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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factor receptors (FGFRs) are a family of transmembrane tyrosine kinases involved in signaling via interactions with the family of fibroblast growth factors. Alternative splicing of the juxtamembrane region of FGFR1-3 leads to the inclusion or exclusion of two amino acids, valine and threonine, the VT site. The presence or absence of VT (VT+ or VT-, respectively) affects the signaling potential of the receptor. The VT+ receptor isoform is required for Erk2 phosphorylation, a component of the mitogen-activated protein kinase signaling pathway. FRS2 is an adaptor protein that links FGFRs to the mitogen-activated protein kinase signaling pathway. FRS2 interacts with a region of the juxtamembrane domain of FGFR1 that includes the alternatively spliced VT site. We investigated the interaction of FRS2 with murine Fgfr1 juxtamembrane domain. We showed the alternatively spliced VT motif, at the juxtamembrane domain of Fgfr1 is required for FRS2 interaction with Fgfr1. Activation of signaling pathways from FRS2 is likely to be regulated by controlling the Fgfr1/FRS2 interaction through alternative splicing of the VT motif of Fgfr1.
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PMID:Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain. 1172 84

Two alternatively spliced stem cell factor (SCF) transcripts encode protein products, which differ in the duration of membrane presentation. One form, soluble SCF (S-SCF) gets rapidly processed to yield predominantly secreted protein. The other form, membrane-associated SCF (MA-SCF) lacks the primary proteolytic cleavage site but is cleaved slowly from an alternate site, and thus represents a more stable membrane form of SCF. Mutants of SCF that lack the expression of MA-SCF (Steel-dickie) or possess a defect in its presentation (Steel(17H)) manifest deficiencies in erythroid cell development. In this study, we have compared the consequence(s) of activating Kit, the receptor for SCF by MA-SCF with S-SCF, and an obligate membrane-restricted (MR) form of SCF (MR-SCF) on erythroid cell survival, proliferation, cell cycle progression, and the activation of p38 and ERK MAP kinase pathways. Activation of Kit by MR-SCF was associated with a significantly lower incidence of apoptosis and cell death in erythroid cells compared to either other isoform. MR- or MA-SCF-induced stimulation of erythroid cells resulted in similar and significantly greater proliferation and cell cycle progression compared to soluble SCF. The increase in proliferation and cell cycle progression via MA- or MR-SCF stimulation correlated with sustained and enhanced activation of p38 and ERK MAP kinase pathways. In addition, MR- or MA-SCF-induced proliferation was more sensitive to the inhibitory effects of ERK inhibitor compared to S-SCF-induced proliferation. In contrast, soluble SCF-induced proliferation was more sensitive to the inhibitory effects of p38 inhibitor compared with MR- or MA-SCF. These results suggest that different isoforms of SCF may use different biochemical pathways in stimulation of survival and/or proliferation of erythroid cells.
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PMID:Role of p38 and ERK MAP kinase in proliferation of erythroid progenitors in response to stimulation by soluble and membrane isoforms of stem cell factor. 1214 9

The p85alpha regulatory subunit of class I(A) phosphoinositide 3-kinases (PI3K) is derived from the Pik3r1 gene, which also yields alternatively spliced variants p50alpha and p55alpha. It has been proposed that excess monomeric p85 competes with functional PI3K p85-p110 heterodimers. We examined embryonic stem (ES) cells with heterozygous and homozygous disruptions in the Pik3r gene and found that wild type ES cells express virtually no monomeric p85alpha. Although, IGF-1-stimulated PI3K activity associated with insulin receptor substrates was unaltered in all cell lines, p85alpha-null ES cells showed diminished protein kinase B activation despite increased PI3K activity associated with the p85beta subunit. Furthermore, p85alpha-null cells demonstrated growth retardation, increased frequency of apoptosis, and altered cell cycle regulation with a G(0)/G(1) cell cycle arrest and up-regulation of p27(KIP), whereas signaling through CREB and MAPK was enhanced. These phenotypes were reversed by re-expression of p85alpha via adenoviral gene transfer. Surprisingly, all ES cell lines could be differentiated into adipocytes. In these differentiated ES cells, however, compensatory p85beta signaling was lost in p85alpha-null cells while increased signaling by CREB and MAPK was still observed. Thus, loss of p85alpha in ES cells induced alterations in IGF-1 signaling and regulation of apoptosis and cell cycle but no defects in differentiation. However, differentiated ES cells partially lost their ability for compensatory signaling at the level of PI3K, which may explain some of the defects observed in mice with homozygous deletion of the Pik3r1 gene.
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PMID:Altered signaling and cell cycle regulation in embryonal stem cells with a disruption of the gene for phosphoinositide 3-kinase regulatory subunit p85alpha. 1243 53

