signaling upstream of the BRAF/MAPK pathway. These data unmask an epigenetically controlled FGFR2 signal that imposes precisely on the intragenically modified BRAF/MAPK pathway to modulate thyroid cancer behavior.
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PMID:Epigenetically controlled fibroblast growth factor receptor 2 signaling imposes on the RAS/BRAF/mitogen-activated protein kinase pathway to modulate thyroid cancer progression. 1754 28

Fibroblast growth factor-2 (FGF-2) has been shown to induce both angiogenesis and lymphangiogenesis in the mouse corneum; however, the signalling mechanism underlying FGF-2-induced lymphangiogenesis remains unknown. Here we investigated the effect of FGF-2 on newly developed temperature-sensitive rat lymphatic endothelial (TR-LE) cells. The supernatant of PC-3 prostate cancer cells facilitated tube-like formation in TR-LE cells, and formation was inhibited by neutralising antibodies against FGF-2. The addition of FGF-2 stimulated tube-like formation as well as proliferation and chemotactic migration of TR-LE cells. Blockade of the Akt signalling pathway by LY294002 abolished the elongation of tubes induced by FGF-2, whereas inhibition of the extracellular signal-regulated kinase (ERK) signalling pathway had no effect. Rapamycin abrogated the phosphorylation of p70S6kinase and consistently inhibited the formation of tubes induced by FGF-2. Furthermore, tube-like formation induced by the supernatant of PC-3 cells was inhibited by LY294002 or rapamycin. These data suggest that FGF-2 exerts lymphangiogenic effects by activating the Akt/mammalian target of rapamycin (mTOR)/p70S6kinase pathway in lymphatic endothelial cells, and that the pathway provides a potent target for tumour lymphangiogenesis.
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PMID:Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells. 1757 Jun 54

Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH)2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/P(i)) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 microg/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P < 0.001) in brush-border membrane (BBM) Na/Pi cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P(i) cotransporter protein in BBM. Multiple injections (6, 12, and 24 mug/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1alpha-hydroxylase mRNA (P < 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1alpha-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1alpha-hydroxylase mRNA with a maximum suppression of 37% (P < 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1alpha-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1alpha-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1alpha-hydroxylase gene expression via activation of the ERK1/2 signaling pathway.
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PMID:Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. 1769 49

Tumor cell migration is crucial for the formation of tumor metastases and the progression of tumor disease. Fibroblast growth factor-2 (FGF-2) is one of the cytokines involved in the autocrine stimulation of tumor development. FGF-2 also stimulates transcription of Ca(2+)-sensitive K(+) channels (IK1 or K(Ca)3.1), which are part of the migration machinery in many cell types. Here, we tested whether FGF-2 acutely stimulates migration of transformed MDCK cells in a K(Ca)3.1 channel-dependent way. FGF-2 accelerates migration dose dependently. The speed of migration increases almost instantaneously. After 2 min, ERK1/2 phosphorylation has almost doubled. FGF-2 does not stimulate migration when ERK1/2 phosphorylation is inhibited. K(Ca)3.1 channel blockade also prevents the stimulatory effect of FGF-2 on cell migration. In addition, FGF-2 treatment leads to an activation of K(Ca)3.1 channels and a rapid rise of the cell area, which is because of an elevated rate of exocytosis. However, the amount of K(Ca)3.1 channels within the plasma membrane does not change. Our results show that there is a reciprocal interrelation between FGF-2 and K(Ca)3.1 channels. K(Ca)3.1 channels that are under the transcriptional control of FGF-2 are part of the FGF-2-mediated signaling cascade leading to an acceleration of migration.
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PMID:Activation of cell migration with fibroblast growth factor-2 requires calcium-sensitive potassium channels. 1822 36

