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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Engagement and clustering of integrins triggers a number of intracellular signaling events, including activation of the mitogen-activated protein (MAP) kinases Erk1 and Erk2. To investigate the mechanism by which integrins mediate the activation of MAP kinases upon binding of NIH 3T3 cells to fibronectin, we assessed the effects of both inhibiting and activating the small GTPase Rho. We observed that inhibition of Rho by the Rho-specific inhibitor C3 exoenzyme or by a dominant negative Rho A (RhoN19) inhibited MAP kinase activation. Conversely, activation of Rho by expression of an activated Rho A mutant (RhoQ63L), or the Rho-specific guanine nucleotide exchange factor lbc, enhanced and partially mimicked activation of Erk2 by plating on fibronectin. These results therefore show that Rho is involved in the integrin-dependent activation of MAP kinase.
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PMID:Involvement of the small GTPase rho in integrin-mediated activation of mitogen-activated protein kinase. 870 60

The small GTPase RhoB is immediate-early inducible by DNA damaging treatments and thus part of the early response of eukaryotic cells to genotoxic stress. To investigate the regulation of this cellular response, we isolated the gene for rhoB from a mouse genomic library. Sequence analysis of the rhoB gene showed that its coding region does not contain introns. The promoter region of rhoB harbors regulatory elements such as TATA, CAAT, and Sp1 boxes but not consensus sequences for AP-1, Elk-1, or c-Jun/ATF-2. The rhoB promoter was activated by UV irradiation, but not by 12-O-tetradecanoylphorbol-13-acetate treatment. rhoB promoter deletion constructs revealed a fragment of 0.17 kilobases in size which was sufficient in eliciting the UV response. This minimal promoter fragment contains TATA and CAAT boxes but no other known regulatory elements. Neither MEK inhibitor PD98059 nor p38 kinase inhibitor SB203580 blocked stimulation of rhoB by UVC (UV light, 254 nm) which indicates that ERK or p38 mitogen-activated protein (MAP) kinase are not involved in the UV induction of rhoB. Also, phosphatidylinositol 3-kinase inhibitor wortmannin, which blocks UV stimulation of both JNK and p38 MAP kinase, did not inhibit rhoB activation. Furthermore, activation of JNK by interleukin-1beta did not affect rhoB expression. These data indicate that JNK is not involved in the regulation of rhoB. Overexpression of wild-type Rac as well as the Rho guanine-dissociation inhibitor caused activation of rhoB. Wild-type RhoB inhibited both basal and UV-stimulated rhoB promoter activity, indicating a negative regulatory feedback by RhoB itself. The data provide evidence both for a signal transduction pathway independent of JNK, ERK, and p38 MAP kinase to be involved in the induction of rhoB by genotoxic stress, and furthermore, indicate autoregulation of rhoB.
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PMID:rhoB encoding a UV-inducible Ras-related small GTP-binding protein is regulated by GTPases of the Rho family and independent of JNK, ERK, and p38 MAP kinase. 938 98

In Saccharomyces cerevisiae, the phosphatidylinositol kinase homologue Tor2 controls the cell-cycle-dependent organisation of the actin cytoskeleton by activating the small GTPase Rho1 via the exchange factor Rom2 [1,2]. Four Rho1 effectors are known, protein kinase C 1 (Pkc1), the formin-family protein Bni1, the glucan synthase Fks and the signalling protein Skn7 [2,3]. Rho1 has been suggested to signal to the actin cytoskeleton via Bni1 and Pkc1; rho1 mutants have never been shown to have defects in actin organisation, however [2,4]. We have further investigated the role of Rho1 in controlling actin organisation and have analysed which of the Rho1 effectors mediates Tor2 signalling to the actin cytoskeleton. We show that some, but not all, rho1 temperature-sensitive (rho1ts) mutants arrest growth with a disorganised actin cytoskeleton. Both the growth defect and the actin organisation defect of the rho1-2ts mutant were suppressed by upregulation of Pkc1 but not by upregulation of Bni1, Fks or Skn7. Overexpression of Pkc1, but not overexpression of Bni1, Fks or Skn7, also rescued a tor2ts mutant, and deletion of BNI1 or SKN7 did not prevent the suppression of the tor2ts mutation by overexpressed Rom2. Furthermore, overexpression of the Pkc1-controlled mitogen-activated protein (MAP) kinase Mpk1 suppressed the actin defect of tor2ts and rho1-2ts mutants. Thus, Tor2 signals to the actin cytoskeleton via Rho1, Pkc1 and the cell integrity MAP kinase cascade.
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PMID:The Rho1 effector Pkc1, but not Bni1, mediates signalling from Tor2 to the actin cytoskeleton. 981 7