Evolution of human organismal complexity from a relatively small number of genes--only approximately twice that of worm or fly--is explained mainly by mechanisms generating multiple proteins from a single gene, the most prevalent of which is alternative pre-messenger-RNA splicing. Appropriate spatial and temporal generation of splice variants demands that alternative splicing be subject to extensive regulation, similar to transcriptional control. Activation by extracellular cues of several cellular signalling pathways can indeed regulate alternative splicing. Here we address the link between signal transduction and splice regulation. We show that the nuclear RNA-binding protein Sam68 is a new extracellular signal-regulated kinase (ERK) target. It binds exonic splice-regulatory elements of an alternatively spliced exon that is physiologically regulated by the Ras signalling pathway, namely exon v5 of CD44. Forced expression of Sam68 enhanced ERK-mediated inclusion of the v5-exon sequence in mRNA. This enhancement was impaired by mutation of ERK-phosphorylation sites in Sam68, whereas ERK phosphorylation of Sam68 stimulated splicing of the v5 exon in vitro. Finally, Ras-pathway-induced alternative splicing of the endogenous CD44-v5 exon was abolished by suppression of Sam68 expression. Our data define Sam68 as a prototype regulator of alternative splicing whose function depends on protein modification in response to extracellular cues.
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PMID:Signal-dependent regulation of splicing via phosphorylation of Sam68. 1247 98

Mounting experimental evidence has suggested that the trophic environment of cells in culture is an important determinant of their vulnerability to the cytotoxic effects of reactive oxidants such as peroxynitrite (ONOO(-)). However, acidic fibroblast growth factor (FGF-1)-induced signaling renders some cells more sensitive and others resistant to the cytotoxic effects of ONOO(-). To determine whether alternatively spliced fibroblast growth factor receptor (FGFR-1) isoforms are responsible for this differential response, we have stably transfected FGFR-negative rat brain-derived resistant vessel endothelial cells (RVEC) with human cDNA sequences encoding either FGFR-1 alpha or FGFR-1 beta. FGF-1 treatment of RVEC(R-1 alpha) transfectants enhanced ONOO(-)-mediated cell death in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and p38 MAP kinase activities and independent of Src-family kinase (SFK) activity. FGF-1 treatment of RVEC(R-1 beta) transfectants inhibited the cytotoxic effects of ONOO(-) in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and SFK activities and independent of p38 MAP kinase activity. FGF-1-induced preactivation of both FGFR-1 tyrosine and Erk 1/2 kinases was detected in both RVEC(R-1 alpha) and RVEC(R-1 beta) transfectants. FGF-1-induced preactivation of p38 MAPK was restricted to RVEC(R-1 alpha) transfectants, whereas, ligand-induced preactivation of SFK was limited to RVEC(R-1 beta) transfectants. Collectively, these results both reemphasize the role of extracellular trophic factors and their receptor-mediated signaling pathways during cellular responses to oxidant stress and provide a first indication that the alternatively spliced FGFR-1 isoforms induce differential signal transduction pathways.
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PMID:Alternatively spliced FGFR-1 isoform signaling differentially modulates endothelial cell responses to peroxynitrite. 1257 78

Germline mutations of the RET proto-oncogene cause multiple endocrine neoplasia (MEN) 2A or 2B by different mechanisms. As is the case for other receptor tyrosine kinases, mutant RET recruits a variety of signalling molecules via phosphorylated tyrosine residues present in the kinase domain and carboxy-terminal tail. As we previously reported, the signaling via phosphorylated tyrosine 1062 plays a crucial role in the transforming activities of both RET-MEN2A and RET-MEN2B mutant protein. Interestingly, this single tyrosine residue represents a binding site for several signalling molecules including SHC, Enigma, SNT/FRS2, DOK and IRS1 and is responsible for activation of the RAS/ERK, PI3-K/AKT, JNK, p38MAPK and ERK5 signalling pathways. Amongst these, the PI3-K/AKT and JNK pathways appeared to be more strongly activated in the cells expressing RET-MEN2B than in the cells expressing RET-MEN2A, suggesting the possibility that these pathways may be involved in the disease phenotype. In addition, RET is alternatively spliced to produce three isoforms and the splicing site is present just downstream of tyrosine 1062. These isoforms play different roles for the tumour development associated with MEN 2 or the development of the kidney and the enteric nervous system. Moreover, using differential display analysis, we identified several genes whose expression is highly induced by RET-MEN2B mutant proteins. The differential gene expression by RET-MEN2A and RET-MEN2B may also be important for the development of their phenotypes.
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PMID:Cell signalling and gene expression mediated by RET tyrosine kinase. 1275 58

Insulin is a potent inducer of adipogenesis, and differentiation of adipocytes requires many components of the insulin signaling pathway, including the insulin receptor substrate IRS-1 and phosphatidylinositol 3-kinase (PI3K). Brown pre-adipocytes in culture exhibit low levels of insulin receptor (IR), and during differentiation there is both an increase in total IR levels and a shift in the alternatively spliced forms of IR from the A isoform (-exon 11) to the B isoform (+exon 11). Brown pre-adipocyte cell lines from insulin receptor-deficient mice exhibit dramatically impaired differentiation and an inability to regulate alternative splicing of the insulin receptor. Surprisingly, re-expression of either splice isoform of IR in the IR-deficient cells fails to rescue differentiation in these cells. Likewise, overexpression of IR in control IRlox cells also results in inhibition of differentiation and a failure to accumulate expression of the adipogenic markers peroxisome proliferator-activated receptor gamma, Glut4, and fatty acid synthase, although cells overexpressing IR retain the ability to activate PI3K and down-regulate mitogen-activated protein kinase (MAPK) phosphorylation. Thus, differentiation of brown adipocytes requires a timed and regulated expression of IR, and either the absence or overabundance of insulin receptors in these cells dramatically inhibits differentiation.
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PMID:Bi-directional regulation of brown fat adipogenesis by the insulin receptor. 2803 34

