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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages are activated during an inflammatory response and produce multiple inflammatory cytokines. IL-18 is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. Monocyte chemoattractant protein (MCP-1) is expressed in many inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, and its expression is correlated with the severity of the disease. Both IL-18 and MCP-1 have been shown to be involved in inflammatory immune responses. However, it has been unclear whether IL-18 is involved in the induction of MCP-1. This investigation was initiated to determine whether IL-18 can induce MCP-1 production, and if so, by which signal transduction pathways. We found that IL-18 induced the production of MCP-1 in macrophages, which was IL-12-independent and was not mediated by autocrine cytokines such as IFN-gamma or TNF-alpha. We then examined signal transduction pathways involved in IL-18-induced MCP-1 production. We found that IL-18 did not activate the IkappaB kinase/NF-kappaB pathway, evidenced by no degradation of IkappaBalpha and no translocation of NF-kappaB p65 to the nucleus in IL-18-stimulated macrophages. Instead, IL-18 activated the PI3K/Akt and MEK/ERK1/2 pathways. Inhibition of either of these pathways attenuated MCP-1 production in macrophages, and inhibition of both signaling pathways resulted in the complete inhibition of MCP-1 production. On the basis of these observations, we conclude that IL-18 induces MCP-1 production through the PI3K/Akt and MEK/ERK1/2 pathways in macrophages.
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PMID:IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. 1633 68

MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that functions upstream of the MAP kinases and IkappaB kinase. Phosphorylation is believed to be a critical component for MEKK3-dependent signal transduction, but little is known about the phosphorylation sites of this MAP3K. To address this question, point mutations were introduced in the activation loop (T-loop), substituting alanine for serine or threonine, and the mutants were transfected into HEK293 Epstein-Barr virus nuclear antigen cells. MEKK3-dependent activation of an NF-kappaB reporter gene as well as ERK, JNK, and p38 MAP kinases correlated with a requirement for serine at position 526. Constitutively active mutants of MEKK3, consisting of S526D and S526E, were capable of activating a NF-kappaB luciferase reporter gene as well as ERK and MEK, suggesting that a negative charge at Ser526 was necessary for MEKK3 activity and implicating Ser526 as a phosphorylation site. An antibody was developed that specifically recognized phospho-Ser526 of MEKK3 but did not recognize the S526A point mutant. The catalytically inactive (K391M) mutant of MEKK3 was not phosphorylated at Ser526, indicating that phosphorylation of Ser526 occurs via autophosphorylation. Endogenous MEKK3 was phosphorylated on Ser526 in response to osmotic stress. In addition, phosphorylation of Ser526 was required for MKK6 phosphorylation in vitro, whereas dephosphorylation of Ser526 was mediated by protein phosphatase 2A and sensitive to okadaic acid and sodium fluoride. Finally, the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented dephosphorylation of Ser526. In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins.
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PMID:Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation. 1640 1

The interleukin-17B receptor (IL-17BR) is expressed in a variety of tissues and is upregulated under inflammatory conditions. This receptor binds both its cognate ligand IL-17B and IL-17E/IL-25, a novel cytokine known to promote Th2 responses. The present study shows that airway smooth muscle cells express IL-17BR in vitro and that its expression is upregulated by TNF-alpha and downregulated by IFN-gamma. Our data indicate that TNF-alpha upregulates IL-17BR mainly through nuclear factor-kappaB as assessed with the IkappaB kinase 2 inhibitor AS-602868. In addition, both IFN-gamma and dexamethasone are able to antagonize a TNF-alpha-induced IL-17BR increase in mRNA expression. The mitogen-activated protein kinase kinase inhibitor U0126 totally reversed the inhibition observed with IFN-gamma, suggesting the involvement of the extracellular signal-regulated kinase pathway in this effect. In addition, on stimulation with IL-17E, airway smooth muscle cells increase their expression of ECM components, namely procollagen-alphaI and lumican mRNA. Furthermore, immunohistochemical analysis of biopsies from asthmatic subjects reveals that this receptor is abundant in smooth muscle layers. This is the first report showing IL-17BR receptor in structural cells of the airways. Our results suggest a potential proremodeling effect of IL-17E on airway smooth muscle cells through the induction of ECM and that its receptor is upregulated by proinflammatory conditions.
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PMID:TNF-alpha and IFN-gamma inversely modulate expression of the IL-17E receptor in airway smooth muscle cells. 1642 71