The signalling pathway leading to an activation of mitogen-activated protein (MAP) kinase subtypes Erk-1 and -2 upon stimulation of muscarinic receptor with carbachol in human neuroblastoma SK-N-BE2(C) cells was investigated. Carbachol activated Erk-1/-2 by stimulating M3 muscarinic receptor, as determined by specific antagonists for individual muscarinic receptors. The activation of Erk-1/-2 by carbachol was blocked by the inhibition or down-regulation of protein kinase C (PKC). Among the multiple PKC isoforms expressed in SK-N-BE2(C) cells, only PKCepsilon was activated by the treatment of carbachol, and selective down-regulation of PKCepsilon was sufficient to block Erk-1/-2 activation. Carbachol treatment induced activation of the serine/threonine protein kinase Raf, and an inhibition of Raf blocked Erk-1/-2 activation. Ectopic expression of inhibitory small GTPase Ras, RasN17, blocked the carbachol-induced Raf activation without affecting the activation of PKCepsilon, while the inhibition of PKC blocked the Raf activation. Thus, these results suggest that carbachol-induced activation of PKCepsilon mediates Erk-1/-2 activation by a sequential activation of Ras, Raf and MAP kinase kinase.
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PMID:Signalling pathway leading to an activation of mitogen-activated protein kinase by stimulating M3 muscarinic receptor. 988 25

Pathogenic Yersinia spp. utilize a plasmid-encoded type III secretion system to deliver a set of Yop effector proteins into eukaryotic cells. Previous studies have shown that the effector YopJ is required for Yersinia to cause downregulation of the mitogen-activated protein (MAP) kinases c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK) 1 and 2 in infected macrophages. Here we demonstrate that YopJ is sufficient to cause downregulation of multiple MAP kinases in eukaryotic cells. Cellular fractionation experiments confirmed that YopJ is delivered into the cytoplasmic fraction of macrophages by the type III system. Production of YopJ in COS-1 cells by transfection significantly reduced (5- to 10-fold) activation of JNK, p38, and ERK in response to several different stimuli, including serum and tumor necrosis factor alpha. JNK activation mediated by RacV12, an activated mutant of Rac1, was also blocked by YopJ in COS-1 cells, indicating that YopJ acts downstream of this small GTPase to downregulate MAP kinase signaling. Analysis of transfected COS-1 cells by immunofluorescence microscopy revealed that YopJ is recruited from the cytoplasmic compartment to the cell periphery in response to stimuli (e.g., serum) that induce membrane ruffling. These data indicate that YopJ functions as a "MAP kinase toxin" to selectively block nuclear responses that are triggered by Yersinia-host cell interaction.
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PMID:YopJ of Yersinia spp. is sufficient to cause downregulation of multiple mitogen-activated protein kinases in eukaryotic cells. 991 81

CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen-activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav GDP releasing factor (GRF) to the plasma membrane and assembly of GTPase/GRF complexes, an event critical for Ag receptor-triggered T cell activation. Here, we show that TCR/CD28 costimulation synergistically induces Rac-1 GDP/GTP exchange. Our findings, obtained by using ZAP-70-negative Jurkat T cells, indicate that CD28 costimulation augments TCR-mediated T cell activation by increasing the ZAP-70-mediated Tyr phosphorylation of Vav. This event regulates the Rac-1-associated GTP/GDP exchange activity of Vav and downstream pathway(s) leading to PAK-1 and p38 MAPK activation. CD28 amplifies TCR-induced ZAP-70 activity and association of Vav with ZAP-70 and linker for activation of T cells (LAT). These results favor a model in which ZAP-70 regulates the intersection of the TCR and CD28 signaling pathways, which elicits the coupling of TCR and CD28 to the Rac-1, PAK-1, and p38 MAPK effector molecules.
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PMID:TCR and CD28 are coupled via ZAP-70 to the activation of the Vav/Rac-1-/PAK-1/p38 MAPK signaling pathway. 1039 78

