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)

Signals elicited by transforming growth factor-beta (TGF-beta) superfamily ligands are generated following the formation of heteromeric receptor complexes consisting of type I and type II receptors. TAK1, a member of the MAP kinase kinase kinase family, and its activator, TAB1, participate in the bone morphogenetic protein (BMP) signaling pathway involved in mesoderm induction and patterning in early Xenopus embryos. However, the events leading from receptor activation to TAK1 activation remain to be identified. A yeast interaction screen was used to search for proteins that function in the pathway linking the receptors and TAB1-TAK1. The human X-chromosome-linked inhibitor of apoptosis protein (XIAP) was isolated as a TAB1-binding protein. XIAP associated not only with TAB1 but also with the BMP receptors in mammalian cells. Injection of XIAP mRNA into dorsal blastomeres enhanced the ventralization of Xenopus embryos in a TAB1-TAK1-dependent manner. Furthermore, a truncated form of XIAP lacking the TAB1-binding domain partially blocked the expression of ventral mesodermal marker genes induced by a constitutively active BMP type I receptor. These results suggest that XIAP participates in the BMP signaling pathway as a positive regulator linking the BMP receptors and TAB1-TAK1.
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PMID:XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. 987 61

Smad proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-beta (TGF-beta) superfamily of growth factors. Certain Smad proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these proteins by activated TGF-beta superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated protein kinase kinase-1 (MEK-1) or TGF-beta-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-beta type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells.
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PMID:MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. 1008 21

Upon transforming growth factor-beta (TGF-beta) binding to its cognate receptor, Smad3 and Smad4 form heterodimers and transduce the TGF-beta signal to the nucleus. In addition to the Smad pathway, another pathway involving a member of the mitogen-activated protein kinase kinase kinase family of kinases, TGF-beta-activated kinase-1 (TAK1), is required for TGF-beta signaling. However, it is unknown how these pathways function together to synergistically amplify TGF-beta signaling. Here we report that the transcription factor ATF-2 (also called CRE-BP1) is bound by a hetero-oligomer of Smad3 and Smad4 upon TGF-beta stimulation. ATF-2 is one member of the ATF/CREB family that binds to the cAMP response element, and its activity is enhanced after phosphorylation by stress-activated protein kinases such as c-Jun N-terminal kinase and p38. The binding between ATF-2 and Smad3/4 is mediated via the MH1 region of the Smad proteins and the basic leucine zipper region of ATF-2. TGF-beta signaling also induces the phosphorylation of ATF-2 via TAK1 and p38. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. These results indicate that ATF-2 plays a central role in TGF-beta signaling by acting as a common nuclear target of both Smad and TAK1 pathways.
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PMID:ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling. 1008 40

The Wnt signalling pathway regulates many developmental processes through a complex of beta-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors. Wnt stabilizes cytosolic beta-catenin, which then binds to TCF and activates gene transcription. This signalling cascade is conserved in vertebrates, Drosophila and Caenorhabditis elegans. In C. elegans, the proteins MOM-4 and LIT-1 regulate Wnt signalling to polarize responding cells during embryogenesis. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-beta) mitogen-activated protein-kinase-kinase kinase (MAP3K) and MAP kinase (MAPK)-related NEMO-like kinase (NLK), respectively, in mammalian cells. These results raise the possibility that TAK1 and NLK are also involved in Wnt signalling in mammalian cells. Here we show that TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected beta-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.
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PMID:The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. 1039 Dec 47

Stimulation of monocytes/macrophages with lipopolysaccharide (LPS) results in activation of nuclear factor-kappaB (NF-kappaB), which plays crucial roles in regulating expression of many genes involved in the subsequent inflammatory responses. Here, we investigated roles of transforming growth factor-beta activated kinase 1 (TGF-TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), in the LPS-induced signaling cascade. A kinase-negative mutant of TAK1 inhibited the LPS-induced NF-kappaB activation both in a macrophage-like cell line, RAW 264.7, and in human embryonic kidney 293 cells expressing toll-like receptor 2 or 4. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated upon simulation of RAW 264.7 cells with LPS. These results indicate that TAK1 functions as a critical mediator in the LPS-induced signaling pathway.
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PMID:TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages. 1067 30

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

Antioxidant response element (ARE) regulates the induction of a number of cellular antioxidant and detoxifying enzymes. However, the signaling pathways that lead to ARE activation remain unknown. Here, we report that the expression of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1), transforming growth factor-beta-activated kinase (TAK1), and apoptosis signal-regulating kinase (ASK1) in HepG2 cells activated the ARE reporter gene, whereas the expression of their dominant-negative mutants impaired ARE activation by the chemicals sodium arsenite and mercury chloride. Coexpression of downstream kinases, MAP kinase kinase 4, MAP kinase kinase 6, and c-Jun NH(2)-terminal kinase-1, but not MAP kinase kinase 3 and p38, augmented ARE activation by MEKK1, TAK1, and ASK1. The coexpression of a basic leucine zipper transcription factor Nrf2 but not c-Jun also greatly enhanced the activation of reporter gene by MEKK1, TAK1, and ASK1; however, a dominant-negative mutant of Nrf2 (NF-E2-related factor 2) blocked this event. Furthermore, when overexpressed, MEKK1, TAK1, and ASK1 induced the expression of heme oxygenase-1, a gene regulated by ARE, and the cotransfection with the dominant-negative mutant of Nrf2 abolished the induction. Taken together, these results suggest that MAP kinase pathways that are activated by MEKK1, TAK1, and ASK1 may link chemical signals to Nrf2, leading to the activation of ARE-dependent genes.
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PMID:Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. 1098 82