Helicobacter pylori, the etiological agent of various human gastric diseases, induces the transcription factor nuclear factor kappaB (NF-kappaB) and proinflammatory cytokines/chemokines. We have characterised the direct interaction between p21-activated kinase 1 (PAK1) and NF-kappaB-inducing kinase (NIK) in H. pylori-infected epithelial cells. The dimerisation (DI) motif, which is part of the NH2-terminal autoregulatory domain of PAK1, is critical for this interaction, whereas NIK forms complexes with PAK1 through its carboxy-terminal IkappaB kinase alpha (IKKalpha) binding site. Since the identified interaction sites are also crucial for the binding of activator (Rac/Cdc42 in the case of PAK1) or effector molecules (IKKalpha in the case of NIK), sequential stepwise signalling is suggested. Furthermore, we show that mitogen-activated protein kinase kinase kinases (MAP3K), like TPL2 (tumour progression locus 2) and transforming growth factor beta-activated kinase 1 (TAK1), have no impact on H. pylori-induced activation of NF-kappaB. These results identify the roles of PAK1 and NIK in a unique pathway involved in H. pylori-induced NF-kappaB activation, which is crucial for the induction of the innate immune response.
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PMID:The PAK1 autoregulatory domain is required for interaction with NIK in Helicobacter pylori-induced NF-kappaB activation. 1649 67

The vasoactive hormone angiotensin II (Ang II) probably triggers inflammatory cardiovascular diseases by activating transcription factors such as NF-kappaB. We describe here a novel mode of NF-kappaB activation in cultured vascular smooth muscle cells exposed to Ang II. Ang II treatment resulted in an increase in the phosphotransferase activity of the IKK complex, which was mediated through the AT1 receptor subtype. The typical phosphorylation and proteasome-dependent degradation of the NF-kappaB inhibitor IkappaBalpha were not observed. Rather, Ang II treatment of vascular smooth muscle cells led to the phosphorylation of p65 on serine 536, a signal detected in both the cytoplasm and the nuclear compartments. The use of pharmacological inhibitors that inhibit the activation of MEK by Ang II revealed that phosphorylation of p65 on serine 536 did not require the MEK-ERK-RSK signaling pathway. On the other hand, specifically targeting the IKKbeta subunit of the IKK complex by overexpression of a dominant negative version of IKKbeta (IKKbeta K44A) or silencing RNA technology demonstrated that the IKKbeta subunit of the IKK complex was responsible for the detected phosphoserine 536 signal in Ang II-treated cells. Characterization of the signaling pathway leading to activation of the IKK complex by Ang II revealed that neither epidermal growth factor receptor transactivation nor the phosphatidylinositol 3-kinase-AKT signaling cascade were involved. Collectively, our data demonstrate that the proinflammatory activity of Ang II is independent of the classical pathway leading to IkappaBalpha phosphorylation and degradation but clearly depends on the recruitment of an IKK complex signaling cascade leading to phosphorylation of p65 on serine 536.
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PMID:The proinflammatory actions of angiotensin II are dependent on p65 phosphorylation by the IkappaB kinase complex. 1651 50

The diabetes-prone biobreeding (BB-DP) rat contains the lyp mutation which results in lymphopenia and promotes the progression of a T cell-mediated autoimmune attack of the pancreas in certain rat strains. This mutation has been mapped to a gene which bears homology to human Gimap5/Ian5 and results in the truncation and loss of activity of this protein. The lymphopenic state induced by the loss of this protein has led to the proposal that Gimap5 has an anti-apoptotic function. Previously we described an additional phenotype of incomplete activation mediated by the loss of Gimap5 function. Here we further characterize this incomplete activation phenotype and map a potential signal transduction pathway leading to activation. We show that CD5 expression on peripheral T cells is elevated in Gimap5 animals, while thymocyte expression remains similar between the two strains. Additionally, we show that NF-kappaB but not NFAT is activated in unstimulated Gimap5 mutant T cells as compared to unstimulated wild type T cells. Mapping this activation to its upstream source we show that activation of NF-kappaB is correlated with an activation of IKK. Using a variety of kinase inhibitors we further map this increase in IKK to an increase in MEK activation. Finally, to counter the possibility that activation is an indirect consequence of the lymphopenic environment, we created bone marrow chimeras in which Gimap5 mutant T cells developed in a normal environment and show that these cells retain their activated phenotype. Together, we interpret these data as demonstrating that the activation caused by loss of Gimap5 is a cell intrinsic phenomenon caused, in part, by a MEK-dependent activation of IKK. This, in turn, would suggest that Gimap5 functions to promote both T cell survival and quiescence and that these pathways are biochemically linked.
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PMID:Loss of a gimap/ian gene leads to activation of NF-kappaB through a MAPK-dependent pathway. 1658 74

