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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein/ERK kinase kinases (MEKKs) phosphorylate and activate protein kinases which in turn phosphorylate and activate the p42/44 mitogen-activated protein kinase (MAPK), c-Jun/stress-activated protein kinases (JNKs), and p38/Hog1 kinase. We have isolated the cDNAs for two novel mammalian MEKKs (MEKK 2 and 3). MEKK 2 and 3 encode proteins of 69.7 and 71 kDa, respectively. The kinase domains encoded in the COOH-terminal moiety are 94% conserved; the NH2-terminal moieties are approximately 65% homologous, suggesting this region may encode sequences conferring differential regulation of the two kinases. Expression of MEKK 2 or 3 in HEK293 cells results in activation of p42/44MAPK and JNK but not of p38/Hog1 kinase. Immunoprecipitated MEKK 2 phosphorylated the MAP kinase kinases, MEK 1, and JNK kinase. Titration of MEKK 2 and 3 expression in transfection assays indicated that MEKK 2 preferentially activated JNK while MEKK 3 preferentially activated p42/44MAPK. These findings define a family of MEKK proteins capable of regulating sequential protein kinase pathways involving MAPK members.
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PMID:Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. 862 89

MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) kinases (MEKKs) regulate c-Jun N-terminal kinase and extracellular response kinase pathways. The 14-3-3zeta and 14-3-3epsilon isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. 14-3-3 proteins bound both the N-terminal regulatory and C-terminal kinase domains of MEKK3. The binding affinity of 14-3-3 for the MEKK3 N terminus was 90 nM, demonstrating a high affinity interaction. 14-3-3 proteins also interacted with MEKK1 and MEKK2, but not MEKK4. Endogenous 14-3-3 protein and MEKK1 and MEKK2 were similarly distributed in the cell, consistent with their in vitro interactions. MEKK1 and 14-3-3 proteins colocalized using two-color digital confocal immunofluorescence. Binding of 14-3-3 proteins mapped to the N-terminal 393 residues of 196-kDa MEKK1. Unlike MEKK2 and MEKK3, the C-terminal kinase domain of MEKK1 demonstrated little or no ability to interact with 14-3-3 proteins. MEKK1, but not MEKK2, -3 or -4, is a caspase-3 substrate that when cleaved releases the kinase domain from the N-terminal regulatory domain. Functionally, caspase-3 cleavage of MEKK1 releases the kinase domain from the N-terminal 14-3-3-binding region, demonstrating that caspases can selectively alter protein kinase interactions with regulatory proteins. With regard to MEKK1, -2 and -3, 14-3-3 proteins do not appear to directly influence activity, but rather function as "scaffolds" for protein-protein interactions.
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PMID:14-3-3 proteins interact with specific MEK kinases. 945 71

Recent evidence indicates that nuclear factor-kappaB (NF-kappaB), a transcription factor critically important for immune and inflammatory responses, is activated by a protein kinase cascade. The essential features of this cascade are that a mitogen-activated protein kinase kinase kinase (MAP3K) activates an IkappaB kinase (IKK) that site-specifically phosphorylates IkappaB. The IkappaB protein, which ordinarily sequesters NF-kappaB in the cytoplasm, is subsequently degraded by the ubiquitin-proteasome pathway, thereby allowing the nuclear translocation of NF-kappaB. Thus far, only two MAP3Ks, NIK and MEKK1, have been identified that can activate this pathway. We now show that MEKK2 and MEKK3 can in vivo activate IKK-alpha and IKK-beta, induce site-specific IkappaBalpha phosphorylation, and, relatively modestly, activate an NF-kappaB reporter gene. In addition, dominant negative versions of either IKK-alpha or IKK-beta abolish NF-kappaB activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediate the NF-kappaB-inducing activities of these MEKKs. In contrast, other MAP3Ks, including MEKK4, ASK1, and MLK3, fail to show evidence of activation of the NF-kappaB pathway. We conclude that a distinct subset of MAP3Ks can activate NF-kappaB.
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PMID:Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. 1008 62