Fibroblast growth factor (FGF2), but not vascular endothelial growth factor (VEGF), upregulates endothelial nitric oxide synthase (eNOS) protein expression, at least partially, via activation of extracellular signal-regulated kinase 2/1 (ERK2/1) in ovine fetoplacental artery endothelial (oFPAE) cells. Herein we further investigated the temporal effects of FGF2 and VEGF on other signalling pathways including members (Jun N-terminal kinase JNK1/2 and p38MAPK) of mitogen-activated protein kinases (MAPK), phosphatidylinositol-3 kinase/v-akt murine thymoma viral oncogene homologue 1 (PI3K/AKT1), and the tyrosine kinase c-SRC, and examined if either one or more of these pathways play a role in the differential regulation of eNOS by FGF2 and VEGF. We first confirmed that in oFPAE cells, FGF2, but not VEGF, increased eNOS protein. FGF2 stimulated eNOS protein in a time- and concentration-dependent manner, which also depended on cell density. FGF2 provoked sustained (5min to 12h) whereas VEGF only stimulated transient (5min) ERK2/1 phosphorylation. FGF2 was 1.7-fold more potent in stimulating ERK2/1 phosphorylation than VEGF. FGF2 and VEGF only transiently activated JNK1/2 and AKT1 within 5min; however, FGF2 was a stronger stimulus than VEGF. FGF2 and VEGF did not significantly activate p38MAPK at 5min; however, VEGF stimulated p38MAPK phosphorylation at 60min. VEGF but not FGF2 significantly stimulated c-SRC phosphorylation. Inhibitors of MEK-ERK2/1 (PD98059), JNK1/2 (SP600125) and PI3K (wortmannin), but not p38MAPK (SB203580) and SRC (PP2), decreased the FGF2-increased eNOS protein expression. Thus, the FGF2-induced eNOS protein expression requires activation of multiple signalling pathways including ERK2/1, JNK1/2 and PI3K/AKT1. Differences in intensity and temporal patterns of activation of these pathways by FGF2 and VEGF may account for their differential effects on eNOS expression in OFPAE cells.
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PMID:Differential activation of multiple signalling pathways dictates eNOS upregulation by FGF2 but not VEGF in placental artery endothelial cells. 1857 18

The syndecans are a family of cell-surface heparan sulfate proteoglycans consisting of a core protein with covalently attached glycosaminoglycan (GAG) chains. Syndecan-4 expression in skeletal muscle is increased in growth-selected animals during proliferation. Previous studies have suggested that cell-surface heparan sulfate proteoglycans like syndecan-4 are involved in fibroblast growth factor 2 (FGF2) signaling by FGF2 binding to the heparan sulfate chains. Fibroblast growth factor 2 is a potent stimulator of muscle proliferation and an intense inhibitor of differentiation. To investigate the functional contribution of the attached syndecan-4 GAG chains, a turkey syndecan-4 full length cDNA was cloned and mutated at two or all three potential GAG attachment sites at Ser38, Ser65, and Ser67 resulting in all possible one-chain mutants and a no-chain mutant. Turkey satellite cells were transfected with the wild-type syndecan-4, one-chain mutants, no-chain mutant, or the empty vector and assayed for cell proliferation, differentiation, and FGF2 responsiveness. The wild-type syndecan-4, one-chain mutants, and no-chain mutant inhibited cell proliferation and delayed initial differentiation but did not alter FGF2 responsiveness or function through the mitogen-activated protein kinase pathway. There was no difference between the wild-type syndecan-4, one-chain, and no-chain mutants during these stages. These data suggest that syndecan-4 functions in an FGF2-independent manner and the GAG chains attached to the syndecan-4 core protein are not required for syndecan-4 to affect turkey satellite cell proliferation and the initial differentiation.
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PMID:The role of syndecan-4 and attached glycosaminoglycan chains on myogenic satellite cell growth. 1860 69

