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:2.7.11.25 (MEKK1)
1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Axin is a multidomain protein that coordinates a variety of critical factors in Wnt signaling and JNK activation. In this study, we found that overexpression of Axin leads to apoptosis in several cell lines. A mutant Axin (Axin-deltaMID) that does not contain the MEKK1-interacting domain and is not capable of activating JNK, has less apoptotic effect. Together with the observations that dominant-negative forms of MEKK1 and JNK1 can attenuate Axin-induced apoptosis, we suggest that JNK activation is required for Axin-mediated apoptosis. Wild-type Axin proteins that can lead to destabilization of beta-catenin are more effective at causing cell death than those constructs (Axin-deltaGSK/beta-cat, Axin-deltaRGS/GSK/beta-cat) that are defective in regulation of beta-catenin but still fully capable of JNK activation. Furthermore, enhanced beta-catenin signaling by coexpression of beta-catenin or PP2C alpha attenuate cell death. Taken together, we suggest that the ability of Axin to induce apoptosis is determined by its ability to activate JNK and destabilize beta-catenin.
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PMID:Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels. 1087 18

The TAK1 MAPKKK mediates activation of JNK and NF-KB in the IL-1-activated signaling pathway. Here we report the identification of TAB2, a novel intermediate in the IL-1 pathway that functionally links TAK1 to TRAF6. Expression of TAB2 induces JNK and NF-kappaB activation, whereas a dominant-negative mutant TAB2 impairs their activation by IL-1. IL-1 stimulates translocation of TAB2 from the membrane to the cytosol where it mediates the IL-1-dependent association of TAK1 with TRAF6. These results define TAB2 as an adaptor linking TAK1 and TRAF6 and as a mediator of TAK1 activation in the IL-1 signaling pathway.
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PMID:TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. 1088 1

The transcriptional induction of SPRR1B by phorbol 12-myristate 13-acetate (PMA) is mainly mediated by the first -152-base pair 5'-flanking region containing two functional AP-1 sites. In this study, we have analyzed the signaling pathways that mediate the induction in tracheobronchial epithelial cells. PKC inhibitor ablated PMA-stimulated expression of endogenous SPRR1B and reporter gene expression driven by SPRR1B promoter. PKC activator promoted the transcription. The dominant negative protein kinase Cdelta (dn-PKCdelta) and rottlerin (PKCdelta inhibitor) completely suppressed PMA-stimulated promoter activity. dn-Ras or dn-MEKK1 inhibited PMA-stimulated promoter activity, while their corresponding constitutively active mutants augmented it. dn-c-Raf-1 did not have any effect on reporter gene expression. Since MEKK1 activates multiple parallel pathways, we examined involvement of JNK/SAPK, p38, and MKK1 in promoter regulation. Co-expression of the dominant negative forms of MKK4, MKK7, JNK/SAPK, MKK3, MKK6, or p38alpha did not suppress PMA-stimulated reporter gene expression. However, MKK1 inhibitors UO126 and PD98095 suppressed gene expression. Consistent with this, expression of dn-MKK1 strongly suppressed PMA-stimulated promoter activity, while the constitutively active MKK1 augmented it. However, MKK1-mediated induction of SPRR1B probably does not depend on extracellular signal-regulated kinases 1 and 2, suggesting the requirement of another kinase(s). dn-c-Jun mutants abolished PMA-stimulated expression supporting an important role for AP-1 proteins in SPRR1B expression. Together, these results suggest that a PKCdelta/Ras/MEKK1/MKK1-dependent/AP-1 pathway regulates the PMA-inducible expression of the SPRR1B in tracheobronchial epithelial cells.
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PMID:Phorbol ester-induced expression of airway squamous cell differentiation marker, SPRR1B, is regulated by protein kinase Cdelta /Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway. 1091 63

