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)

Extracellular signals are transduced into cells through mitogen-activated protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a protein, JLP (c-Jun NH2-terminal kinase-associated leucine zipper protein), which acts as a scaffolding protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
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PMID:JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. 1239 7

Mitogen-activated protein kinase (MAPK) cascades are central components of signal transduction pathways induced by mitogens and stresses. They consist of a three-kinase module in which a mitogen-activated protein kinase kinase kinase (MAP3K) activates a mitogen-activated protein kinase kinase (MAP2K), which in turn activates MAPK. The molecular determinants that underlie specific MAP3K-MAP2K interactions are poorly understood. In this study, we examined the interaction between the MAP3K MEKK1 and MKK4, a MAP2K of the JNK pathway. Select point mutations in subdomain X of the catalytic domain of MEKK1 (MEKK1delta) were found to impair the ability of MEKK1delta to bind to and activate MKK4. Such mutations were also found to impair MEKK1delta-induced activation of an AP1 reporter gene. These studies point to a critical role for subdomain X in the interaction of MEKK1 with MKK4.
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PMID:A subdomain of MEKK1 that is critical for binding to MKK4. 1240 21

MEKK1 is a MAPK kinase kinase that is activated in response to stimuli that alter the cytoskeleton and cell shape. MEKK1 phosphorylates and activates MKK1 and MKK4, leading to ERK1/2 and JNK activation. MEKK1 has a plant homeobox domain (PHD) that has been shown to have E3 ligase activity. (Lu, Z., Xu, S., Joazeiro, C., Cobb, M. H., and Hunter, T. (2002) Mol. Cell 9, 945-956). MEKK1 kinase activity is required for ubiquitylation of MEKK1. MEKK1 ubiquitylation is inhibited by mutation of cysteine 441 to alanine (C441A) within the PHD. The functional consequence of MEKK1 ubiquitylation is the inhibition of MEKK1 catalyzed phosphorylation of MKK1 and MKK4 resulting in inhibition of ERK1/2 and JNK activation. The C441A mutation within the PHD of MEKK1 prevents ubiquitylation and preserves the ability of MEKK1 to catalyze MKK1 and MKK4 phosphorylation. MEKK1 ubiquitylation represents a mechanism for inhibiting the ability of a protein kinase to phosphorylate substrates and regulate downstream signaling pathways.
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PMID:Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. 1245 88

MAP kinase pathways comprise a group of parallel protein phosphorylation cascades, which are involved in signaling triggered by a variety of stimuli. Previous findings suggested that the ERK and the JNK pathways have opposing roles in regulating proliferation and survival or apoptosis and that apoptosis can be promoted by inhibiting the ERK pathway or by activation of the JNK pathway. In order to test this hypothesis and explore whether it can be exploited as a strategy for killing human cancer cells, we used gene transfer experiments with a range of cancer cell lines. We expressed the catalytic fragment of human MEKK1 to activate JNK and the Ras-binding domain (RBD) of Raf-1 to inhibit the Ras-ERK pathway. In addition, we designed several RBD-MEKK1 fusion proteins aiming to simultaneously activate the JNK and block the ERK pathway. We found that the MEKK1 proteins as well as the RBD alone could reduce colony formation in all cell lines. The survival time of MEKK1-expressing cells depended on the cell line. In HeLa cells, survival could be prolonged by inhibition of caspases but not by coexpression of the anti-apoptotic protein Bcl-2. Due to a lower kinase activity the RBD-MEKK1 fusion proteins were less effective in apoptosis induction than the MEKK1 kinase domain alone. Using mutant forms of Ras and Raf-1 we could show that the reduced kinase activity of RBD-MEKK1 fusion proteins was caused by binding to the Ras protein. The expression of lethal doses of MEKK1 resulted in a strong activation of all three major MAP kinase families JNK, ERK, and p38. Blocking these pathways either by coexpressing a dominant negative form of MKK4 or with inhibitors of MEK or p38 failed to inhibit apoptosis. This suggests that MEKK1 induces apoptosis by causing a general deregulation of MAP kinase signaling rather than by the activation of a single pathway.
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PMID:The kinase domain of MEKK1 induces apoptosis by dysregulation of MAP kinase pathways. 1256 21

MAPK/ERK kinase kinase 2 (MEKK2) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family of protein kinases. MAP3Ks are components of a three-tiered protein kinase pathway in which a MAP3K phosphorylates and activates a mitogen-activated protein kinase kinase (MAP2K), which in turn activates a mitogen-activated protein kinase (MAPK). We have previously identified residues within protein kinase subdomain X in the MAP3K, MEKK1, that are critical for its interaction with the MAP2K, MKK4, and MEKK1-induced MKK4 activation. We report here that kinase subdomain X also plays a critical role in MEKK2 activity. Select point mutations in subdomain X impair MEKK2 phosphorylation of the MAP2Ks, MKK7 and MEK5, abolish MEKK2-induced activation of the MAPKs, JNK1 and ERK5, and diminish MEKK2-dependent activation of an AP-1 reporter gene. Interestingly, the spectrum of mutations in subdomain X of MEKK2 that affects its activity is overlapping with but not identical to those that have effects on MEKK1. Thus, mutations in subdomain X differentially affect MEKK2 and MEKK1.
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PMID:Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. 1265 51

Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.
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PMID:TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3. 1276 57

DNA damaging agents such as 1-beta-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are widely used in the treatment of acute nonlymphocytic leukemia. These drugs have, of course, been the objects of intense basic research, as well as preclinical and clinical study. Although specific biochemical lesions (DNA damage) have been associated with Ara-C- and DNR-mediated cytotoxicity, the pathways leading to the induction of apoptosis remain ill defined. This standpoint has forced investigators to explore a new concept in cell response to cytotoxic stress: apoptosis signaling. The recent identification of a ceramide (CER) mediated apoptotic signaling pathway triggered by antitumor agents offers a new perspective for the treatment of neoplastic cells. Indeed, these agents have been shown to induce apoptosis through the activation of a sphingomyelinase (SMase) responsible for the hydrolysis of sphingomyelin (SM) and the generation of CER. The latter acts as a potent apoptosis mediator, triggering several downstream signaling pathways among which the stress-activated protein kinase cascade (MEKK1-SEK1-SAP/JNK) plays a critical role in apoptosis induction. However, the spacio-temporal organization of the key early signaling events is unclear. The present review delineates what appears to be a critical factor in apoptosis signaling: sphingomyelin enriched plasma membrane rafts. The apparent topological partitioning between DNA damage and apoptosis signaling (integrated into specialized plasma membrane domains) is discussed.
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PMID:Implication of raft microdomains in drug induced apoptosis. 1276 72

Apoptosis occurs in influenza virus (IV)-infected cells. There are a number of mechanisms for the regulation of apoptosis. However, the molecular mechanism of IV infection-induced apoptosis is still controversial. Apoptosis signal-regulating kinase1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the SEK1-c-Jun N-terminal kinase (JNK) and MKK3/MKK6-p38 MAPK signaling cascades. ASK1 has been implicated in cytokine- and stress-induced apoptosis. Here, we show the following: (1) IV infection activated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells; (2) the activation of JNK and p38 MAPK but not extracellular-regulated kinase (ERK) in embryonic fibroblasts (MEFs) derived from ASK1 knockout mice (ASK1(-/-) MEFs) was depressed compared to MEFs derived from wild type mice (ASK1(+/+) MEFs); and (3) ASK1(-/-) MEFs were defective in IV infection-induced caspase-3 activation and cell death. These results indicate that apoptosis in IV-infected BEC is mediated through ASK1-dependent cascades.
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PMID:ASK1 regulates influenza virus infection-induced apoptotic cell death. 1287 92

MAPK/ERK kinase kinase 1 (MEKK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) of the stress-induced JNK pathway. Once activated, MEKK1 phosphorylates the MAP2K MKK4, which in turn phosphorylates JNK. MEKK1 also has the capacity to activate IKK, the central protein kinase of the NF-kappa B pathway. The molecular determinants responsible for the ability of MEKK1 to recognize specific substrates are poorly understood. We report here that select point mutations in subdomain VIII of the protein kinase domain of MEKK1 (MEKK1 Delta) differentially affect its ability to activate MKK4 and IKK, and consequently AP1 and NF-kappa B reporter genes. Moreover, binding of MKK4 to MEKK1 Delta protects the latter from cleavage at an engineered protease target site in subdomain VIII. Collectively these results provide evidence that subdomain VIII of MEKK1 is involved not only in binding to, but also in discrimination of, protein substrates.
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PMID:Subdomain VIII is a specificity-determining region in MEKK1. 1450 Jul 27

MEKK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that can regulate the c-Jun amino-terminal kinase (JNK) MAP kinase cascade. MEKK1 is comprised of a kinase domain and a long amino-terminal regulatory domain. This amino-terminal domain has a scaffold function in that it can assemble modules of the JNK and ERK MAP kinase cascades. Recently, we have demonstrated that MEKK1 binds to p115 Rho GTPase-activating protein, which has GTPase-activating protein activity toward RhoA. Thus, we tested whether Rho GTPases interact with the regulatory domain of MEKK1. RhoA, but not Rac or Cdc42, binds to a site in the aminoterminal one-third of MEKK1, which includes its PHD domain. The interaction is prevented by mutation of the essential cysteine in the MEKK1 PHD domain. Rho-GTP stimulates the kinase activity of full-length MEKK1 as much as 10-fold toward MEK4 but does not appear to be ubiquitinated by MEKK1 under conditions that result in modification of ERK2. In summary, we have characterized a novel point at which Rho GTPases impinge upon the regulation and function of MEKK1.
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PMID:RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. 1458 71


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