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)

Two cDNA clones (ASK1 and ASK2) for plant protein kinases were cloned from Arabidopsis thaliana by screening cDNA libraries with a degenerate oligonucleotide probe that corresponds to a highly conserved motif among protein kinases. Sequence analysis shows that the clones contain open reading frames that encode 41.2 kDa (ASK1) and 40.1 kDa (ASK2) proteins, respectively. These coding regions contain all the conserved motifs of protein kinases. Structural analysis of the coding regions revealed that the two protein kinase genes share high sequence similarity to each other (76.6% identity). The catalytic domain located in the amino terminal region is most similar to the calcium/calmodulin-dependent protein kinase subfamily (47.2% to 54.2% similarity) and the SNF1 kinase subfamily (48.1% to 53.3% similarity). However, the carboxy terminal regions contain distinctive stretches of 21 (ASK1) and 19 (ASK2) acidic amino acids. These clones are the first report of protein kinases with such acidic amino acid regions. The transcripts of both genes are most abundant in leaf but are also expressed in other organs. The expression of the two genes is highly affected by light regime.
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PMID:Two putative protein kinases from Arabidopsis thaliana contain highly acidic domains. 839 17

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. We report herein the isolation of a cDNA encoding a novel protein kinase designated MAPKKK5 from a human macrophage library. The nucleotide sequence predicts that MAPKKK5 encodes an open reading frame of 1374 amino acids with all 11 kinase subdomains. The putative catalytic domain of MAPKKK5 shows significant sequence homology to the kinase domains of the MAPKKK/MEKK level protein kinases from mouse MEKK2 and -3, Drosophila melanogaster PK92B, Saccharomyces cerevisiae STE11, and Schizosaccharomyces pombe BYR2. Northern blot analysis showed that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. When transiently expressed in COS and 293 cells, MAPKKK5 markedly activated c-Jun N-terminal kinase or stress-activated protein kinase, but not MAPK/ERK. Furthermore, MAPKKK5 that was immunoprecipitated from transfected 293 cells was able to phosphorylate and activate MKK4 in vitro, suggesting that MAPKKK5 may be an upstream activator of MKK4 in the c-Jun N-terminal kinase pathway.
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PMID:Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. 894 Jan 79

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

Multiple signal transduction pathways are capable of modifying BCL-2 family members to reset susceptibility to apoptosis. We used two-dimensional peptide mapping and sequencing to identify three residues (Ser70, Ser87, and Thr69) within the unstructured loop of BCL-2 that were phosphorylated in response to microtubule-damaging agents, which also arrest cells at G(2)/M. Changing these sites to alanine conferred more antiapoptotic activity on BCL-2 following physiologic death signals as well as paclitaxel, indicating that phosphorylation is inactivating. An examination of cycling cells enriched by elutriation for distinct phases of the cell cycle revealed that BCL-2 was phosphorylated at the G(2)/M phase of the cell cycle. G(2)/M-phase cells proved more susceptible to death signals, and phosphorylation of BCL-2 appeared to be responsible, as a Ser70Ala substitution restored resistance to apoptosis. We noted that ASK1 and JNK1 were normally activated at G(2)/M phase, and JNK was capable of phosphorylating BCL-2. Expression of a series of wild-type and dominant-negative kinases indicated an ASK1/Jun N-terminal protein kinase 1 (JNK1) pathway phosphorylated BCL-2 in vivo. Moreover, the combination of dominant negative ASK1, (dnASK1), dnMKK7, and dnJNK1 inhibited paclitaxel-induced BCL-2 phosphorylation. Thus, stress response kinases phosphorylate BCL-2 during cell cycle progression as a normal physiologic process to inactivate BCL-2 at G(2)/M.
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PMID:BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. 1056 72

The Ser/Thr kinase Raf-1 is a protooncogene product that is a central component in many signaling pathways involved in normal cell growth and oncogenic transformation. Upon activation, Raf-1 phosphorylates mitogen-activated protein kinase kinase (MEK), which in turn activates mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERKs), leading to the propagation of signals. Depending on specific stimuli and cellular environment, the Raf-1--MEK--ERK cascade regulates diverse cellular processes such as proliferation, differentiation, and apoptosis. Here, we describe a MEK--ERK-independent prosurvival function of Raf-1. We found that Raf-1 interacts with the proapoptotic, stress-activated protein kinase ASK1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. Deletion analysis localized the Raf-1 binding site to the N-terminal regulatory fragment of ASK1. This interaction allows Raf-1 to act independently of the MEK--ERK pathway to inhibit apoptosis. Furthermore, catalytically inactive forms of Raf-1 can mimic the wild-type effect, raising the possibility of a kinase-independent function of Raf-1. Thus, Raf-1 may promote cell survival through its protein-protein interactions in addition to its established MEK kinase function.
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PMID:Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. 1142 28