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are pleiotropic cytokines that activate two transcription factors, Activator Protein-1 (AP-1) and Nuclear Factor-kappa B (NF-kappa B). Apoptosis signal-regulating kinase 1 (ASK 1) is a mitogen-activated protein (MAP) kinase kinase kinase (MAPKKK) that is activated by TNF and IL-1, and stimulates c-Jun N-terminal kinase (JNK also known as SAPK; stress-activated protein kinase) and p38 activation. Through genetic screening for ASK 1-binding proteins, Transforming Growth Factor beta (TGF-beta)-activated kinase (TAK 1), another MAPKKK family protein, was identified. Here we report that ASK 1 binds to TAK 1 and dissociates TAK 1 from TNF receptor-associated factor 6 (TRAF 6), and inhibits TAK 1- and TRAF 6-, but not NF-kappa B-inducing kinase (NIK)-induced NF-kappa B activation.
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PMID:[Functional analysis of apoptosis signal-regulating kinase 1 (ASK 1)-binding proteins]. 1092 Dec 42

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the MAPKKK family in the JNK and p38 mitogen-activated protein kinase cascades and critically involved in stress- and cytokine-induced apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) is a pivotal regulator of immune and inflammatory responses and exerts anti-apoptotic roles in various cells. Here we show that ASK1 directly interacts with transforming growth factor-beta-activated kinase 1 (TAK1), another MAPKKK that has been identified as a signaling intermediate in the interleukin 1 (IL-1)-induced NF-kappaB pathway as well as the transforming growth factor-beta superfamily-induced JNK/p38 pathway. Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced, but not NF-kappaB-inducing kinase-induced, NF-kappaB activation. ASK1 dissociates TAK1 but not NF-kappaB-inducing kinase from TRAF6. Moreover, IL-1-induced complex formation of endogenous TAK1 and TRAF6 was blocked by ASK1 overexpression. It thus appears that the inhibition of NF-kappaB by ASK1 may result at least in part from the disruption of the TRAF6.TAK1 complex formation in the IL-1 signaling pathway. These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPKKKs in the same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB.
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PMID:ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction. 1092 14

A novel mixed lineage kinase-like protein ZAK, containing a leucine-zipper (LZ) and a sterile-alpha motif (SAM), was cloned. This cDNA has 2456 bp and encodes a protein of 800 amino acids that contains a kinase catalytic domain, a leucine-zipper and a SAM. The molecular weight of this protein is 91kDa. Northern blot analysis revealed that the expression of this ZAK gene is found in various parts of human tissues. We also found that ZAK proteins might form homodimers or oligomers in mammalian cells. MLKs have been proposed to function as mitogen-activated protein kinase kinase kinase in pathways leading to MAPK cascade. The expression of ZAK in mammalian cells specifically leads to the activation of the JNK/SAPK pathway as well as the activation of transcription factor, NF-kappaB. Overexpression of the ZAK gene induces the apoptosis of a hepatoma cell line.
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PMID:Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. 1092 58

Mitogen-activated protein kinase (MAPK) cascades are the major signaling systems transducing extracellular signals into intracellular responses, which mainly include the extracellular signal-regulated kinase (ERK) pathway, the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, and the p38 pathway. From dendritic cell cDNA library, we isolated a full-length cDNA encoding a potentially novel 898-residue kinase, which was designated DPK. The protein contained a potential kinase domain at the N-terminal exhibiting homology with MEKK1-, MEKK2-, MEKK3-, MEKK4-, MEKK5-, Tpl-2-, and p21-activated kinases (PAKs), but no GTPase-binding domain which is characteristic of PAKs. Northern blotting analysis showed that DPK was ubiquitously expressed in normal tissues, with abundant expression in kidney, skeletal muscle, heart, and liver. When overexpressed in transfected NIH3T3 cells, it could activate both the ERK1/ERK2 pathway and the SAPK pathway in a dose-dependent manner, but not affect the p38 pathway. These findings suggested that DPK might be a novel candidate MAPKKK.
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PMID:Cloning of DPK, a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/SAPK pathways. 1092 69