The neural cell adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation necessary for proper development of synaptic connections. Mutations of human L1 cause an X-linked mental retardation syndrome termed CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, and hydrocephalus), and L1 knock-out mice display defects in neuronal process extension resembling the CRASH phenotype. Little is known about the biochemical or cellular mechanism by which L1 performs neuronal functions. Here it is demonstrated that clustering of L1 with antibodies or L1 protein in rodent B35 neuroblastoma and cerebellar neuron cultures induced the phosphorylation/activation of the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases 1 and 2. MAPK activation was essential for L1-dependent neurite outgrowth, because chemical inhibitors [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one and 1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadiene] of the MAPK kinase MEK strongly suppressed neurite outgrowth by cerebellar neurons on L1. The nonreceptor tyrosine kinase pp60(c-src) was required for L1-triggered MAPK phosphorylation, as shown in src-minus cerebellar neurons and by expression of the kinase-inactive mutant Src(K295M) in B35 neuroblastoma cells. Phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase p21(rac) were identified as signaling intermediates to MAPK by phosphoinositide and Rac-GTP assays and expression of inhibitory mutants. Antibody-induced endocytosis of L1, visualized by immunofluorescence staining and confocal microscopy of B35 cells, was blocked by expression of kinase-inactive Src(K295M) and dominant-negative dynamin(K44A) but not by inhibitors of MEK or PI3-kinase. Dynamin(K44A) also inhibited L1 antibody-triggered MAPK phosphorylation. This study supports a model in which pp60(c-src) regulates dynamin-mediated endocytosis of L1 as an essential step in MAPK-dependent neurite outgrowth on an L1 substrate.
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PMID:A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. 1081 53

The p38 mitogen-activated protein (MAP) kinase is activated during engagement of the type I interferon (IFN) receptor and mediates signals essential for IFNalpha-dependent transcriptional activation via interferon-stimulated response elements without affecting formation of the ISGF3 complex. In the present study, we provide evidence that the small GTPase Rac1 is activated in a type I IFN-dependent manner and that its function is required for downstream engagement of the p38 MAP kinase pathway. We also demonstrate that p38 is required for IFNalpha-dependent gene transcription via GAS elements and regulates activation of the promoter of the PML gene that mediates growth inhibitory responses. In studies to determine whether the regulatory effects of p38 are mediated by serine phosphorylation of Stat1 or Stat3, we found that the p38 kinase inhibitors SB203580 or SB202190 or overexpression of a dominant negative p38 mutant do not inhibit phosphorylation of Stat1 or Stat3 on Ser-727 in several IFNalpha-sensitive cell lines. Altogether these data demonstrate that the Rac1/p38 MAP kinase signaling cascade plays a critical role in type I IFN signaling, functioning in cooperation with the Stat-pathway, to regulate transcriptional regulation of IFNalpha-sensitive genes and generation of growth inhibitory responses.
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PMID:The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. 1087 8

The induction of connective tissue growth factor (CTGF) was investigated in a human renal fibroblast cell line that exhibited many characteristics of primary human renal fibroblasts. Induction of CTGF mRNA was observed after treatment of the cells with transforming growth factor-beta (TGF-beta) or, even more prominently, lysophosphatidic acid (LPA). LPA induced a rapid transient increase in CTGF mRNA expression, with maximal levels being observed after 1 to 2 h. This increase was accompanied by CTGF protein synthesis. Induction of CTGF was insensitive to pertussis toxin and was not dependent on the activation of p42/44 mitogen-activated protein kinases. Inhibition of the proteins of the Rho family with toxin B from Clostridium difficile abrogated basal and LPA-mediated induction of CTGF. Specific targeting of RhoA with C3 exotoxin or of the Rho kinases with the inhibitor Y-27632 similarly prevented induction of CTGF, implicating RhoA as a signaling module downstream of LPA. Inhibition of RhoA depolymerized the actin cytoskeleton, as did treatment with cytochalasin D. Preincubation of the human renal fibroblasts with cytochalasin D prevented induction of CTGF by LPA, indicating a strong contribution of an intact cytoskeleton. Interference with RhoA signaling similarly inhibited the induction of CTGF by TGF-beta. Elevation of intracellular levels of cAMP and thus activation of protein kinase A prevented induction of CTGF expression. The cytoskeletal effects of cAMP, however, were reversed by LPA. These data indicate complex interactions involving LPA-mediated activation of RhoA- and protein kinase A-dependent signaling pathways. The data thus demonstrate the regulatory functions of the small GTPase RhoA and of an intact cytoskeleton in the expression of CTGF after stimulation with LPA or TGF-beta. Analogous signal transduction pathways were previously demonstrated in rat mesangial cells, suggesting a more general role for RhoA in the regulation of CTGF expression.
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PMID:Expression of connective tissue growth factor in human renal fibroblasts: regulatory roles of RhoA and cAMP. 1151 78

The oncogenic Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has structural features and functions reminiscent of a constitutively active TNF family receptor. LMP1 aggregates at the plasma membrane and initiates the activation of signalling pathways, such as NF- kappa B, the mitogen-activated protein kinases JNK and p38, the small GTPase Cdc42 and the JAK/STAT cascade. The constitutive engagement of these signals and the characteristic molecular interactions that regulate them provide the basis for the molecular explanation of the transforming properties of this key EBV protein.
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PMID:LMP1 structure and signal transduction. 1166 5


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