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 factors (FGFs) are pleiotrophic growth factors that control cell proliferation, migration, differentiation and embryonic patterning. During early zebrafish embryonic development, FGFs regulate dorsoventral patterning by controlling ventral bone morphogenetic protein (BMP) expression. FGFs function by binding and activating high-affinity tyrosine kinase receptors. FGF activity is negatively regulated by members of the Sprouty family, which antagonize Ras signalling induced by receptor tyrosine kinases. On the basis of similarities in their expression patterns during embryonic development, we have identified five genes that define a synexpression group -- fgf8, fgf3, sprouty2, sprouty4, as well as a novel gene, sef (similar expression to fgf genes). Sef encodes a conserved putative transmembrane protein that shares sequence similarities with the intracellular domain of the interleukin 17 receptor. Here we show that in zebrafish, Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling.
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PMID:Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. 1180 65

Fibroblast growth factor 2 (FGF-2) is an important regulator of bone formation and osteoblast activity. However, its mechanism of action on bone cells is largely unknown. A major route for FGF signaling is through the mitogen-activated protein kinase (MAPK) pathway. We showed recently that this pathway is important for activation and phosphorylation of Cbfa1/Runx2, an osteoblast-related transcription factor (Xiao, G., Jiang, D., Thomas, P., Benson, M. D., Guan, K., Karsenty, G., and Franceschi, R. T. (2000) J. Biol. Chem. 275, 4453-4459). The present study examined the mechanism of FGF-2 regulation of the mouse osteocalcin gene in MC3T3-E1 preosteoblastic cells. FGF-2 stimulated osteocalcin mRNA and promoter activity in a dose- and time-dependent manner in MC3T3-E1 preosteoblastic cells. Similar results were obtained in mouse bone marrow stromal cells. This stimulation required Runx2 and its DNA binding site in the osteocalcin promoter. FGF-2 also dramatically increased phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) followed by phosphorylation of Runx2. Furthermore, a specific ERK1/2 phosphorylation inhibitor, U0126, completely blocked both FGF-2-stimulated Runx2 phosphorylation and osteocalcin promoter activity, indicating that this regulation requires the MAPK pathway. Deletion studies showed that the C-terminal PST domain of Runx2 is required for the FGF-2 response. This study is the first demonstration that Runx2 is phosphorylated and activated by FGF-2 via the MAPK pathway and suggests that FGF-2 plays an important role in regulation of Runx2 function and bone formation.
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PMID:Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. 1211 Jun 89

Fibroblast growth factor (FGF) is an important modulator of cell growth and differentiation of various cells including neuron. Cells need to adhere specifically to cellular and extracellular components of their environment to carry out diverse physiological functions. Here, we examined whether fibronectin (FN) and FGF can cooperate for neuronal adhesion and neurite outgrowth. Using recombinant FN peptide (FNIII9-10), we found that FNIII9-10-mediated adhesion promotes the effect of FGF1 on neurite outgrowth of PC12 cells, while FGF1 enhances the FNIII9-10-mediated neuronal adhesion of PC12 cells. This collaboration of FNIII9-10 and FGF1 was the result of the sustained activation of extracellular signal-regulated kinase (ERK)-type MAP kinase. Finally, the synergistic activity of FGF1 and FN was inhibited by PD98059, an MEK inhibitor. Taken together, these findings indicate that FN-mediated signaling can collaborate with FGFRs signaling for neurite outgrowth through selective activation of ERK-type MAP kinase in PC12 cells, and suggest that FN and FGF act in concert to regulate cell differentiation in the nervous system.
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PMID:Synergistic activity of fibronectin and fibroblast growth factor receptors on neuronal adhesion and neurite extension through extracellular signal-regulated kinase pathway. 1212 79

Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of activities. Signaling of the 23 members of the FGF family is mediated through FGFR1-4. We show that FGF-19, which selectively binds FGFR4, can induce prolactin (PRL) but not growth hormone expression. FGF-19 also stimulated MAPK activation, an effect that was abrogated by a soluble dominant negative (dn) form of FGFR4. The response of the pituitary PRL promoter to FGF maps to an Ets-Pit1 binding site. We have previously shown that the hematopoietic zinc finger-containing transcription factor Ikaros (Ik) regulates FGFR4 as part of an overlapping site with that for an Ets-type factor in the FGFR4 promoter. Thus, we examined whether FGF-19 might regulate its own receptor through the Ets-Ik element in the FGFR4 promoter. Ets stimulated and dn-Ets inhibited basal FGFR4 and PRL promoter activity. In contrast, Ets enhanced FGF-19-induced PRL activation but failed to confer an effect for FGF-19 on the FGFR4 promoter. We conclude that FGFR4 mediates FGF-19 signaling to the PRL promoter. Our data also suggest a possible functional role for Ik in sorting Ets signals to the FGFR4 promoter, as distinct from the PRL promoter, where Ets partners with Pit1.
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PMID:Fibroblast growth factor receptor 4 (FGFR4) mediates signaling to the prolactin but not the FGFR4 promoter. 1216 42

