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)

The cellular integrity and response to hypoosmotic conditions in the yeast Saccharomyces cerevisiae are ensured by a MAP kinase signal transduction pathway mediated by the yeast homolog of mammalian protein kinase C. Bck1p functions as the MAP kinase kinase kinase of this pathway. Here we report on the cloning and analysis of the BCK1 homolog from the milk yeast Kluyveromyces lactis (KlBCK1). The deduced protein sequences display three highly conserved domains with the serine/threonine kinase domain containing 89 % identical amino acid residues. Interestingly, a region identified in KlBck1p as a putative SAM domain, mediating protein-protein interactions, is also conserved in ScBck1p. Yet, two-hybrid analyses indicate that this region may not be involved in dimerization of KlBck1p in contrast to its S. cerevisiae counterpart. Expression of KlBCK1 fully complements the defects in a Scbck1 null mutant and is capable of activating the pathway as indicated by a reporter system based on the transcription factor Rlm1p. However, deletion from the haploid K. lactis genome does not result in a loss of cellular integrity under a variety of conditions tested. Thus, despite the functional conservation in this component of the MAP kinase pathway in both yeast, cellular integrity in K. lactis may depend at least in part on different signalling mechanisms when compared with S. cerevisiae.
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PMID:Characterization of KLBCK1, encoding a MAP kinase kinase kinase of Kluyveromyces lactis. 1032 46

Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine that exerts its effects through a heteromeric complex of transmembrane serine/threonine kinase receptors. At least two intracellular pathways are activated by TGF-beta as follows: the SAPK/JNK, involving the MEKK1, MKK4, and JNK cascade, and the Smad pathway. Here, we report that the SAPK/JNK pathway inhibits the Smad3 pathway. Expression of dominant negative or constitutively active mutants of kinases of the SAPK/JNK pathway, respectively, activates or represses a TGF-beta-induced reporter containing Smad3-binding sites. This effect is not dependent on blocking of Smad3 nuclear translocation but involves a functional interaction between Smad3 and c-Jun, a transcription factor activated by the SAPK/JNK pathway. Overexpression of constitutively active MEKK1 or MKK4 mutants stabilizes the physical interaction between Smad3 and c-Jun, whereas dominant negative mutants inhibit this interaction. Moreover, overexpression of wild-type c-Jun inhibits Smad3-dependent transcription. However, c-Jun does not inhibit Smad3 binding to DNA in vitro. The repression obtained with a c-Jun mutant unable to activate transcription through AP-1 sites indicates that the inhibitory mechanism does not rely on the induction of a Smad3 repressor by c-Jun, suggesting that c-Jun could act as a Smad3 co-repressor. The inhibition of the Smad3 pathway by the SAPK/JNK pathway, both triggered by TGF-beta, could participate in a negative feedback loop to control TGF-beta responses.
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PMID:c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity. 1087 33

Interleukin-1 (IL-1) is a proinflammatory cytokine that recognizes a surface receptor complex and generates multiple cellular responses. IL-1 stimulation activates the mitogen-activated protein kinase kinase kinase TAK1, which in turn mediates activation of c-Jun N-terminal kinase and NF-kappaB. TAB2 has previously been shown to interact with both TAK1 and TRAF6 and promote their association, thereby triggering subsequent IL-1 signaling events. The serine/threonine kinase IL-1 receptor-associated kinase (IRAK) also plays a role in IL-1 signaling, being recruited to the IL-1 receptor complex early in the signal cascade. In this report, we investigate the role of IRAK in the activation of TAK1. Genetic analysis reveals that IRAK is required for IL-1-induced activation of TAK1. We show that IL-1 stimulation induces the rapid but transient association of IRAK, TRAF6, TAB2, and TAK1. TAB2 is recruited to this complex following translocation from the membrane to the cytosol upon IL-1 stimulation. In IRAK-deficient cells, TAB2 translocation and its association with TRAF6 are abolished. These results suggest that IRAK regulates the redistribution of TAB2 upon IL-1 stimulation and facilitates the formation of a TRAF6-TAB2-TAK1 complex. Formation of this complex is an essential step in the activation of TAK1 in the IL-1 signaling pathway.
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PMID:Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway. 1125 96

