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)

The YadA protein of Yersinia pseudotuberculosis promotes tight adhesion and invasion into mammalian cells through beta(1)-integrins. In this work, we demonstrate that YadA also triggers the production of interleukin-8 (IL-8) in host cells and we identify intracellular signal transduction mechanisms involved in YadA-initiated cell invasion and/or IL-8 synthesis. Tyrosine protein kinases, including the focal adhesion kinase (FAK) and c-Src, as well as the small GTPase Ras, were shown to play a significant role in both YadA-promoted cell processes. YadA-mediated cell contact led to autophosphorylation of FAK at position Tyr397 and induced GTP-loading of Ras. Furthermore, IL-8 production and invasion induced by YadA were strongly reduced in FAK- and c-Src-deficient cells and in cells overexpressing dominant interfering forms of FAK, c-Src or Ras. We also demonstrate that YadA activates the Ras-dependent Raf-MEK1/2-ERK1/2 pathway and mitogen-activated protein kinases (MAPKs) p38 and JNK. Moreover, inhibition of ERK1/2 by pharmacological agents or overexpression of dominant negative FAK, c-Src or Ras abrogated IL-8 release, whereas invasion remained unaffected. In contrast, actin polymerization and phosphatidylinositol 3-kinase (PI3K) activity is essential for YadA-promoted cell entry, but not for cytokine secretion. We conclude that YadA triggers FAK-Src complex formation and subsequent Ras activation, which leads to the stimulation of MAPKs-dependent IL-8 production or to PI3K-dependent invasion.
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PMID:Cell invasion and IL-8 production pathways initiated by YadA of Yersinia pseudotuberculosis require common signalling molecules (FAK, c-Src, Ras) and distinct cell factors. 1561 24

Macrophages respond to infection with pathogenic Yersinia species by activating MAPK- and NF-kappaB-signaling pathways. To counteract this response, Yersiniae secrete a protease (Yersinia outer protein J (YopJ)) that is delivered into macrophages, deactivates MAPK- and NF-kappaB-signaling pathways, and induces apoptosis. NF-kappaB promotes cell survival by up-regulating expression of several apoptosis inhibitor genes. Previous studies show that deactivation of the NF-kappaB pathway by YopJ is important for Yersinia-induced apoptosis. To determine whether deactivation of the NF-kappaB pathway is sufficient for Yersinia-induced apoptosis, two inhibitors of the NF-kappaB pathway, IkappaBalpha superrepressor or A20, were expressed in macrophages. Macrophages expressing these proteins were infected with Yersinia pseudotuberculosis strains that secrete functionally active or inactive forms of YopJ. Apoptosis levels were substantially higher (5- to 10-fold) when active YopJ was delivered into macrophages expressing IkappaBalpha superrepressor or A20, suggesting that deactivation of the NF-kappaB pathway is not sufficient for rapid Yersinia-induced apoptosis. When macrophages expressing A20 were treated with specific inhibitors of MAPKs, similar levels of apoptosis (within approximately 2-fold) were observed when active or inactive YopJ were delivered during infection. These results suggest that MAPK and NF-kappaB pathways function together to up-regulate apoptosis inhibitor gene expression in macrophages in response to Yersinia infection and that YopJ deactivates both pathways to promote rapid apoptosis. In addition, treating macrophages with a proteasome inhibitor results in higher levels of infection-induced apoptosis than can be achieved by blocking NF-kappaB function alone, suggesting that proapoptotic proteins are stabilized when proteasome function is blocked in macrophages.
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PMID:Inhibition of MAPK and NF-kappa B pathways is necessary for rapid apoptosis in macrophages infected with Yersinia. 1594