Osteopontin (OPN) is a secreted, non-collagenous, sialic-acid rich, glycosylated adhesive phospho- protein. Several highly metastatic transformed cells synthesized a higher level of OPN compared with non-tumorigenic cells. We have recently reported that OPN induces nuclear factor-kappaB (NF-kappaB)-mediated promatrix metalloproteinase-2 activation through IkappaBalpha/IKK signaling pathways. However, the molecular mechanism(s) by which OPN regulates pro-matrix metalloproteinase-9 (pro-MMP-9) activation and involvement of upstream kinases in regulation of these processes that ultimately control cell motility and tumor growth in murine melanoma cells are not well defined. Here we report that OPN induces alphavbeta3 integrin-mediated phosphorylation and activation of nuclear factor inducing kinase (NIK) and enhances the interaction between phosphorylated NIK and IkappaBalpha kinase alpha/beta (IKKalpha/beta) in B16F10 cells. Moreover, NIK is involved in OPN-induced phosphorylations of MEK-1 and ERK1/2 in these cells. OPN induces NIK-dependent NF-kappaB activation through ERK/IKKalpha/beta-mediated pathways. Furthermore, OPN enhances NIK-regulated urokinase-type plasminogen activator (uPA) secretion, uPA-dependent pro-MMP-9 activation, and cell motility. Pretreatment of cells with anti-MMP-2 antibody along with anti-MMP-9 antibody drastically inhibited the OPN-induced cell migration and chemoinvasion, whereas cells pretreated with anti-MMP-2 antibody had no effect on OPN-induced pro-MMP-9 activation suggesting that OPN induces pro-MMP-2 and pro-MMP-9 activations through two distinct pathways. Taken together, NIK acts as crucial regulator in OPN-induced MAPK/IKK-mediated NF-kappaB-dependent uPA secretion and MMP-9 activation thereby controlling melanoma cell motility and chemoinvasion.
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PMID:Nuclear factor inducing kinase: a key regulator in osteopontin- induced MAPK/IkappaB kinase dependent NF-kappaB-mediated promatrix metalloproteinase-9 activation. 1669 5

Benzo[alpha]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), the major metabolite of benzo[a]pyrene (B[a]P), shows an ultimate complete carcinogen in various animals and is a causative agent for human cancers. However, its effects on the activation of signal pathways and the expression of genes involved in its carcinogenic effect remain largely unknown. In this study, the effects of B[a]PDE on induction of cyclooxygenase (COX)-2 and the signal pathways leading to the induction were investigated. Treatment of mouse epidermal Cl41 cells with B[a]PDE caused an increase in the expression of COX-2 at both transcription and protein levels, while its parental compound B[a]P did not show significant inductive effect. The COX-2 induction by B[a]PDE was dependent on the activation of mitogen-activated protein kinases (MAPK)s/activation protein (AP)-1 pathway, because inhibition of AP-1 by either overexpression of TAM67 (dominant negative mutant of c-jun), or pretreatment of cells with PD98059 (MEK1/2-ERKs pathway inhibitor) or SB202190 (p38K inhibitor), markedly inhibited B[a]PDE-induced COX-2 expression. In addition, impairment of NF-kappaB pathway by either NEMO-BDBP (an NF-kappaB specific inhibitor) or IkappaB kinase (IKK)beta-KM (dominant negative mutant of IKKbeta) also caused marked reduction of COX-2 induction by B[a]PDE. In contrast, inhibition of nuclear factor of activated T cells (NFAT) with FK506, did not show any effect on B[a]PDE-induced COX-2 expression. Collectively, these data indicate that exposure of Cl41 cells to B[a]PDE can induce COX-2 expression by increasing its transcription, which requires the activation of MAPKs/AP-1 and IKKbeta/NF-kappaB pathways, but not NFAT pathway. In view of the importance of COX-2 in carcinogenesis, we anticipate that the induction of COX-2 by B[a]PDE may coordinate its mutagenic effects to facilitate the development of skin cancer.
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PMID:Benzo[a]pyrene diol-epoxide (B[a]PDE) upregulates COX-2 expression through MAPKs/AP-1 and IKKbeta/NF-kappaB in mouse epidermal Cl41 cells. 1692 90