The serine/threonine kinase Mst1, a mammalian homolog of the budding yeast Ste20 kinase, is cleaved by caspase-mediated proteolysis in response to apoptotic stimuli such as ligation of CD95/Fas or treatment with staurosporine. Furthermore, overexpression of Mst1 induces morphological changes characteristic of apoptosis in human B lymphoma cells. Mst1 may therefore represent an important target for caspases during cell death which serves to amplify the apoptotic response. Here we report that Mst1 has two caspase cleavage sites, and we present evidence indicating that cleavage may occur in an ordered fashion and be mediated by distinct caspases. We also show that caspase-mediated cleavage alone is insufficient to activate Mst1, suggesting that full activation of Mst1 during apoptosis requires both phosphorylation and proteolysis. Another role of phosphorylation may be to influence the susceptibility of Mst1 to proteolysis. Autophosphorylation of Mst1 on a serine residue close to one of the caspase sites inhibited caspase-mediated cleavage in vitro. Finally, Mst1 appears to function upstream of the protein kinase MEKK1 in the SAPK pathway. In conclusion, Mst1 activity is regulated by both phosphorylation and proteolysis, suggesting that protein kinase and caspase pathways work in concert to regulate cell death.
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PMID:Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. 1127 82

Receptor-interacting protein (RIP), a death domain serine/threonine kinase, has been shown to play a critical role in tumor necrosis factor-alpha (TNF-alpha)-induced activation of the nuclear factor-kappaB signaling pathway. We demonstrate here that ectopically expressed RIP induces I-kappaB kinase-beta (IKKbeta) activation in intact cells and that RIP-induced IKKbeta activation can be blocked by a kinase-inactive form of MEKK1, MEKK1(K1253M). Interestingly, RIP physically associated with MEKK1 both in vitro and in vivo. RIP phosphorylated MEKK1 at Ser-957 and Ser-994. Our data also indicate that RIP induced the stimulation of MEKK1 but not MEKK1(S957A/S994A) in transfected cells. Furthermore, overexpressed MEKK1(S957A/S994A) inhibited the RIP-induced activation of both IKKbeta and nuclear factor-kappaB. We also demonstrated that the TNF-alpha-induced MEKK1 activation was defective in RIP-deficient Jurkat cells. Taken together, our results suggest that RIP phosphorylates and activates MEKK1 and that RIP is involved in TNF-alpha-induced MEKK1 activation.
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PMID:Role of receptor-interacting protein in tumor necrosis factor-alpha -dependent MEKK1 activation. 1136 54

Mixed lineage kinase 3 (MLK3) is a serine/threonine protein kinase that functions as a mitogen-activated protein kinase kinase kinase to activate the c-Jun NH(2)-terminal kinase pathway. MLK3 has also been implicated as an I kappa B kinase kinase in the activation of NF-kappa B. Amino-terminal to its catalytic domain, MLK3 contains a Src homology 3 (SH3) domain. SH3 domains harbor three highly conserved aromatic amino acids that are important for ligand binding. In this study, we mutated one of these corresponding residues within MLK3 to deliberately disrupt the function of its SH3 domain. This SH3-defective mutant of MLK3 exhibited increased catalytic activity compared with wild type MLK3 suggesting that the SH3 domain negatively regulates MLK3 activity. We report herein that the SH3 domain of MLK3 interacts with full-length MLK3, and we have mapped the site of interaction to a region between the zipper and the Cdc42/Rac interactive binding motif. Interestingly, the SH3-binding region contains not a proline-rich sequence but, rather, a single proline residue. Mutation of this sole proline abrogates SH3 binding and increases MLK3 catalytic activity. Taken together, these data demonstrate that MLK3 is autoinhibited through its SH3 domain. The critical proline residue in the SH3-binding site of MLK3 is conserved in the closely related family members, MLK1 and MLK2, suggesting a common autoinhibitory mechanism among these kinases. Our study has revealed the first example of SH3 domain-mediated autoinhibition of a serine/threonine kinase and provides insight into the regulation of the mixed lineage family of protein kinases.
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PMID:Autoinhibition of mixed lineage kinase 3 through its Src homology 3 domain. 1159 Jan 55

Double-stranded RNA-activated protein kinase (PKR), a serine/threonine kinase, is activated in virus-infected cells and acts as an antiviral machinery of type I interferons. PKR controls several stress response pathways induced by double-stranded RNA, tumor necrosis factor-alpha or lipopolysaccharide, which result in the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 of the mitogen-activated protein kinase family. Here we showed a novel interaction between PKR and apoptosis signal-regulating kinase 1 (ASK1), one of the members of the mitogen-activated protein kinase kinase kinase family, which is activated in response to a variety of apoptosis-inducing stimuli. PKR and ASK1 showed predominant cytoplasmic localization in COS-1 cells transfected with both cDNAs, and coimmunoprecipitated from the cell extracts. A dominant negative mutant of PKR (PKR-KR) inhibited both the apoptosis and p38 activation induced by ASK1 in vivo. Consistently, PKR-KR inhibited the autophosphorylation of ASK1 in vitro, and exposure to poly(I)-poly(C) increased the phosphorylation of ASK1 in vivo. These results indicate the existence of a link between PKR and ASK1, which modifies downstream MAPK.
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PMID:Double-stranded RNA-activated protein kinase interacts with apoptosis signal-regulating kinase 1. Implications for apoptosis signaling pathways. 1247 8