The Fraction 1 (F1) antigen of Yersinia pestis is known to induce thymocyte proliferation. It serves as a major protective antigen against challenge of Y. pestis. Recently, we reported rF1-induced activation of macrophages. Current investigation elucidates the role of p42/44 mitogen-activated protein kinases (MAPK)-mediated signal transduction in murine peritoneal macrophages on stimulation with rF1 (10 microg/ml) in vitro. The p42/44 MAPK activation was determined by studying the expression of the phosphorylated p42/44 MAPK in rF1-treated macrophages. PD98059, a specific inhibitor of MAPK kinase (MEK) inhibited the p42/44 MAPK phosphorylation, indicating the specificity of the above response. Furthermore, the rF1-induced phosphorylation of p42/44 MAPK is found to blocked by upstream protein kinase C inhibitor H7, tyrosine kinase inhibitor genistein and phosphoinositol-3-kinase (PI3-K) inhibitor wortmannin. Additionally, phosphorylation of JNK and activation of the transcription factor, c-jun and c-fos was also observed in response to rF1 treatment. The rF1-induced activation of p42/44 MAPK was correlated to the functional activation of macrophages by demonstrating the inhibition of actin rearrangement, IL-1, TNF-alpha and NO production caused by PD98059 in the rF1-treated macrophages.
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PMID:Phosphorylation of p42/44 MAP kinase is required for rF1-induced activation of murine peritoneal macrophages. 1595 Jul 34

Fraction 1 (F1) protein forms a capsule on the surface of Yersinia pestis. Recently, we reported rF1-induced activation of macrophages. In current investigation, we studied the role of JNK MAPK signal transduction pathway in rF1-induced activation of macrophages in vitro. SP600125, a specific inhibitor of JNK, inhibited JNK MAPK phosphorylation, indicating the specificity of the above response. Though, the rF1-induced phosphorylation of JNK MAPK was also inhibited by upstream protein kinase C inhibitor H7, tyrosine kinase inhibitor genestein and PI3-K inhibitor wotmannin. Activation of the transcription factor NF-kB (phosphorylation of IkB) and c-Jun was observed in response to rF1 treatment. The rF1-induced JNK MAPK activity was correlated to the functional activation of macrophages by demonstrating the inhibition of NO, TNF-alpha production and microtubule polymerization caused by SP600125. Taken together, the data suggests the involvement of JNK MAPK/NF-kB pathway in rF1-induced activation of macrophages.
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PMID:Involvement of c-Jun N-terminal kinase in rF1 mediated activation of murine peritoneal macrophages in vitro. 1598 Oct 86

Yersinia antigenic proteins LcrV and YopB are translocators of effector Yops in type III secretion system. Recently, we have reported that rLcrV and rYopB inhibit the production of TNF-alpha, IFN-gamma, and IL-12 in murine peritoneal macrophages. It was also demonstrated that IL-10 and TLR2 signaling pathways and inhibition of MAPK cascade is involved in rLcrV- and rYopB-induced immunomodulation. In the present study, it is reported that rLcrV and rYopB inhibited the LPS-induced production of IL-1beta in macrophages. Pretreatment of macrophages with rLcrV and rYopB also inhibited the LPS-induced transcription of IL-6 but not of GM-CSF. However, the transcription of chemokines like MCP-1, MIP-1alpha, MIP-1beta, and RANTES were inhibited by rLcrV and rYopB. Both proteins also affected the cytoskeleton and lipid rafts in macrophages. It is further observed that IL-10 antibodies abrogated the rLcrV- and rYopB-induced inhibition of IL-1beta production in LPS-treated macrophages. The data, therefore, suggests a possible role of IL-10 in rLcrV and rYopB mediated inhibition of LPS-induced production of IL-1beta in macrophages.
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PMID:Yersinia rLcrV and rYopB inhibits the activation of murine peritoneal macrophages in vitro. 1600 64

The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IkappaBalpha. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-kappaB signaling by selectively removing K63-linked polyubiquitin chains that activate IkappaB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IkappaBalpha. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.
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PMID:Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation. 1630 42