We have cloned and characterized a novel human serine/threonine protein kinase gene from chromosome 12p13.3 encoding 2382 amino acids. Remarkably, the catalytic domain sequence contains a cysteine in place of a lysine residue conserved in subdomain II of most kinases. The same amino acid alteration was recently described for rat WNK1 (with no K=lysine) in which another nearby lysine residue was shown to confer kinase activity to the protein. Rat WNK1 is 85% identical to a splice variant lacking exons 11 and 12 of the described human kinase which we have called human WNK1. The WNK1 catalytic domain has closest homology with human PAK2, MEKK3, and Raf-1. Three additional, partial human protein kinase sequences, WNK2, WNK3 and WNK4, are also reported here with catalytic domains that are 95% homologous to WNK1. These genes differ both in chromosomal location and tissue-specific expression. Moreover, we have identified in the database a total of 18 WNK-related genes, all exclusively from multi-cellular organisms, which share a WNK kinase sequence signature within subdomains I and II of the catalytic domain. We suggest that they constitute a novel subfamily of protein kinases that evolved together with cell adhesion and tissue-formation.
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PMID:WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. 1157 56

The proteasome is a multisubunit proteolytic enzyme comprising activator complexes bound to the 20 S catalytic core. The functions of the proteasomal activator (PA) 700 in ubiquitin/ATP-dependent protein degradation and of the PA28 alpha/beta activators in antigen presentation are well defined. However, the function of a third PA, PA28 gamma, remains elusive. We now show that mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase kinase 3 (MEKK3), a MAPK kinase kinase (MAPKKK) involved in MAPK kinase 7 (MKK7)-c-Jun N-terminal kinase ('JNK') and MKK6-p38 signalling, can bind PA28 gamma but not PA28 alpha. In contrast, B-Raf, a MAPKKK specific for the MAPK/ERK kinase ('MEK')-ERK module, binds PA28 gamma and alpha. The PA28 gamma-binding domain of MEKK3 is located within its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells led to an increase in endogenous and co-expressed PA28 gamma protein levels, whereas kinase-deficient MEKK3 had no effect on PA28 gamma expression. Furthermore, in vitro assays indicated that PA28 gamma was a MEKK3 substrate. MEKK3 represents the first protein kinase capable of binding and phosphorylating a PA, and provides a potential mechanism to link stress-activated protein kinase signalling with the PA28 gamma-dependent proteasome.
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PMID:MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome. 1265 Jun 40

Interleukin 1 receptor (IL-1R) and Toll-like receptors (TLRs) induce inflammatory genes through the complex of MyD88, IL-1R-associated protein kinase (IRAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which is believed to function 'upstream' of the cascades of IkappaB kinase (IKK) and nuclear factor-kappaB (NF-kappaB); extracellular signal-regulated protein kinase (ERK); c-Jun N-terminal kinase (JNK); and p38 mitogen-activated protein kinase (MAPK). Here we show that MAPK-ERK kinase kinase (MEKK3) is an essential signal transducer of the MyD88-IRAK-TRAF6 complex in IL-1R-TLR4 signaling. MEKK3 forms a complex with TRAF6 in response to IL-1 and lipopolysaccharide (LPS) but not CpG, and is required for IL-1R- and TLR4-induced IL-6 production. Furthermore, MEKK3 is crucial for IL-1- and LPS-induced activation of NF-kappaB and JNK-p38 but not ERK, indicating that MAPKs are differentially activated during IL-1R-TLR4 signaling. These data demonstrate that MEKK3 is crucial for IL-1R and TLR4 signaling through the IKK-NF-kappaB and JNK-p38 MAPK pathways.*Note: In the version of this article originally published online, the third author's name was incorrect. The correct author name should be Yong Lin. This error has been corrected for the HTML and print versions of this article.
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PMID:Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. 1466 Oct 19

WNK1 belongs to a unique protein kinase family that lacks the catalytic lysine in its normal position. Mutations in human WNK1 and WNK4 have been implicated in causing a familial form of hypertension. Here we report that overexpression of WNK1 led to increased activity of cotransfected ERK5 in HEK293 cells. ERK5 activation was blocked by the MEK5 inhibitor U0126 and expression of a dominant negative MEK5 mutant. Expression of dominant negative mutants of MEKK2 and MEKK3 also blocked activation of ERK5 by WNK1. Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates. WNK1 phosphorylated both MEKK2 and -3 in vitro, and MEKK3 was activated by WNK1 in 293 cells. Finally, ERK5 activation by epidermal growth factor was attenuated by suppression of WNK1 expression using small interfering RNA. Taken together, these results place WNK1 in the ERK5 MAP kinase pathway upstream of MEKK2/3.
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PMID:WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. 1468 Dec 16

