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)

Protein tyrosine phosphorylation is an important regulatory mechanism for many cellular processes in eucaryotic cells. During the invasion of the gram-positive pathogen, Listeria monocytogenes, into host epithelial cells, two host proteins become tyrosine phosphorylated. We have identified these major tyrosine phosphorylated species to be two isoforms of mitogen-activated protein (MAP) kinase, the 42 and 44 kDa MAP kinases. This activation begins within 5 to 15 min of bacterial infection. The tyrosine kinase inhibitor, genistein, blocks invasion as well as the tyrosine phosphorylation of these MAP kinases. Using cytochalasin D to block bacterial internalization but not adhesion, we showed that bacterial adherence rather than uptake is required for MAP kinase activation. Internalin mutants, which are unable to adhere efficiently to host cells, do not trigger MAP kinase activation. Other invasive bacteria, including enteropathogenic Escherichia coli (EPEC), and E. coli expressing Yersinia enterocolitica invasion, were not observed to activate MAP kinase during invasion into cultured epithelial cells. These results suggest that L. monocytogenes activates MAP kinase during invasion and a MAP kinase signal transduction pathway may be involved in mediating bacterial uptake.
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PMID:Listeria monocytogenes, an invasive bacterium, stimulates MAP kinase upon attachment to epithelial cells. 805 86

The enteropathogenic bacterium Yersinia enterocolitica counteracts host defense mechanisms by interfering with eukaryotic signal transduction pathways. In this study, we investigated the mechanism by which Y. enterocolitica prevents macrophage tumor necrosis factor-alpha (TNFalpha) production. Murine J774A.1 macrophages responded to Y. enterocolitica infection by rapid activation of mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK). However, after initial activation, the virulent Y. enterocolitica strain harboring the Y. enterocolitica virulence plasmid caused a substantial decrease in ERK1/2 and p38 tyrosine phosphorylation. Simultaneously, the virulent Y. enterocolitica strain gradually suppressed phosphorylation of the transcription factors Elk-1, activating transcription factor 2 (ATF2), and c-Jun, indicating time-dependent inhibition of ERK1/2, p38, and JNK kinase activities, respectively. Analysis of different Y. enterocolitica mutants revealed that (i) MAPK inactivation parallels the inhibition of TNFalpha release, (ii) the suppressor effect on TNFalpha production, which originates from the lack of TNFalpha mRNA, is distinct from the ability of Y. enterocolitica to resist phagocytosis and to prevent the oxidative burst, (iii) the tyrosine phosphatase YopH, encoded by the Y. enterocolitica virulence plasmid, is not involved in the decrease of ERK1/2 and p38 tyrosine phosphorylation or in the cytokine suppressive effect. Altogether, these results indicate that Y. enterocolitica possesses one or more virulence proteins that suppress TNFalpha production by inhibiting ERK1/2, p38, and JNK kinase activities.
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PMID:Yersinia enterocolitica promotes deactivation of macrophage mitogen-activated protein kinases extracellular signal-regulated kinase-1/2, p38, and c-Jun NH2-terminal kinase. Correlation with its inhibitory effect on tumor necrosis factor-alpha production. 918 92

Exposure of macrophages to lipopolysaccharide (LPS) leads to production of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-alpha). Previous studies have suggested that pathogenic Yersinia spp. inhibit LPS-mediated production of TNF-alpha in macrophages, and that one of the Yop proteins secreted by the plasmid-encoded type III pathway is required for this activity. We found that TNF-alpha production was inhibited when J774A.1 murine macrophages were infected with wild-type Y. pseudotuberculosis but not with an isogenic ysc mutant defective for Yop secretion. We inactivated multiple yop genes to identify which of these factors are required for the inhibition of TNF-alpha production. A mutant unable to express yopJ was defective for the inhibition of TNF-alpha production. Production of TNF-alpha is regulated at the transcriptional and translational levels by several mitogen-activated protein (MAP) kinases. The MAP kinases p38 and JNK underwent sustained activation in macrophages infected with the yopJ mutant. Conversely, p38 and JNK were downregulated in macrophages infected with the wild-type strain. The ability of the yopJ mutant to downregulate p38 and JNK and to inhibit production of TNF-alpha was restored by the expression of yopJ+ in trans. Therefore, YopJ is required for Y. pseudotuberculosis to downregulate MAP kinases and inhibit the production of TNF-alpha in macrophages.
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PMID:YopJ of Yersinia pseudotuberculosis is required for the inhibition of macrophage TNF-alpha production and downregulation of the MAP kinases p38 and JNK. 953 85

The Yersinia plasmid-encoded Yop virulon enables extracellular adhering bacteria to deliver toxic effector proteins inside their target cells. It includes a type III secretion system (Ysc), at least two translocator proteins (YopB, YopD), and a set of intracellular Yop effectors (YopE, YopH, YopO, YopM, and YopP). Infection of macrophages with a wild-type strain leads to low levels of tumor necrosis factor alpha (TNF-alpha) release compared to infection with plasmid-cured strains, suggesting that the virulence plasmid encodes a factor impairing the normal TNF-alpha response of infected macrophages. This effect is correlated with the inhibition of the macrophage mitogen-activated protein kinase (MAPK) activities. To identify the Yop protein responsible for the suppression of TNF-alpha release, we infected J774A.1 and PU5-1.8 macrophages with a battery of knockout Yersinia enterocolitica mutants and we quantified the TNF-alpha released. Mutants affected in secretion (yscN), in translocation (yopB and yopD), or in synthesis of all the known Yop effectors (yopH, yopO, yopP, yopE, and yopM polymutants) were unable to block the TNF-alpha response of the macrophages. In contrast, single yopE, yopH, yopO, and yopM mutants behaved like the wild-type strain. A yopP mutant elicited elevated TNF-alpha release, and complementation of the yopP mutant or the yop effector polymutant strain with yopP alone led to a drop in TNF-alpha release. In addition, YopP was also responsible for the inhibition of the extracellular signal-regulated kinase2 (ERK2) and p38 MAPK activities. These results show that YopP is the Yop effector responsible for the Yersinia-induced suppression of TNF-alpha release by infected macrophages.
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PMID:Role of YopP in suppression of tumor necrosis factor alpha release by macrophages during Yersinia infection. 957 64