Pathogenic Yersinia spp. use a panel of virulence proteins that antagonize signal transduction processes in infected cells to undermine host defense mechanisms. One of these proteins, Yersinia enterocolitica outer protein P (YopP), down-regulates the NF-kappaB and MAPK signaling pathways, which suppresses the proinflammatory host immune response. In this study, we explored the mechanism by which YopP succeeds to simultaneously disrupt several of these key signaling pathways of innate immunity. Our data show that YopP operates upstream of its characterized eukaryotic binding partner IkappaB kinase-beta to shut down the NF-kappaB signaling cascade. Accordingly, YopP efficiently impaired the activities of TGF-beta-activated kinase-1 (TAK1) in infected cells. TAK1 is an important activator of the IkappaB kinase complex in the TLR signaling cascade. The repression of TAK1 activities correlated with reduced activation of NF-kappaB- as well as AP-1-dependent reporter gene expression in Yersinia-infected murine macrophages. This suggests that the impairment of the TAK1 enzymatic activities by Yersinia critically contributes to down-regulate activation of NF-kappaB and of MAPK members in infected host cells. The inhibition of TAK1 potentially results from the blockade of signaling events that control TAK1 induction. This process could involve the attenuation of ubiquitination of the upstream signal transmitter TNFR-associated factor-6. Together, these results indicate that, by silencing the TAK1 signaling complex, Yersinia counteracts the induction of several conserved signaling pathways of innate immunity, which aids the bacterium in subverting the host immune response.
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PMID:Yersinia outer protein P suppresses TGF-beta-activated kinase-1 activity to impair innate immune signaling in Yersinia enterocolitica-infected cells. 1633 60

Yersinia species use a variety of type III effector proteins to target eukaryotic signaling systems. The effector YopJ inhibits mitogen-activated protein kinase (MAPK) and the nuclear factor kappaB (NFkappaB) signaling pathways used in innate immune response by preventing activation of the family of MAPK kinases (MAPKK). We show that YopJ acted as an acetyltransferase, using acetyl-coenzyme A (CoA) to modify the critical serine and threonine residues in the activation loop of MAPKK6 and thereby blocking phosphorylation. The acetylation on MAPKK6 directly competed with phosphorylation, preventing activation of the modified protein. This covalent modification may be used as a general regulatory mechanism in biological signaling.
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PMID:Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. 1673 19

Yersinia enterocolitica invasin (Inv) protein confers internalization into and expression of proinflammatory cytokines by host cells. Both events require binding of Inv to beta1 integrins, which initiates signaling cascades including activation of focal adhesion complexes, Rac1, mitogen-activated protein kinase, and NF-kappaB. Here we tested whether Inv might be suitable as a delivery molecule and adjuvant if used as a component of a vaccine. For this purpose, hybrid proteins composed of Inv and ovalbumin (OVA) were prepared, applied as a coating to microparticles, and used for vaccination. Fusion of OVA to Inv did not significantly disturb the ability of Inv to promote host cell binding, internalization, and interleukin-8 (IL-8) secretion when applied as a coating to microparticles. The microparticles were used for vaccination of mice adoptively transferred with OVA-specific T cells from OT-1 or DO11.10 mice. Administration of OVA-Inv-coated microparticles induced OVA-specific T-cell responses. OVA-specific CD4 T cells produced both gamma interferon (IFN-gamma) and IL-4 as determined by enzyme-linked immunosorbent assay. Likewise, pronounced OVA-specific CD8 T-cell responses associated with IFN-gamma production were observed. Together, these results suggest that Inv might be an attractive tool in vaccination as it confers both host cell uptake and adjuvant activity by engagement of beta1 integrins of host cells, which leads to CD4 as well as CD8 T-cell responses.
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PMID:The Yersinia enterocolitica invasin protein promotes major histocompatibility complex class I- and class II-restricted T-cell responses. 1679 Aug 6

Innate immunity comprises physical barriers, pattern-recognition receptors, antimicrobial substances, phagocytosis, and fever. Here we report that increased temperature results in the activation of a conserved pathway involving the heat-shock (HS) transcription factor (HSF)-1 that enhances immunity in the invertebrate Caenorhabditis elegans. The HSF-1 defense response is independent of the p38 MAPK/PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins. In addition, HSF-1 is needed for the effects of the DAF-2 insulin-like pathway in defense to pathogens, indicating that interacting pathways control stress response, aging, and immunity. The results also show that HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis, indicating that HSF-1 is part of a multipathogen defense pathway. Considering that several coinducers of HSF-1 are currently in clinical trials, this work opens the possibility that activation of HSF-1 could be used to boost immunity to treat infectious diseases and immunodeficiencies.
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PMID:Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. 1691 33


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