The monofunctional alkylating agent N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is a widespread environmental carcinogen that causes DNA lesions, leading to cell death. However, MNNG can also trigger a cell-protective response by inducing the expression of DNA repair/transcription-related genes. We demonstrate that the urokinase-type plasminogen activator (uPA) gene product, a broad spectrum extracellular protease to which no DNA repair function has been assigned, is transcriptionally induced by MNNG in C2C12 and NIH3T3 cells. This induction required an AP1-enhancer element located at -2.4 kilobase (kb), because it was abrogated by deletion of this site. MNNG was found to induce the activation of JNK/SAPK and p38 mitogen-activated protein kinases (MAPKs). Accordingly, we attempted to assess the contribution of each of these MNNG-inducible MAPKs to uPA gene induction by this alkylating agent. Coexpression of dominant negative versions of kinases of the JNK pathway, such as catalytically inactive forms of MEKK1, MKK7, and JNKK, and of cytoplasmic JNK-inhibitor JIP-1, as well as treatment of cells with curcumin (which blocks JNK activation by MNNG), inhibited MNNG-induced uPA transcriptional activity. In contrast, neither dominant negative MKK6 nor SB203580, which specifically inhibit p38 MAP kinase activation, abrogated the MNNG-induced effect. Taken together, our results show that the JNK signaling pathway links external MNNG stimulation and AP1-dependent uPA gene expression, providing the first functional dissection of a transcription-coupled signal transduction pathway for MNNG. (Blood. 2000;96:1415-1424)
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PMID:The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. 1094 86

Mitogen-activated protein (MAP) kinase cascades are involved in transmitting signals that are generated at the cell surface into the cytosol and nucleus and consist of three sequentially acting enzymes: a MAP kinase, an upstream MAP/extracellular signal-regulated protein kinase (ERK) kinase (MEK), and a MEK kinase (MEKK). Protein-protein interactions within these cascades provide a mechanism to control the localization and function of the proteins. MEKK1 is implicated in activation of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and ERK1/2 MAP kinase pathways. We showed previously that MEKK1 binds directly to JNK/SAPK. In this study we demonstrate that endogenous MEKK1 binds to endogenous ERK2, MEK1, and another MEKK level kinase, Raf-1, suggesting that it can assemble all three proteins of the ERK2 MAP kinase module.
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PMID:MEKK1 binds raf-1 and the ERK2 cascade components. 1096 79

Optimal activation of Rel/NF-kappaB transcription factors in T lymphocytes requires a CD28-delivered co-stimulatory signal in addition to TCR engagement. Although, Rel/NF-kappaB transcription factors are critical regulators of many T cell functions, the mechanisms and molecules, which link the surface receptors to their activation, are poorly characterized. Using Jurkat T cells stimulated with superantigen presented on B7-positive APC, we showed that CD28- and TCR-stimulated NF-kappaB-dependent transcription is associated to the activation of IkappaB kinase beta (IKKbeta) and, to a lesser extent, of IkappaB kinase alpha (IKKalpha). A dominant negative mutant of the MAP3 kinase MEKK1, a kinase known to regulate the JNK pathway and to activate NF-kappaB-dependent transcription in many cell types, strongly inhibits CD28- and TCR-induced IKK activity, whereas the dominant negative mutants of the NF-kappaB-inducing kinase (NIK) did not exert any significant effects. In addition, TCR/CD28 stimulation results in the recruitment and autophosphorylation of endogenous MEKK1, whereas endogenous NIK was not detectably activated. Our data identify MEKK1 as a critical step in coupling signals initiated by TCR and CD28 to the downstream pathways which lead to both AP-1 and NF-kappaB activation in T lymphocytes.
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PMID:Mitogen-activated kinase kinase kinase 1 regulates T cell receptor- and CD28-mediated signaling events which lead to NF-kappaB activation. 1100 75


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