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

---

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

The effects of interleukin 1 (IL-1) are mediated by the activation of protein kinase signalling pathways, which have been well characterized in cultured cells. We have investigated the activation of these pathways in rabbit liver and other tissues after the systemic administration of IL-1alpha. In liver there was 30-40-fold activation of c-Jun N-terminal kinase (JNK) and 5-fold activation of both JNK kinases, mitogen-activated protein kinase (MAPK) kinase (MKK)4 and MKK7. IL-1alpha also caused 2-3-fold activation of p38 MAPK and degradation of the inhibitor of nuclear factor kappaB ('IkappaB'), although no activation of extracellular signal-regulated protein kinase (ERK) (p42/44 MAPK) was observed. The use of antibodies against specific JNK isoforms showed that, in liver, short (p46) JNK1 and long (p54) JNK2 are the predominant forms activated, with smaller amounts of long JNK1 and short JNK2. No active JNK3 was detected. A similar pattern of JNK activation was seen in lung, spleen, skeletal muscle and kidney. Significant JNK3 activity was detectable only in the brain, although little activation of the JNK pathway in response to IL-1alpha was observed in this tissue. This distribution of active JNK isoforms probably results from a different expression of JNKs within the tissues, rather than from a selective activation of isoforms. We conclude that IL-1alpha might activate a more restricted set of signalling pathways in tissues in vivo than it does in cultured cells, where ERK and JNK3 activation are often observed. Cultured cells might represent a 'repair' phenotype that undergoes a broader set of responses to the cytokine.
...
PMID:Analysis of mitogen-activated protein kinase pathways used by interleukin 1 in tissues in vivo: activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated protein kinase kinases 4 and 7. 1113 91

The mixed lineage kinase (MLK) family is a recently described protein kinase family. The MLKs contain a kinase domain followed by a dual leucine zipper-like motif. We previously reported the molecular cloning of LZK (leucine zipper-bearing kinase), a novel MLK, and that LZK activated the c-Jun NH2 terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway through MKK7 in cells. Here, we reveal that LZK forms dimers/oligomers through its dual leucine zipper-like motif, and that this is necessary for activation of the JNK/SAPK pathway. We also identify the C-terminal functional region of LZK, which is indispensable for the activation of SEK1, but not that of MKK7.
...
PMID:Identification and characterization of functional domains in a mixed lineage kinase LZK. 1116 70

We have studied the role of phosphorylation in the activation of metal-regulatory transcription factor-1 (MTF-1) and metallothionein (MT) gene expression. We showed that MTF-1 is phosphorylated in vivo and that zinc stimulates MTF-1 phosphorylation 2-4-fold. Several kinase inhibitors were used to examine the possible involvement of kinase cascades in the activation of MTF-1. Metal-induced MT gene expression was abrogated by protein kinase C (PKC), c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase, and tyrosine-specific protein kinases inhibitors, as assayed by Northern analysis and by cotransfection experiments using a metal regulatory element-luciferase reporter plasmid. The extracellular signal-activated protein kinase and the p38 kinase cascades did not appear to be essential for the activation of MT gene transcription by metals. By using dominant-negative mutants of PKC, JNK, mitogen-activated kinase kinase 4 (MKK4), and MKK7, we provide further evidence supporting a role for PKC and JNK in the activation of MTF-1 in response to metals. Notably, increased MTF-1 DNA binding in response to zinc and MTF-1 nuclear localization was not inhibited in cells preincubated with the different kinase inhibitors despite strong inhibition of MTF-1-mediated gene expression. This suggests that phosphorylation is essential for MTF-1 transactivation function. We hypothesize that metal-induced phosphorylation of MTF-1 is one of the primary events leading to increased MTF-1 activity. Thus, metal ions such as cadmium could activate MTF-1 and induce MT gene expression by stimulating one or several kinases in the MTF-1 signal transduction pathway.
...
PMID:Phosphorylation is involved in the activation of metal-regulatory transcription factor 1 in response to metal ions. 1155 72