Nurr1, NGFI-B, and Nor1 form the NR4A subfamily of orphan nuclear receptors. The NR4A receptors are immediate early genes that can be rapidly induced in response to a variety of stimuli in many cell types, for example, in osteoblasts. Nurr1 regulates the differentiation of osteoblasts and the expression of several osteoblastic genes. Fibroblast growth factor 8b (FGF-8b) regulates osteoblastic differentiation. We show here that treatment of preosteoblastic MC3T3-E1 cells or mouse bone marrow mesenchymal cells with FGF-8b induces the expression of NR4A receptors rapidly and in a dose-dependent manner. This induction involves mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI-3K), and protein kinase C (PKC) pathways. FGF-8b stimulates the proliferation of MC3T3-E1 cells. This effect is enhanced by overexpression of Nurr1 and NGFI-B whereas it is abolished by a dominant negative Nurr1 variant. In conclusion, FGF-8b induces the expression of NR4A orphan nuclear receptors that are involved in mediating the growth promoting effect of FGF-8b in osteoblasts.
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PMID:FGF-8 stimulates the expression of NR4A orphan nuclear receptors in osteoblasts. 1880 62

Lens epithelial cells withdraw from the cell cycle to differentiate into secondary fibre cells in response to vitreal factors. Fibroblast growth factor (FGF) in the vitreous has been shown to induce lens fibre differentiation in vivo and in vitro through the activation of defined intracellular signalling, namely via MAPK/ERK1/2 and PI3-K/Akt pathways. To better understand the role of these growth factor-activated signalling pathways in lens fibre differentiation, FGF- and vitreous-induced lens fibre differentiation was examined in primary rat lens epithelial cell explants. The induction of cell elongation and fibre specific beta- and gamma-crystallin expression in lens explants was accompanied by distinct phosphorylation profiles for ERK1/2 and Akt. Using selective inhibitors (U0126 and LY294002) in blocking studies, these pathways were shown to be required for different aspects of lens fibre differentiation. Furthermore, a short 'pulse' treatment of explants with FGF showed that the activation of ERK1/2 over 24 h was not sufficient for the progression of lens fibre differentiation and that cyclic ERK1/2 phosphorylation was required throughout the extended differentiation process. In conclusion, these results support a key role for both ERK1/2 and PI3-kinase/Akt signalling pathways in FGF- and vitreous-induced lens fibre differentiation.
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PMID:MAPK/ERK1/2 and PI3-kinase signalling pathways are required for vitreous-induced lens fibre cell differentiation. 1893 58

Fibroblast growth factor (FGF) family signaling mediates cell-to-cell communication in development and organ homeostasis in adults. Of the FGF receptor (FGFR) isotypes, FGFR4 is the sole resident isotype present in mature parenchymal hepatocytes. FGFR1 that is normally associated with activated nonparenchymal cells appears ectopically in hepatoma cells. Ectopic expression and chronic activity of FGFR1 in hepatocytes accelerates diethylnitrosamine (DEN)-initiated hepatocarcinogenesis by driving unrestrained cell proliferation and tumor angiogenesis. Hepatocyte FGFR4 mediates liver's role in systemic cholesterol/bile acid and lipid metabolism and affects proper hepatolobular restoration after damage without effect on cell proliferation. Here we ask whether FGFR4 plays a role in progression of hepatocellular carcinoma (HCC). We report that although spontaneous HCC was not detected in livers of FGFR4-deficient mice, the ablation of FGFR4 accelerated DEN-induced hepatocarcinogenesis. In contrast to FGFR1 that induced a strong mitogenic response and depressed rate of cell death in hepatoma cells, FGFR4 failed to induce a mitogenic response and increased the rate of cell death. FGFR1 but not FGFR4 induced cyclin D1 and repressed p27 expression. Analysis of activation of Erk, JNK, and PI3K-related AKT signaling pathways indicated that in contrast to FGFR1, FGFR4 failed to sustain Erk activation and did not activate AKT. These differences may underlie the opposing effects of FGFR1 and FGFR4. These results suggest that in contrast to ectopic FGFR1 that is a strong promoter of hepatoma, resident FGFR4 that mediates differentiated hepatocyte metabolic functions also serves to suppress hepatoma progression.
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PMID:Resident hepatocyte fibroblast growth factor receptor 4 limits hepatocarcinogenesis. 1900 64


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