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

The bacterial pathogen Yersinia uses a type III secretion system to inject several virulence factors into target cells. One of the Yersinia virulence factors, YopJ, was shown to bind directly to the superfamily of MAPK (mitogen-activated protein kinase) kinases (MKKs) blocking both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the extracellular signal-regulated kinase, c-Jun amino-terminal kinase, p38, and nuclear factor kappa B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.
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PMID:Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. 1048 73

Pathogenic bacteria of the genus Yersinia possess a type III secretion apparatus by which they can inject up to six effector proteins into host cells. These so-called effector Yops (Yersinia outer proteins) disrupt cellular immune defense functions such as TNF-alpha release, O2-production or phagocytosis and thereby allow Yersinia to grow extracellularly. Recent findings indicate that the effector Yops are highly active proteins that engage in crucial eukaryotic signaling mechanisms. For instance, the translocated tyrosine phosphatase YopH dephosphorylates the focal adhesion proteins paxillin and p130Cas within target cells. Furthermore, the Yersinia effector YopP is able to induce apoptosis in macrophages presumably by blocking MAP kinase and NFKB mediated signaling events. Here we discuss recent advances concerning the intracellular targets and biochemical signaling mechanisms regulated by the translocated Yersinia effectors.
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PMID:The tranquilizing injection of Yersinia proteins: a pathogen's strategy to resist host defense. 1049 28

We have examined the functional consequences of ADP-ribosyltransferase modification of Ras by the exoenzyme S (ExoS) protein of Pseudomonas aeruginosa. ExoS has been shown previously to ADP-ribosylate a number of proteins, including members of the Ras superfamily, which play an essential role in the processes of cell proliferation, differentiation, motility and cell division. HeLa and NIH3T3 cells were infected with ExoS protein, which was delivered via the type III secretion system of the heterologous host Yersinia pseudotuberculosis. Infection of mammalian cells with ExoS results in a change in the ratio of GTP/GDP bound directly to Ras in vivo. This ADP-ribosylation of Ras in vivo is mediated by the C-terminal domain of ExoS. Further, ExoS ADP-ribosylation of Ras in vivo inhibits activation of Ras and the ability to interact with the Ras binding domain of Raf upon stimulation with epidermal growth factor (EGF). In the present study, we show that ExoS activity does not interfere with EGF receptor phosphorylation itself, nor with the formation of a Grb2-activated Shc complex upon EGF stimulation, consistent with ExoS blockage of this mitogenic signalling pathway at the level of Ras. This is further supported by our observation of a substantial inhibition of extracellular signal-regulated kinase and protein kinase B/Akt kinase activation in response to EGF upon ExoS infection. In conclusion, in the present study, the consequences of ExoS infection on Ras effector pathway in vivo have been defined.
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PMID:Ras effector pathway activation by epidermal growth factor is inhibited in vivo by exoenzyme S ADP-ribosylation of Ras. 1072 22

Homologs of the Yersinia virulence effector YopJ are found in both plant and animal bacterial pathogens, as well as plant symbionts. These YopJ family members were shown to act as cysteine proteases. The catalytic triad of the protease was required for inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) signaling in animal cells and for induction of localized cell death in plants. The substrates for YopJ were shown to be highly conserved ubiquitin-like molecules, which are covalently added to numerous regulatory proteins. YopJ family members exert their pathogenic effect on cells by disrupting this posttranslational modification.
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PMID:Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. 1118 96

Yersinia enterocolitica induces apoptosis in macrophages by injecting the plasmid-encoded YopP (YopJ in other Yersinia species). Recently it was reported that YopP/J is a member of an ubiquitin-like protein cysteine protease family and that the catalytic core of YopP/J is required for its inhibition of the MAPK and NF-kappaB pathways. Here we analyzed the YopP/J-induced apoptotic signaling pathway. YopP-mediated cell death could be inhibited by addition of the zVAD caspase inhibitor, but not by DEVD or YVAD. Generation of truncated Bid (tBid) was the first apoptosis-related event that we observed. The subsequent translocation of tBid to the mitochondria induced the release of cytochrome c, leading to the activation of procaspase-9 and the executioner procaspases-3 and -7. Inhibition of the postmitochondrial executioner caspases-3 and -7 did not affect Bid cleavage. Bid cleavage could not be observed in a yopP-deficient Y. enterocolitica strain, showing that this event requires YopP. Disruption of the catalytic core of YopP abolished the rapid generation of tBid, thereby hampering induction of apoptosis by Y. enterocolitica. This finding supports the idea that YopP/J induces apoptosis by directly acting on cell death pathways, rather than being the mere consequence of gene induction inhibition in combination with microbial stimulation of the macrophage.
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PMID:Yersinia enterocolitica YopP-induced apoptosis of macrophages involves the apoptotic signaling cascade upstream of bid. 1127 13


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