Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferongamma inducible protein-10 (IP10 or CXCL10), a Th-1 affiliated chemokine, is expressed by activated glial cells and may contribute to the trafficking of immune cells in the inflamed central nervous system. This study examines the regulation of the expression of this chemokine in cultured microglial cells focusing on the roles of mitogen-activated protein (MAP) kinase cascades. Exposure of a mouse microglial cell line, BV-2, to lipopolysaccharide (LPS) and IFNgamma led to an induction of IP10 mRNA and protein as determined by RT-PCR and ELISA, respectively. This induction was suppressed by pharmacological inhibitors of p38 MAPK (i.e., SB203580) and c-Jun N-terminal kinase (JNK, SP600125), suggesting the involvement of the two kinases in IP10 expression. LPS also induced the activity of an IP10 promoter reporter (luciferase) construct transfected into BV-2 cells in a MAP kinase- and NFkappaB-dependent manner. The use of deletion constructs revealed that the kinase-targeted sequences were within the region between -533 bp and -332 bp upstream of the transcriptional start site. Co-transfection of IP10 luciferase with the active forms of the upstream kinases in the MAP kinase cascades, i.e., MAPK kinase-3 (MKK3), MKK6 (the immediately upstream activators of p38 kinase) and a MAP3K, i.e., TGFbeta-activated kinase-1 (TAK1), produced a marked stimulation of the promoter activity. The results of this study indicate that the MAP kinase cascades prominently regulate IP10 gene expression in microglial cells.
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PMID:MAP kinase regulation of IP10/CXCL10 chemokine gene expression in microglial cells. 1663 81

The ubiquitin ligase Smurf1 can target a handful of signaling proteins for ubiquitin-mediated proteasomal destruction or functional modification, including TGF-beta receptors, Smads, transcription factors, RhoA and MEKK2. Smurf1 was initially implicated in BMP pathway regulation in embryonic development, but its potential role in vertebrate embryogenesis has yet to be clarified. Here we demonstrate that inhibition of Smurf1 in Xenopus laevis embryos with an antisense morpholino oligonucleotide or a dominant-negative protein disrupts early development, with the nervous system being the principal target. Smurf1 is enriched on the dorsal side of gastrula stage embryos, and blocking Smurf1 disturbs neural folding and neural, but not mesoderm differentiation, enhances BMP/Smad1 signaling, and elevates phospho-Smad1 levels in the dorsal ectoderm. We conclude that in Xenopus embryos, the BMP pathway is a major physiological target of Smurf1, and we propose that in normal development Smurf1 cooperates with secreted BMP antagonists to limit BMP signaling in dorsal ectoderm. Our data also reveal a novel role for Smurf1 and Smad1 in neural plate morphogenesis.
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PMID:Smurf1 regulates neural patterning and folding in Xenopus embryos by antagonizing the BMP/Smad1 pathway. 1697 50

Several members of the mitogen-activated protein kinase kinase kinase (MAP3K) family including MEKK3 and TGFbeta-activating kinase (TAK1) play nonredundant roles in activation of the NF-kappaB transcription factor. However, the mechanism by which MEKK3 mediates NF-kappaB signaling is not fully understood. In this report we investigate the association of murine MEKK3 with other proteins and their roles in NF-kappaB activation. Using tandem affinity purification TAK1 was identified as an endogenous protein that interacts with MEKK3. MEKK3-TAK1 interactions were confirmed by fluorescence resonance energy transfer and coimmunoprecipitation. MEKK3-TAK1 complexes contain non-phosphorylated forms of both molecules. Expression of non-phosphorylated TAK1 interferes with MEKK3 phosphorylation and NF-kappaB reporter activity induced by transient MEKK3 expression or TNFalpha stimulation. Addition of TAB1 facilitates TAK1 autophosphorylation and reverses the inhibitory effects of TAK1 on MEKK3 phosphorylation and NF-kappaB signal transduction in human 293 cells and TAK1 deficient mouse embryonic fibroblasts. The data provide insights into the homeostatic interactions that maintain basal NF-kappaB levels by holding the enzymes MEKK3 and TAK1 in their inactive state.
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PMID:Homeostatic interactions between MEKK3 and TAK1 involved in NF-kappaB signaling. 1820 50

