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)

Because the catalytic domain of dual leucine zipper-bearing kinase (DLK) bears sequence similarity to members of the mitogen-activated protein (MAP) kinase kinase kinase subfamily, this protein kinase was investigated for its ability to activate MAP kinase pathways. When transiently transfected and overexpressed in either COS 7 cells or NIH3T3 cells, wild type DLK potently activated p46(SAPK) (SAPK/JNK) but had no detectable effect in activating p42/44(MAPK). DLK also activated p38(mapk) when overexpressed in NIH3T3 cells. A catalytically inactive point mutant of DLK had no effect in these experiments. Consistent with its specificity in activating SAPK, DLK activated Elk-1 but not Sap1a-mediated transcription. In NIH3T3 cells, activation of SAPK by v-Src was markedly attenuated by coexpression of K185A, a catalytically inactive mutant of DLK, suggesting that this mutant could function in a dominant negative fashion in a pathway that leads from v-Src to SAPKs. In a series of co-transfection experiments, activation of p46(SAPK) by DLK was not inhibited by dominant negative mutants of Rac1 and Cdc42Hs, PAK65-R, or PAK65-A, but was attenuated by MEKK1(K432M). DLK(K185A) did not inhibit the ability of constitutively active MEKK1 to activate SAPK. Moreover, K185A significantly inhibited the activation of SAPK by constitutively active V-12 Rac1 and V-12 Cdc42Hs. These results suggest that DLK lies distal to Rac1 and/or Cdc42Hs but proximal to MEKK1 in a pathway leading from v-Src to SAPKs activation.
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PMID:Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. 879 50

TPK-IIB is a protein kinase that is predominant in the cytosol of spleen and is characterized by a high specific activity toward acidic peptide substrates and a low auto-phosphorylation activity. A prominent 52-kDa component purifies with the kinase [Marin, O., Donella-Deana, A., Brunati, A. M., Fischer, S. & Pinna, L. A. (1991) J. Biol. Chem. 266, 17798-17803]. Here we demonstrate that the 52-kDa protein displays sequence identity with the Miller-Dieker lissencephaly protein (LIS 1). The protein is not related to any known protein kinase and lacks an ATP-binding motif. The ATP binding and phosphotransferase activities of TPK-IIB can be fully accounted for by a minor 38-kDa protein band (p38/TPK-IIB) which can be separated from the 52-kDa protein by Mono-Q/FPLC in the presence of EDTA. Sequence analysis of p38/TPK-IIB reveals a high level of similarity, if not identity, with the catalytic domain of p72syk, a protein-tyrosine kinase implicated in the activation of hematopoietic cells. Antibodies raised against the catalytic domain of p72syk, but not antibodies raised against its N-terminal segment, cross-react with p38/TPK-IIB. The peptide substrate specificity of p72syk is almost identical to that of p38/TPK-IIB, which also supports the classification of TPK-IIB as a close relative (possibly a proteolytic or alternative spliced form) of p72syk. p38/TPK-IIB, however, exhibits a specific activity which is sixfold higher than that of p72syk and appears to be 50-fold more sensitive to inhibition by heparin. Thus, the observation that Ca(2+)-dependent degradation of p72syk by particulate fraction of rat spleen is accompanied by increased catalytic activity and increased sensitivity to heparin would be consistent with the possibility that hyperactive p38/TPK-IIB might be proteolytically generated from p72syk in response to an increase of intracellular Ca2+.
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PMID:The spleen protein-tyrosine kinase TPK-IIB is highly similar to the catalytic domain of p72syk. 884 5

Mammalian homologs of the yeast protein kinase, Sterile 20 (Ste20), can be divided into two groups based on their regulation and structure. The first group, which includes PAK1, is regulated by Rac and Cdc42Hs, and activators have been identified. In contrast, very little is known about activators, regulatory mechanisms or physiological roles of the other group, which consists of GC kinase and MST1. We have identified a human Ste20-like kinase from the GC kinase group, SOK-1 (Ste20/oxidant stress response kinase-1), which is activated by oxidant stress. The kinase is activated by autophosphorylation and is markedly inhibited by its non-catalytic C-terminal region. SOK-1 is activated 3- to 7-fold by reactive oxygen intermediates, but is not activated by growth factors, alkylating agents, cytokines or environmental stresses including heat shock and osmolar stress. Although these data place SOK-1 on a stress response pathway, SOK-1, unlike GC kinase and PAK1, does not activate either of the stress-activated MAP kinase cascades (p38 and SAPKs). SOK-1 is the first mammalian Ste20-like kinase which is activated by cellular stress, and the activation is relatively specific for oxidant stress. Since SOK-1 does not activate any of the known MAP kinase cascades, its activation defines a novel stress response pathway which is likely to include a unique stress-activated MAP kinase cascade.
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PMID:Activation of a human Ste20-like kinase by oxidant stress defines a novel stress response pathway. 888 45