Fibroblast growth factor (FGF)-2 and transforming growth factor alpha (TGFalpha) promote astroglial proliferation during brain development and reactive processes. The mitogenic potential of both growth factors is attenuated by increasing intracellular cAMP levels, an effect currently assumed to depend on the inhibition of the mitogen-activated protein kinase cascade. In the present study, we sought to determine whether cAMP interferes with the mitogenic potential of FGF-2 and TGFalpha on astroglia by affecting the expression of respective growth factor receptors. Treatment of highly enriched cultures of cortical astrocytes with dibutyryl cAMP accelerated the TGFalpha-induced internalization and subsequent functional inactivation of epidermal growth factor (EGF) receptor by transiently inhibiting EGF receptor mRNA synthesis. In apparent contrast, both short- and long-term activation of cAMP-dependent signaling pathways robustly promoted the expression of FGF receptors 1 and 2, whereas expression levels of FGF receptor 3 remained unaffected. Moreover, elevation of intracellular cAMP levels did not prevent translocation of FGF receptor 1 to the cell nucleus, a mechanism thought to be essential for FGF-2-induced cell proliferation. We propose that cAMP controls the mitogenic effects of TGFalpha and FGF-2 on astroglial cells by distinctly different mechanisms. Whereas cAMP seems to interfere with the mitogenic effects of TGFalpha on astroglial cells by affecting both the expression level and signaling of the EGF receptor, the modulatory effects of cAMP on FGF-2-induced astroglial proliferation seem to solely result from an inhibition of FGF receptor-activated signaling pathways.
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PMID:Cyclic AMP differentially regulates the expression of fibroblast growth factor and epidermal growth factor receptors in cultured cortical astroglia. 1220 56

Fibroblast growth factor homologous factors (FHFs) form native intracellular complexes with the mitogen-activated protein kinase (MAPK) scaffold protein islet-brain 2 (IB2) in adult brain. FHF binding to IB2 facilitates recruitment of the MAPK p38delta (SAPK4), while failing to stimulate binding of JNK, the preferred kinase of the related scaffold IB1 (JIP-1). We now report further biochemical evidence supporting FHFs as regulators of IB2 scaffold activity. Mixed lineage kinase 3 (MLK3) and IB2 synergistically activate p38delta but not the MAPKs JNK-1 and p38alpha. Binding of p38delta to IB2 is mediated by the carboxyl-terminal half of the scaffold (IB2(Delta1-436)). FHF2 also binds weakly to IB2(Delta1-436) and can thereby increase p38delta interaction with IB2(Delta1-436). FHF-induced recruitment of p38delta to IB2 is accompanied by increased levels of activated p38delta, and synergistic activation of p38delta by MLK3 and IB2 is further enhanced by FHF2. Consistent with a role for FHFs as signaling molecules, FHF2 isolated from rat brain is serine/threonine-phosphorylated, and FHF can serve as a substrate for p38delta in vitro. These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38delta kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates.
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PMID:Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase. 1224 47

We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. Inhibition of this activity by treating the cells with a MEK1-specific inhibitor (U0126 or PD98059) prior to the induction of differentiation significantly attenuated the expression of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, perilipin, and adipocyte-specific fatty acid-binding protein (aP2). Treating the preadipocytes with troglitazone, a potent PPARgamma ligand, could circumvent the inhibition of adipogenic gene expression by U0126. Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors. Consequently, preadipocytes treated with U0126 in the presence of fibroblast growth factor-2 (FGF-2) express normal post-induction levels of MEK activity, and, in so doing, are capable of undergoing adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process. Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression.
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PMID:Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor gamma (PPARgamma ) and C/EBPalpha gene expression during the differentiation of 3T3-L1 preadipocytes. 1227 Sep 34

Fibroblast growth factor receptors (FGFRs) genes have been shown to be translocated in multiple myeloma (MM) and myeloproliferative disorder (MPD), indicating an important role for the FGFRs in hematologic malignancies. Here, we describe a novel splice variant of FGFR2 (FGFR2AT-I) arising from skipping exons 7-10 in human myeloid leukemia HL-60 cells, encoding a FGFR2 in which the Ig-like-III domain is deleted while the remainder of the mature molecule is fused in-frame to the transmembrane and COOH-terminal cytoplasmic kinases. Binding assays demonstrated that the FGFR2AT-I was able to bind FGF1, FGF2, and FGF7, leading to loss of ligand binding specificity. Furthermore, overexpression of FGFR2AT-I resulted in increased AKT and MAPK activation, conferring a survival advantage. Taken together, these findings indicate that the dysregulation of FGFRs' function by aberrant mRNA splicing contributes to tumor progression.
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PMID:A novel splice variant of fibroblast growth factor receptor 2 in human leukemia HL-60 cells. 1248 14

Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.
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PMID:Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons. 1249 61

Cyclic stretch of alveolar epithelial cells (AEC) can alter normal lung barrier function. Fibroblast growth factor-10 (FGF-10), an alveolar type II cell mitogen that is critical for lung development, may have a role in promoting AEC repair. We studied whether cyclic stretch induces AEC DNA damage and whether FGF-10 would be protective. Cyclic stretch (30 min of 30% strain amplitude and 30 cycles/min) caused AEC DNA strand break formation, as assessed by alkaline unwinding technique and DNA nucleosomal fragmentation. Pretreatment of AEC with FGF-10 (10 ng/ml) blocked stretch-induced DNA strand break formation and DNA fragmentation. FGF-10 activated AEC mitogen-activated protein kinase (MAPK), and MAPK inhibitors prevented FGF-10-induced AEC MAPK activation and abolished the protective effects of FGF-10 against stretch-induced DNA damage. In addition, a Grb2-SOS inhibitor (SH(3)b-p peptide), a RAS inhibitor (farnesyl transferase inhibitor 277), and a RAF-1 inhibitor (forskolin) each prevented FGF-10-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in AEC. Moreover, N17-A549 cells that express a RAS dominant/negative protein prevented the FGF-10-induced ERK1/2 phosphorylation and RAS activation in AEC. We conclude that cyclic stretch causes AEC DNA damage and that FGF-10 attenuates these effects by mechanisms involving MAPK activation via the Grb2-SOS/Ras/RAF-1/ERK1/2 pathway.
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PMID:FGF-10 prevents mechanical stretch-induced alveolar epithelial cell DNA damage via MAPK activation. 1253 12


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