Verotoxin (VT)-producing Escherichia coli (E. coli) O157:H7 infections are frequently complicated by thrombotic angiopathy, hemolytic uremic syndrome (HUS) and neurological symptoms. The present data demonstrate that VT-1 (Shiga toxin) stimulation of macrophage-like THP-1 cells up-regulates the activity, antigen and mRNA levels of tissue factor (TF), a key cofactor of the coagulation-inflammation-thrombosis circuit. This up-regulation is accompanied by phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase), IkappaB kinase beta (IKKbeta) and extracellular signal-regulated kinase 2 (ERK2). Changes in TF mRNA levels were in parallel with the activation of NF-kappaB/Rel and Egr-1 activation, but not with AP-1. Inhibition of PI3-kinase attenuated VT-1-induced phosphorylation of IKKbeta and ERK2, and the up-regulation of TF mRNA levels. VT-1 stimulation rapidly activated c-Yes tyrosine kinase, a member of the Src family. Treatment of the cells with c-Yes antisense oligos attenuated the VT-1-induced phosphorylation of PI3-kinase, IKKbeta and ERK2, activations of NF-kappaB/Rel and Egr-1, and up-regulation of TF mRNA levels. These results suggest that VT-1-induced macrophage stimulation activates c-Yes, which then up-regulates TF expression through activation of the IKKbeta/proteasome/NF-kappaB/Rel and MEK/ERK2/Egr-1 pathways via activation of PI3-kinase. Induction of macrophage TF expression by VT-1 may play an important role in the acceleration of the coagulation-inflammation-thrombosis circuit during infections by VT-producing E. coli.
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PMID:Verotoxin-1 stimulation of macrophage-like THP-1 cells up-regulates tissue factor expression through activation of c-Yes tyrosine kinase: Possible signal transduction in tissue factor up-regulation. 1693 Sep 53

Toll-like receptors (TLRs) are a recently described receptor class involved in the regulation of innate and adaptive immunity. Here, we demonstrate that arrestin-2 and GRK5 (G protein-coupled receptor kinase 5), proteins that regulate G protein-coupled receptor signaling, play a negative role in TLR4 signaling in Raw264.7 macrophages. We find that lipopolysaccharide (LPS)-induced ERK1/2 phosphorylation is significantly enhanced in arrestin-2 and GRK5 knockdown cells. To elucidate the mechanisms involved, we tested the effect of arrestin-2 and GRK5 knockdown on LPS-stimulated signaling components that are upstream of ERK phosphorylation. Upon LPS stimulation, IkappaB kinase promotes phosphorylation and degradation of NFkappaB1 p105 (p105), which releases TPL2 (a MAP3K), which phosphorylates MEK1/2, which in turn phosphorylates ERK1/2. We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation. GRK5 knockdown also results in enhanced IkappaB kinase-mediated p105 phosphorylation and degradation, whereas GRK2 and GRK6 knockdown have no effect on this pathway. In vitro analysis demonstrates that arrestin-2 directly binds to the COOH-terminal domain of p105, whereas GRK5 binds to and phosphorylates p105. Taken together, these results suggest that p105 phosphorylation by GRK5 and binding of arrestin-2 negatively regulates LPS-stimulated ERK activation. These results reveal that arrestin-2 and GRK5 are important negative regulatory components in TLR4 signaling.
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PMID:Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. 1698 Mar 1


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