Toll-like receptors and the IL-1R are part of the innate immune response aimed at mobilizing defense mechanisms in response to infections or injury. These receptors can initiate common intracellular signaling cascades. One intermediate component in these signaling cascades is Pellino, which was first identified in Drosophila and shown to interact with IL-1R-associated kinase. Two homologues, Pellino1 and Pellino2, have been identified in mammals. A novel member of the Pellino protein family has been identified and named Pellino3. Pellino3 shares 84 and 85% amino acid identity with Pellino1 and Pellino2, respectively. Two alternatively spliced Pellino3 mRNAs, Pellino3a and Pellino3b, are widely expressed. Pellino3 physically interacts with IL-1R-associated kinase-1, TNF receptor-associated factor-6, TGF-beta-activated kinase-1, and NF-kappaB-inducing kinase in an IL-1-dependent manner, suggesting that it plays a role as a scaffolding protein. In reporter assays Pellino3 leads to activation of c-Jun and Elk-1, but not NF-kappaB. Pellino3 also leads to activation of c-Jun N-terminal kinase. These data suggest that Pellino3 plays an important role in the innate immune response.
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PMID:Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein. 1287 43

In mammals, members of the tumor necrosis factor (TNF) family play an important role in the regulation of cellular proliferation, differentiation and programmed cell death. We describe isolation and characterization of an orthologous ligand/receptor axis in Drosophila. The ligand, designated Eiger, is a type II membrane glycosylated protein, which can be cleaved at residue 145 and released from the cell surface as a soluble factor, thereby representing the first potential cytokine to be described in Drosophila. Eiger exists in two alternatively spliced isoforms, Eiger long (Eiger-L) and Eiger short (Eiger-s), both of which are expressed throughout development and in the adult. We also describe the isolation and characterization of a novel Drosophila member of the TNF receptor family, designated Wengen, which is a type I membrane protein that can physically interact with the recently described TRAF2 homolog dTRAF2. Both Eiger and Wengen are expressed in distinctive patterns during embryogenesis and Eiger is responsive to genotoxic stress. Forced expression of Eiger-L, Eiger-s or Wengen, caused apoptotic cell death which could be rescued by caspase inhibitors or the JNK phosphatase Puckered. In addition, Eiger-induced cell killing was attenuated by RNAi-mediated suppression of Wengen. Our results illustrate that Eiger and Wengen represent proximal components of an evolutionarily conserved TNF-like signaling pathway in Drosophila.
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PMID:Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. 1289 27

The K15 gene of Kaposi's sarcoma-associated herpesvirus (also known as human herpesvirus 8) consists of eight alternatively spliced exons and has been predicted to encode membrane proteins with a variable number of transmembrane regions and a common C-terminal cytoplasmic domain with putative binding sites for SH2 and SH3 domains, as well as for tumor necrosis factor receptor-associated factors. These features are reminiscent of the latent membrane proteins LMP-1 and LMP2A of Epstein-Barr virus and, more distantly, of the STP, Tip, and Tio proteins of the related gamma(2)-herpesviruses herpesvirus saimiri and herpesvirus ateles. These viral membrane proteins can activate a number of intracellular signaling pathways. We have therefore examined the abilities of different K15-encoded proteins to initiate intracellular signaling. We found that a 45-kDa K15 protein derived from all eight K15 exons and containing 12 predicted transmembrane domains in addition to the cytoplasmic domain activated the Ras/mitogen-activated protein kinase (MAPK) and NF-kappaB pathways, as well as (more weakly) the c-Jun N-terminal kinase/SAPK pathway. Activation of the MAPK and NF-kappaB pathways required phosphorylation of tyrosine residue 481 within a putative SH2-binding site (YEEVL). This motif was phosphorylated by the tyrosine kinases Src, Lck, Yes, Hck, and Fyn. The region containing the YEEVL motif interacted with tumor necrosis factor receptor-associated factor 2 (TRAF-2), and a dominant negative TRAF-2 mutant inhibited the K15-mediated activation of the Ras/MAPK pathway, suggesting the involvement of TRAF-2 in the initiation of these signaling routes. In contrast, several smaller K15 protein isoforms activated these pathways only weakly. All of the K15 isoforms tested were, however, localized in lipid rafts, suggesting that incorporation into lipid rafts is not sufficient to initiate signaling. Additional regions of K15, located presumably in exons 2 to 5, may therefore contribute to the activation of these pathways. These findings illustrate that the 45-kDa K15 protein engages pathways similar to LMP1, LMP2A, STP, Tip, and Tio but combines functional features that are separated between LMP1 and LMP2A or STP and Tip.
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PMID:Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein. 1291 50


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