The MAP Kinase pathway is a key signalling mechanism that regulates many cellular functions such as cell growth, transformation and apoptosis. One of the essential components of this pathway is the serine/threonine kinase, Raf. Raf (MAPKK kinase, MAPKKK) relays the extracellular signal from the receptor/Ras complex to a cascade of cytosolic kinases by phosphorylating and activating MAPK/ERK kinase (MEK; MAPK kinase, MAPKK) that phosphorylates and activates extracellular signal regulated kinase (ERK; mitogen-activated protein kinase, MAPK), which phosphorylates various cytoplasmic and nuclear proteins. Regulation of both Ras and Raf is crucial in the proper maintenance of cell growth as oncogenic mutations in these genes lead to high transforming activity. Ras is mutated in 30% of all human cancers and B-Raf is mutated in 60% of malignant melanomas. The mechanisms that regulate the small GTPase Ras as well as the downstream kinases MEK and extracellular signal regulated kinase (ERK) are well understood. However, the regulation of Raf is complex and involves the integration of other signalling pathways as well as intramolecular interactions, phosphorylation, dephosphorylation and protein-protein interactions. From studies using mammalian isoforms of Raf, as well as C. elegans lin45-Raf, common patterns and unique differences of regulation have emerged. This review will summarize recent findings on the regulation of Raf kinase.
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PMID:Mechanisms of regulating the Raf kinase family. 1263 9

Kinase suppressor of Ras (KSR) is an integral and conserved component of the Ras signaling pathway. Although KSR is a positive regulator of the Ras/mitogen-activated protein (MAP) kinase pathway, the role of KSR in Cot-mediated MAPK activation has not been identified. The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known. In this report, we identify an 830-amino acid novel human KSR, designated hKSR-2, using predictions from genomic data base mining based on the structural profile of the KSR kinase domain. We show that, similar to the known human KSR, hKSR-2 co-immunoprecipitates with many signaling components of the Ras/MAPK pathway, including Ras, Raf, MEK-1, and ERK-1/2. In addition, we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot-mediated MAPK and NF-kappaB activation. This inhibition is specific to Cot, because Ras-induced ERK and IkappaB kinase-induced NF-kappaB activation are not significantly affected by hKSR-2 co-expression. Moreover, Cot-induced interleukin-8 production in HeLa cells is almost completely inhibited by the concurrent expression of hKSR-2, whereas transforming growth factor beta-activated kinase 1 (TAK1)/TAK1-binding protein 1 (TAB1)-induced interleukin-8 production is not affected by hKSR-2 co-expression. Taken together, these results indicate that hKSR-2, a new member of the KSR family, negatively regulates Cot-mediated MAP kinase and NF-kappaB pathway signaling.
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PMID:Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. 1297 77

TAK1 (transforming growth factor beta-activated kinase 1) is a serine/threonine kinase that is a mitogen-activated protein kinase kinase kinase and an essential intracellular signaling component in inflammatory signaling pathways. Upon stimulation of cells with inflammatory cytokines, TAK1 binds proteins that stimulate autophosphorylation within its activation loop and is thereby catalytically activated. This activation is transient; it peaks within a couple of minutes and is subsequently down-regulated rapidly to basal levels. The mechanism of down-regulation of TAK1 has not yet been elucidated. In this study, we found that toxin inhibition of type 2A protein phosphatases greatly enhances interleukin 1 (IL-1)-dependent phosphorylation of Thr-187 in the TAK1 activation loop as well as the catalytic activity of TAK1. From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187. Ectopic and endogenous PP6 co-precipitated with TAK1, and expression of PP6 reduced IL-1 activation of TAK1 but did not affect osmotic activation of MLK3, another MAPKKK. Reduction of PP6 expression by small interfering RNA enhances IL-1-induced phosphorylation of Thr-187 in TAK1. Enhancement occurred without change in levels of PP2A showing specificity for PP6. Our results demonstrate that PP6 specifically down-regulates TAK1 through dephosphorylation of Thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via TAK1 signaling pathways.
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PMID:Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. 1707 28


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