Exposure of cells to either proliferative or stressful stimuli elicits a complex response involving one or more distinct phosphorylation cascades culminating in the activation of multiple members of the mitogen-activated protein kinase (MAPK) family, including extracellular signal regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JNK/SAPK), and p38/RK/CSBP protein kinase. While the pathways transducing mitogenic stimuli to these kinases are relatively well established, the early signalling events leading to their activation in response to stress are poorly understood. In the present study, we examined ERK, JNK/SAPK, and p38 activation in cells treated with the sulfhydryl-reactive agent sodium arsenite. Arsenite treatment potently activated both JNK/SAPK and p38, but only moderately activated ERK. Activation of all three kinases was prevented by the free radical scavenger N-Acetyl-L-cysteine, suggesting that an oxidative signal initiates the responses. Suramin, a growth factor receptor poison, significantly inhibited ERK activation by arsenite, but had little effect on either JNK/SAPK or p38 activity. In contrast, suramin inhibited the activation of all three kinases by short wavelength ultraviolet light (UVC) irradiation. In addition, comparative studies with wild-type PC12 cells and PC12 cells expressing a dominant negative Ras mutant allele indicated that arsenite activates ERK primarily through a Ras-dependent pathway(s), while activation of both JNK/SAPK and p38 occurs through a mechanism relatively independent of Ras. These results suggest that JNK/SAPK and p38 may share common upstream regulators distinct from those involved in ERK activation.
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PMID:Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite. 890 23

p38 mitogen-activated protein kinase is activated by environmental stress and cytokines and plays a role in transcriptional regulation and inflammatory responses. The crystal structure of the apo, unphosphorylated form of p38 kinase has been solved at 2.3 A resolution. The fold and topology of p38 is similar to ERK2 (Zhang, F., Strand, A., Robbins, D., Cobb, M. H., and Goldsmith, E. J. (1994) Nature 367, 704-711). The relative orientation of the two domains of p38 kinase is different from that observed in the active form of cAMP-dependent protein kinase. The twist results in a misalignment of the active site of p38, suggesting that the orientation of the domains would have to change before catalysis could proceed. The residues that are phosphorylated upon activation of p38 are located on a surface loop that occupies the peptide binding channel. Occlusion of the active site by the loop, and misalignment of catalytic residues, may account for the low enzymatic activity of unphosphorylated p38 kinase.
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PMID:Crystal structure of p38 mitogen-activated protein kinase. 891 Mar 61

Stress-activated protein kinases are MAP kinase homologues that are activated by cellular stresses, bacterial endotoxin and inflammatory cytokines. They are activated by a dual threonine/tyrosine phosphorylation within a TPY sequence in the case of stress-activated protein kinase-1 and its isoforms (also called JNKs) or a TGY sequence in the case of stress-activated protein kinase-2 and its isoforms (also called p38, p40, RK, CSBPs, XMpk2 and Mxi2). Here we report the cloning and sequencing of a new protein kinase from rat with a TGY sequence in the activation domain. This stress-activated protein kinase-3 is 60% identical to mouse stress-activated protein kinase-2 and 45% identical to HOG1 from Saccharomyces cerevisiae. Transcripts encoding stress-activated protein kinase-3 are widely expressed, with high levels in skeletal muscle.
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PMID:SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. 892 12