MKK7 is a recently discovered mitogen-activated protein kinase (MAPK) kinase that is unique in that it specifically activates only the c-JUN NH(2)-terminal protein kinase (JNK) family of enzymes. Very little is known about the biological role of MKK7. We generated inducible cell lines from the human embryonal kidney carcinoma cell line, HEK293, by stable transfection with a constitutively active mutant of MKK7, MKK7(3E), fused to green fluorescent protein (GFP), under the control of an ecdysone-inducible promoter. Treatment of cells with the synthetic ecdysone analog ponasterone A induced expression of GFP-MKK7(3E) and resulted in sustained activation of endogenous JNK, but neither of the other endogenous MAPKs, ERK or p38. Red and green fluorescing cDNA copies of mRNA extracted from cells obtained before and after induction of GFP-MKK7(3E) were hybridized to microarrays containing more than 6,000 cDNAs in eight independent experiments. By selection criteria, 23 genes were differentially regulated after 24 h of induction of GFP-MKK7(3E) and 16 after 48 h. The expression of 9 genes was consistently changed after both 24 and 48 h of induction. These changes included down-regulation of three genes, c-myc, angiopoietin-2, and glucose-regulated protein 58, and up-regulation of 6 genes, tissue factor pathway inhibitor-2, GRP78, autotaxin, PPP1R7, the DKFZ cDNA p434D0818, and 1 unknown gene. Consistent with previously described roles of several of the altered genes, MKK7(3E) inhibited cell proliferation. These data implicate active MKK7 in the negative regulation of cell proliferation and provide evidence for a new role for this kinase in the regulation of a distinct, hitherto unrecognized set of genes.
...
PMID:Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation. 1171 98

Mitogen-activated protein (MAP) kinase pathways are three-kinase modules that mediate diverse cellular processes and have been highly conserved among eukaryotes. By using a functional complementation screen in yeast, we have identified a human MAP kinase kinase kinase (MAPKKK) that shares homology with members of the mixed lineage kinase (MLK) family and therefore was called MRK (MLK-related kinase). We report the structure of the MRK gene, from which are generated two splice forms of MRK, MRK-alpha and MRK-beta, encoding for proteins of 800 and 456 amino acids, respectively. By using a combination of solid phase protein kinase assays, transient transfections in cells, and analysis of endogenous proteins in stably transfected Madin-Darby canine kidney cells, we found that MRK-beta preferentially activates ERK6/p38gamma via MKK3/MKK6 and JNK through MKK4/MKK7. We also show that expression of wild type MRK increases the cell population in the G(2)/M phase of the cell cycle, whereas dominant negative MRK attenuates the G(2) arrest caused by gamma-radiation. In addition, exposure of cells to gamma-radiation induces MRK activity. These data suggest that MRK may mediate gamma-radiation signaling leading to cell cycle arrest and that MRK activity is necessary for the cell cycle checkpoint regulation in cells.
...
PMID:MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. 1183 44

The cellular response to genotoxic stress includes activation of protein kinase Cdelta (PKCdelta). The functional role of PKCdelta in the DNA damage response is unknown. The present studies demonstrate that PKCdelta is required in part for induction of the stress-activated protein kinase (SAPK/JNK) in cells treated with 1-beta-d-arabinofuranosylcytosine (araC) and other genotoxic agents. DNA damage-induced SAPK activation was attenuated by (i) treatment with rottlerin, (ii) expression of a kinase-inactive PKCdelta(K-R) mutant, and (iii) down-regulation of PKCdelta by small interfering RNA (siRNA). Coexpression studies demonstrate that PKCdelta activates SAPK by an MKK7-dependent, SEK1-independent mechanism. Previous work has shown that the nuclear Lyn tyrosine kinase activates the MEKK1 --> MKK7 --> SAPK pathway but not through a direct interaction with MEKK1. The present results extend those observations by demonstrating that Lyn activates PKCdelta, and in turn, MEKK1 is activated by a PKCdelta-dependent mechanism. These findings indicate that PKCdelta functions in the activation of SAPK through a Lyn --> PKCdelta --> MEKK1 --> MKK7 --> SAPK signaling cascade in response to DNA damage.
...
PMID:Activation of SAPK/JNK signaling by protein kinase Cdelta in response to DNA damage. 1237 81

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.
...
PMID:Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. 1265 51