Esophageal squamous cell carcinoma (ESCC) in the Indian population is associated with poor nutritional status, low socioeconomic conditions, bidi smoking and consumption of smokeless tobacco products, besides alcohol drinking and cigarette smoking. To determine the impact of these risk factors on molecular pathogenesis of ESCC, we determined global gene expression profiles of 7 paired samples of ESCC and histologically confirmed nonmalignant esophageal tissues using 19.1K cDNA microarrays. The most salient finding was identification of 19 differentially expressed genes encoding zinc binding or modulating proteins associated with transcriptional regulation, ubiquitin-protein degradation and maintenance of zinc homeostasis. Validation of differential expression of a subset of genes by real-time quantitative RT-PCR (real-time QRT-PCR) in clinical specimens of ESCC, esophageal dysplasia and histologically nonmalignant esophageal tissues and immunohistochemical analysis using tissue microarrays confirmed the microarray data and demonstrated upregulation of zinc finger proteins, cellular modulator of immune recognition (c-MIR), snail homolog 2 (SLUG), zinc transporter, ZnT7 and downregulation of zinc metabolizing protein, metallothionein MT1G. We also observed upregulation of mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), a kinase anchor protein 13 (AKAP13) and transglutaminase2 (TG2). Interestingly, we found upregulation of ZnT7 transcripts in ESCC cells (TE13) grown in zinc deficient condition. In conclusion, our data suggest deregulation of genes associated with zinc homeostasis in ESCC.
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PMID:Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. 1706 19

The protein kinase TAK1 (transforming growth factor-beta-activated kinase 1), which has been implicated in the activation of MAPK (mitogen-activated protein kinase) cascades and the production of inflammatory mediators by LPS (lipopolysaccharide), IL-1 (interleukin 1) and TNF (tumour necrosis factor), comprises the catalytic subunit complexed to the regulatory subunits, termed TAB (TAK1-binding subunit) 1 and either TAB2 or TAB3. We have previously identified a feedback-control mechanism by which p38alpha MAPK down-regulates TAK1 and showed that p38alpha MAPK phosphorylates TAB1 at Ser(423) and Thr(431). In the present study, we identified two IL-1-stimulated phosphorylation sites on TAB2 (Ser(372) and Ser(524)) and three on TAB3 (Ser(60), Thr(404) and Ser(506)) in human IL-1R cells [HEK-293 (human embryonic kidney) cells that stably express the IL-1 receptor] and MEFs (mouse embryonic fibroblasts). Ser(372) and Ser(524) of TAB2 are not phosphorylated by pathways dependent on p38alpha/beta MAPKs, ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK1/2 (c-Jun N-terminal kinase 1/2). In contrast, Ser(60) and Thr(404) of TAB3 appear to be phosphorylated directly by p38alpha MAPK, whereas Ser(506) is phosphorylated by MAPKAP-K2/MAPKAP-K3 (MAPK-activated protein kinase 2 and 3), which are protein kinases activated by p38alpha MAPK. Studies using TAB1(-/-) MEFs indicate important roles for TAB1 in recruiting p38alpha MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser(60) and Thr(404) and in inhibiting the dephosphorylation of TAB3 at Ser(506). TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1(-/-) MEFs. Surprisingly, the IL-1 and TNFalpha-stimulated activation of MAPK cascades and IkappaB (inhibitor of nuclear factor kappaB) kinases were similar in TAB1(-/-), MEKK3(-/-) [MAPK/ERK (extracellular-signal-regulated kinase) kinase kinase 3] and wild-type MEFs, suggesting that another MAP3K (MAPK kinase kinase) may mediate the IL-1/TNFalpha-induced activation of these signalling pathways in TAB1(-/-) and MEKK3(-/-) MEFs.
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PMID:Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. 1802 Oct 73

Tumor necrosis factor alpha (TNFalpha) triggers a signaling pathway converging on the activation of NF-kappaB, which forms the basis for many physiological and pathological processes. In a kinase gene screen using a NF-kappaB reporter, we observed that overexpression of casein kinase 1alpha (CK1alpha) enhanced TNFalpha-induced NF-kappaB activation, and a CK1alpha kinase dead mutant, CK1alpha (K46A), reduced NF-kappaB activation induced by TNFalpha. We subsequently demonstrated that CK1alpha interacted with receptor interacting protein 1 (RIP1) but not with TRADD, TRAF2, MEKK3, IKKalpha, IKKbeta, or IKKgamma in mammalian cells. RIP1 is an indispensable molecule in TNFalpha/NF-kappaB signaling. We demonstrated that CK1alpha interacted with and phosphorylated RIP1 at the intermediate domain. Finally, we showed that CK1alpha enhanced RIP1-mediated NF-kappaB activation. Taken together, our studies suggest that CK1alpha is another kinase that regulates RIP1 function in NF-kappaB activation.
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PMID:Casein kinase 1alpha interacts with RIP1 and regulates NF-kappaB activation. 1806 72


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