The ubiquitously expressed Na+/H+ exchanger NHE1 is the target of multiple signaling pathways, including those activated by tyrosine kinase receptors, G protein-coupled receptors, and integrins. The intracellular pathways leading to activation of NHE1 are poorly understood. To gain more insight into these activation pathways, we examined the role of mitogen-activated protein kinases (MAPKs) as potential mediators of NHE1 activation by extracellular stimuli such as growth factors and hyperosmotic stress. Whereas p44 MAPK does not appear to phosphorylate NHE1 in vitro, we found that inhibition of the p42/p44 MAPK signaling by expression of a dominant negative form of p44 MAPK, by expression of the MAP kinase phosphatase MKP-1, or by inhibition of MAPK kinase 1 (MKK1) with the PD 98059 compound reduced by 50-60% NHE1 activation in response to growth factors. This inhibitory effect also was observed in C-terminal NHE1 deletion mutants in which the major phosphorylation sites have been deleted. Furthermore, the use of a CCL39-derived cell line expressing an estradiol-regulated form of oncogenic Raf-1 (CCL39-deltaRaf-1:ER) revealed that the exclusive activation of the Raf --> MKK1 --> p42/p44 MAPK cascade was capable of inducing NHE1 activation to the same extent as potent growth factors like thrombin. Together, our findings demonstrate that the p42/p44 MAPK cascade plays a predominant role in the regulation of NHE1 by growth factors, an action that is mediated via accessory proteins that remain to be identified. In contrast, we found no evidence in favor of the contribution of any MAPK, p42/p44, p38 MAPKs, and Jun kinase, in NHE1 activation by osmotic stress.
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PMID:The p42/p44 mitogen-activated protein kinase cascade is determinant in mediating activation of the Na+/H+ exchanger (NHE1 isoform) in response to growth factors. 899 58

The mammalian mitogen-activated protein (MAP) kinase homologue p38 has been shown to be activated by pro-inflammatory cytokines as well as physical and chemical stresses. We now show that a variety of hemopoietic growth factors, including Steel locus factor, colony stimulating factor-1, granulocyte/macrophage-colony stimulating factor, and interleukin-3, activate p38 MAP kinase and the downstream kinase MAPKAP kinase-2. Furthermore, although these growth factors activate both p38 MAP kinase and Erk MAP kinases, we demonstrate using a specific inhibitor of p38 MAP kinase, SB 203580, that p38 MAP kinase activity was required for MAP kinase-activated protein kinase-2 activation. Conversely p38 MAP kinase was shown not to be required for in vivo activation of p90(rsk), known to be downstream of the Erk MAP kinases. Interleukin-4 was unique among the hemopoietic growth factors we examined in failing to induce activation of either p38 MAP kinase or MAP kinase-activated protein kinase-2. These findings demonstrate that the activation of p38 MAP kinase is involved not only in responses to stresses but also in signaling by growth factors that regulate the normal development and function of cells of the immune system.
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PMID:Hemopoietic growth factors with the exception of interleukin-4 activate the p38 mitogen-activated protein kinase pathway. 901 68

IL-1-activated chondrocytes express a large number of genes which contribute to cartilage degradation. The signaling pathways activated in response to IL-1 in these cells are not well-defined. We examined the effects of IL-1 and other stimuli on the mitogen activated protein kinase (MAPK) pathways in rabbit articular chondrocytes. We demonstrate that IL-1 activates three MAPKs, ERK, JNK and p38, in a time and dose-dependent manner. Activation is maximal by 15 minutes and returns to baseline levels by 1 hour. Maximal activation of ERK and p38 occurs with 1 ng/ml IL-1 whereas activation of JNK requires 10-fold higher levels. In contrast to IL-1, the PKC activator, PDBu preferentially activates ERK while TNF alpha preferentially activates JNK. LPS and TGF beta fail to stimulate any of the kinases examined. These results suggest that activation of the various MAPK pathways is important in the response of chondrocytes to IL-1, cytokines and growth factors.
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PMID:The effects of IL-1 on mitogen-activated protein kinases in rabbit articular chondrocytes. 901 64

We observed previously that glia maturation factor (GMF), a 17-kDa brain protein, is rapidly phosphorylated in astrocytes following stimulation by phorbol ester, and that protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. In the current report, we present evidence that PKA-phosphorylated GMF also promotes (11-fold) the catalytic activity of PKA itself, resulting in a positive feedback loop. Furthermore, GMF phosphorylated by protein kinase C (PKC), but not by casein kinase II or p90 ribosomal S6 kinase, also activates PKA (7-fold). It appears that the mutual augmentation of GMF and PKA, and the stimulating effect of PKC, both serve to maximize the influence of PKA on the regulation of MAP kinase cascades by GMF. Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. The generation of various phospho-isoforms of GMF may explain its modulation of signal transduction at multiple locations.
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PMID:Protein kinase A (PKA)- and protein kinase C-phosphorylated glia maturation factor promotes the catalytic activity of PKA. 903 May 86


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