We previously demonstrated that bone morphogenetic proteins (BMPs) induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1. Transcription factors Smads mediate transforming growth factor-beta signaling and the ATF/CREB family transcription factor ATF-2 has recently been shown to act as a common target of the Smad and the TAK1 pathways. We here examined the role of Smads and ATF-2 in cardiomyocyte differentiation of P19CL6, a clonal derivative of murine P19 cells. Although P19CL6 efficiently differentiates into cardiomyocytes when treated with dimethyl sulfoxide, P19CL6noggin, a P19CL6 cell line constitutively overexpressing the BMP antagonist noggin, did not differentiate into cardiomyocytes. Cooverexpression of Smad1, a ligand-specific Smad, and Smad4, a common Smad, restored the ability of P19CL6noggin to differentiate into cardiomyocytes, whereas stable overexpression of Smad6, an inhibitory Smad, completely blocked differentiation of P19CL6, suggesting that the Smad pathway is necessary for cardiomyocyte differentiation. ATF-2 stimulated the betaMHC promoter activity by the synergistic manner with Smad1/4 and TAK1 and promoted terminal cardiomyocyte differentiation of P19CL6noggin, whereas overexpression of the dominant negative form of ATF-2 reduced the promoter activities of several cardiac-specific genes and inhibited differentiation of P19CL6. These results suggest that Smads, TAK1, and their common target ATF-2 cooperatively play a critical role in cardiomyocyte differentiation.
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PMID:Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. 1135 31

In skin, the profibrotic protein connective tissue growth factor (CTGF) is not normally expressed. However, when skin cells are exposed to transforming growth factor-beta (TGF-beta), CTGF is induced in fibroblasts but not in epithelial cells. We have begun to investigate the requirements for the fibroblast-selective induction of CTGF by TGF-beta. Previously we found that this response was Smad-dependent. Now we show that protein kinase C and Ras/MEK/ERK are necessary for the TGF-beta induction of the CTGF promoter but not of a generic Smad-responsive promoter (SBE-lux). Induction of the CTGF promoter is antagonized by c-Jun or by MEKK1, suggesting that a proper balance between the Ras/MEK/ERK and JNK MAPK cascades is necessary for TGF-beta induction of CTGF. We identify the minimal CTGF promoter element necessary and sufficient to confer TGF-beta responsiveness to a heterologous promoter and show that a tandem repeat of a consensus transcription enhancer factor binding element, 5'-GAGGAATGG-3', is necessary for this induction. This element has not been previously shown to play a role in TGF-beta induction of gene expression in fibroblasts. Gel shift analysis shows that this sequence binds nuclear factors that are greatly enriched in fibroblasts relative to epithelial cells. Thus Smads, Ras/MEK/ERK, protein kinase C, and fibroblast-enriched factors that bind GAGGAATGG act together to drive the TGF-beta-mediated induction of CTGF in fibroblasts.
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PMID:Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. 1257 Dec 53

TAK1 (transforming growth factor-beta-activated kinase-1), a MAP3K with considerable sequence similarity to Raf-1 and MEKK-1, has been identified as a transforming growth factor-beta/bone morphogenetic protein (BMP)-activated cytosolic component of the MAPK pathways. In this investigation, the molecular interactions between TAK1 and Smad proteins were characterized as well as their influence on BMP-mediated mesenchymal cell differentiation along the osteogenic/chondrogenic pathway. In co-immunoprecipitations we found an interaction of TAK1 with all Smads tested, R-Smads Smads1-5, the co-Smad Smad4, and the inhibitory Smads (I-Smad6 and I-Smad7). Smad interaction with TAK1 takes place through their MH2 domain. This interaction is dependent on the presence of an active kinase domain in TAK1. TAK1 dramatically interferes with R-Smad transactivation in reporter assays and affects subcellular distribution of Smad proteins. Activated TAK1 also interferes with BMP-dependent osteogenic development in murine mesenchymal progenitor cells (C3H10T 1/2). A potential TAK1-mediated apoptosis process could be excluded for these cells. Both synergistic and interfering influences of TAK1 on BMP-mediated Smad-signaling have been reported previously. We suggest that TAK1 is a factor that is involved in the fine-tuning of BMP effects during osteogenic development.
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PMID:Transforming growth factor-beta-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors. 1591 26


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