Chinese hamster ovary (CHO) cells become committed to initiate DNA replication at specific sites within the dihydrofolate reductase (DHFR) locus at a discrete point during G1 phase, the origin decision point (ODP). To better understand the requirements for passage through the ODP, we evaluated the ability of various inhibitors of G1-phase progression to prevent passage through the ODP. Of several protein kinase inhibitors tested, only inhibitors of cyclin-dependent kinase (cdk) activity (roscovitine, olomoucine) prevented passage through the ODP. Inhibitors of MAP kinase (PD98059), PKA (KT5720), PKG (KT5823), as well as inhibition of integrin-mediated signaling by preventing cell adhesion, all arrested cells in the post-ODP stages of G1 phase. Intriguingly, inhibitors of proteasome-dependent proteolysis (MG132, ALLN, lactacystin) and transcription (DRB, alpha-amanitin, actinomycin D) also inhibited passage through the ODP, whereas inhibition of protein synthesis (cycloheximide) had no effect on the ODP. Cross-checking each inhibitor for its affect on transcription revealed that the ODP could be uncoupled from transcription; MG132 and lactacystin did not inhibit transcription, and KT5720 was a potent inhibitor of transcription. Importantly, cells that were arrested upstream of the ODP with either roscovitine or lactacystin contained functional prereplication complexes (pre-RCs), supporting previous findings that pre-RC formation is not sufficient for origin specification. These results demonstrate that specification of the DHFR origin is independent of growth signaling mechanisms and does not require G1-phase synthesis of a protein regulator such as a cyclin or Dbf4/ASK1, positioning the ODP after pre-RC formation but prior to the activation of the known S-phase promoting kinases.
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PMID:Sensitivity of the origin decision point to specific inhibitors of cellular signaling and metabolism. 1179 46

Most frequently, the physiologic functions of the angiotensin II (Ang II) type 1 receptor (AT1R) and bradykinin B2 receptor (BKB2R) are antagonistic, particularly with respect to the regulation of vascular tone. Despite major differences in their physiologic actions, the receptors share sequence similarities. Both link to Galpha(i) and Galpha(q) and transduce very similar signal paths, not only those relating to the traditional G-protein associated second messengers, but also those involved in transactivation mechanisms involving receptor tyrosine kinases. With respect to these paths, some differences in signaling may be accounted for by cell type specificity. However, alternative signal cascades for these two receptors are becoming increasingly evident. One such is the recruitment of signaling molecules upon receptor translocation and internalization. The AT1R translocates into clathrin-coated pits and internalizes upon recruitment of beta-arrestin 2 which then recruits ASK1 and JNK3. The BKB2R translocates and internalizes mainly via caveolae. Another signaling divergence may be due to the direct activation of small G-proteins by both receptors. AT1R activates the RhoA, Rac1, Cdc42 while BKB2R couples only with Rac1 and Cdc42. Both receptors may serve as docking stations for intracellular proteins. One such example is the YIPP motif within the C-terminus of the ATIR which associates with the JAK/STAT pathway. Another potential alternative is the activation of tyrosine/serine kinase phosphatases by BK. This mechanism may directly oppose some of the protein tyrosine/ serine kinase paths activated by AT1R. These alternative mechanisms in sum are potentially responsible for the diversion in signal transduction between these two receptors. Regardless of the route of action, our results suggest that in Rat-1 fibroblasts stably transfected with BKB2R, BK slightly decreases connective tissue growth factor (CTGF) mRNA level while in ATIR transfected cells Ang II increases CTGF mRNA markedly. To determine whether mutant hybrids can be formed between these two receptors which encompass some of the function of the donor receptor but bind the ligand of the recipient receptor, a series of hybrids were formed with BKB2R the recipient and AT1R the donor receptor. Some of these hybrids show resistance to exchanges with the AT1R and form receptors which either do not bind (IC1 exchanges) or demonstrate poor function but normal internalization (proximal C-terminus exchanges). However, other hybrids have proven very functional. For example, the IC2, IC3 and distal C-terminus of the BKB2R IC face can be replaced simultaneously with the AT1R resulting in an hybrid which binds BK, continues to signal, is internalized and resensitized. Formation of this and other less extensive hybrids is discussed. Some of these hybrids possess the capacity to function as the AT1R as exemplified by their ability to upregulate CTGF expression as wild-type (WT) AT1R.
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PMID:Hybrid formation between the intracellular faces of the bradykinin B2 and angiotensin II AT1 receptors and signal transduction. 1248 95

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.
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PMID:Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. 1457 11

The present study was performed to examine mitogen-activated protein kinase associated pathways in mediation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cell apoptosis in cultured Jurkat T cells. TCDD significantly decreased cell viability in a concentration-dependent manner (P<0.05 at 10-300 nM). TCDD (10 nM) also time-dependently decreased cell viability (P<0.05 at 12-48 hr). c-Jun NH2-terminal kinase was significantly phosphorylated with TCDD treatment in a time dependent manner. p38 Mitogen-activated protein kinase was not significantly changed with TCDD treatment. Extracellular signal-regulated protein kinase was significantly phosphorylated with TCDD treatment for 8 hr and gradually returned to baseline. TCDD induced up-regulation of ASK1 and C-Jun, which are up- and down-stream of JNK, respectively, and up-regulation of cytosolic cytochrome c and caspase-3. These results demonstrate that MAPK signaling pathways including JNK and ERK 1/2, are activated with the treatment of TCDD in Jurkat T cells, which suggest that MAPK pathways may be involved in TCDD-induced cell death.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of mitogen-activated protein kinase signaling pathway in Jurkat T cells. 1462 43

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by beta-amyloid peptide (Abeta) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Abeta peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.
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PMID:Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex. 1562 21


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