To better understand the roles of TGF-beta in bone metabolism, we investigated osteoclast survival in response TGF-beta and found that TGF-beta inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-beta receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-beta treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-beta effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IkappaB, and NFkappaB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFkappaB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFkappaB repressed TGF-beta-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-beta-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX(L) expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-beta-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-beta to support of osteoclast survival.
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PMID:TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival. 1858 26

Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3(KI)) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3(KI) attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFbeta(2), Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFbeta(2)-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.
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PMID:MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis. 1900 76

TGFbeta activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1(col2) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.
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PMID:TAK1 is an essential regulator of BMP signalling in cartilage. 1953 34

TGF-beta-activated kinase 1 (TAK1) is a MAP3K family member that activates NF-kappaB and JNK via Toll-like receptors and the receptors for IL-1, TNF-alpha, and TGF-beta. Because the TAK1 downstream molecules NF-kappaB and JNK have opposite effects on cell death and carcinogenesis, the role of TAK1 in the liver is unpredictable. To address this issue, we generated hepatocyte-specific Tak1-deficient (Tak1DeltaHEP) mice. The Tak1DeltaHEP mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and perisinusoidal fibrosis at age 1 month. Older Tak1DeltaHEP mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including alpha-fetoprotein. Cultures of primary hepatocytes deficient in Tak1 exhibited spontaneous cell death that was further increased in response to TNF-alpha. TNF-alpha increased caspase-3 activity but activated neither NF-kappaB nor JNK in Tak1-deficient hepatocytes. Genetic abrogation of TNF receptor type I (TNFRI) in Tak1DeltaHEP mice reduced liver damage, inflammation, and fibrosis compared with unmodified Tak1DeltaHEP mice. In conclusion, hepatocyte-specific deletion of TAK1 in mice resulted in spontaneous hepatocyte death, inflammation, fibrosis, and carcinogenesis that was partially mediated by TNFR signaling, indicating that TAK1 is an essential component for cellular homeostasis in the liver.
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PMID:Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. 2087 30

Generating appropriate cartilage for clinical applications to heal skeletal tissue loss is a major health concern. In this regard, cell-based approaches offer a potential therapeutic strategy for cartilage repair, although little is known about the precise mechanism of chondrogenesis. Unrestricted somatic stem cell (USSC) is considered as a suitable candidate because of its potential for differentiating into multiple cell types. Recent studies show that microRNAs (miRNAs) are involved in several biological processes including development and differentiation. To identify the chondro-specific miRNA signature, miRNA patterns of USSCs and differentiated chondrocytes were investigated using microarrays and validation by qPCR. Prior to these analyses, chondrogenic commitment of differentiated USSCs was verified by immunocytochemistry, specific staining and evaluation of some main chondrogenic marker genes. Various in silico explorations (for both putative targets and signalling pathways) and empirical analyses (miRNA transfections followed by qPCR of some chondrogenic indicators) were carried out to support our results. Transient modulation of multiple chondro-miRs (such as mir-630, mir-624 and mir-376) with chondrocyte targets (such as TGFbR, MAP3K, collagens, SMADs and cadherins) as mediators of chondrogenic signalling pathways including cell-cell interactions, TGF-beta, and MAPK signalling suggests a mechanism for genetic induction of chondrogenic differentiation. In conclusion, this research reveals more details about the allocation of USSCs into the chondrocytes through identification of miRNA signature which modulates targets and pathways required for chondrogenic lineage and could provide guidelines for future clinical treatments and anti-miRNA therapies.
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PMID:A microRNA signature associated with chondrogenic lineage commitment. 2294 87


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