Mixed lineage kinases (MLKs) belong to the family of mitogen activated protein kinase kinase kinase (MAPKKK) and cause neuronal cell death mediated through c-Jun, N-terminal kinase (JNK) pathway. Recently, genetic studies in Drosophila revealed the presence of an MLK termed slipper (slpr). However, its biochemical features like physiological substrate, role in different MAPK pathways and developmental and tissue-specific expression pattern were not reported. Here, we report cDNA cloning, expression analysis and biochemical characterization of a Drosophila mixed lineage kinase (dMLK) that is also known as slipper. The protein structure analysis of dMLK/slipper revealed, in addition to the conserved domains, a stretch of glutamine in the amino terminus and an asparagine-threonine stretch at the carboxy-terminus. In situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that dMLK is expressed in early embryonic stages, adult brain and thorax. Ectopic expression of dMLK either in Drosophila S2 or in mammalian HEK293 cells leads to activation of JNK, p38 and extracellular signal regulated kinase (ERK) pathways. Further, dMLK directly phosphorylates Hep, dMKK4 and also their mammalian counterparts, MKK7 and SEK1, in an in vitro kinase assay. Taken together, our results provide for the first time a comprehensive expression profile and new biochemical insight of dMLK/slipper.
...
PMID:Drosophila mixed lineage kinase/slipper, a missing biochemical link in Drosophila JNK signaling. 1267 57

The antioxidant protein peroxiredoxin (Prx) I is a thioredoxin peroxidase that is involved in the regulation of proliferation and differentiation of mammalian cells. Here, it is shown that Prx I gene expression was induced transcriptionally by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in cultured rat liver tissue macrophages and RAW264.7 monocytic cells. TPA-dependent induction of Prx I gene expression was mediated by two proximal activator protein-1 sites of the rat Prx I promoter region that were nuclear targets of c-Jun as determined by transfection studies with luciferase reporter gene constructs and electrophoretic mobility shift assays. The transcription factor Nrf2, however, was not involved in the regulation of Prx I promoter activity. Prx I gene induction by TPA was decreased by protein kinase C inhibitors and overexpressed dominant negative forms of Ras and MEKK1, but not Raf-1. The p38 MAPK inhibitor SB202190 and overexpression of dominant negative mutants of MAPK kinase 4 (MKK4), MKK6, and p38 inhibited the TPA-dependent induction of Prx I gene transcription. In contrast, inhibitors of the JNK, SP600125, and the NF-kappaB signaling pathway, caffeic acid phenethyl ester, respectively, as well as overexpressed dominant negative MKK7 and IkappaB, had no effect on the up-regulation of Prx I reporter gene activity by TPA. Cotransfection of wild-type p38alpha and p38beta, but not that of p38gamma and p38delta, increased Prx I promoter activity. The data indicate that a protein kinase C, Ras, MEKK1, p38 MAPK signaling pathway plays a major role for the transcriptional up-regulation of Prx I gene expression.
...
PMID:Phorbol ester-dependent activation of peroxiredoxin I gene expression via a protein kinase C, Ras, p38 mitogen-activated protein kinase signaling pathway. 1296 Jan 65

c-Jun N-terminal protein kinase (JNK) activation and subsequent c-Jun phosphorylation which stimulates its transcriptional activity have been well studied in cerebral ischemia. To determine whether mitogen-activated protein kinase kinase 7 (MKK7) play a role in JNK activation in response to the stress of global cerebral ischemia, we tested the activation of such a kinase by using phospho-Ser and phospho-Thr antibodies. Immunoprecipitation and Western blot analysis revealed that MKK7 was expressed at similar levels in all conditions, whereas phospho-MKK7 was highly augmented from 1 to 5 days and reached its peak at 3 days after 15 min of ischemia. Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation experiments. Moreover, MKK7 activation was markedly reduced by pretreatment of the free radical scavenging thiol antioxidant N-acetylcysteine (NAC). Together with previous studies, the late activation of MKK7 in hippocampal CA1 region may contribute to delayed cell death, and the protective effects of antioxidant against ischemia-induced injury may be partially mediated by the down-regulation of JNK signal pathway.
...
PMID:Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. 1457 11


<< Previous 1 2 3 4 5 6 Next >>

---