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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein (MAP) kinase family includes extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38/RK/CSBP (p38) as structurally and functionally distinct enzyme classes. Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. Although stress-induced activation of p54 SAPKbeta, p46 SAPKgamma (JNK1) or p38 MAP kinases is abolished upon co-transfection with increasing amounts of M3/6 plasmid, epidermal growth factor-stimulated ERK1 is remarkably insensitive even to the highest levels of M3/6 expression obtained. In contrast to M3/6, the dual specificity phosphatase MKP-3 is selective for inactivation of ERK family MAP kinases. Low level expression of MKP-3 blocks totally epidermal growth factor-stimulated ERK1, whereas stress-induced activation of p54 SAPKbeta and p38 MAP kinases is inhibited only partially under identical conditions. Selective regulation by M3/6 and MKP-3 was also observed upon chronic MAP kinase activation by constitutive p21(ras) GTPases. Hence, although M3/6 expression effectively blocked p54 SAPKbeta activation by p21(rac) (G12V), ERK1 activated by p21(ras) (G12V) was insensitive to this phosphatase. ERK1 activation by oncogenic p21(ras) was, however, blocked totally by co-expression of MKP-3. This is the first report demonstrating reciprocally selective inhibition of different MAP kinases by two distinct dual specificity phosphatases.
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PMID:The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. 891 Feb 87

We studied the activation of c-jun N-terminal kinase 1 (JNK 1) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) of mitogen-activated protein kinase (MAPK) family by adriamycin (ADR) in the human T cell leukemia line, H9. ADR caused an elevation of JNK1 activity at sublethal or lethal concentrations; however, at lower doses, ADR did not activate JNK1. The induction of JNK1 peaked at 4 h of treatment (about ten-fold over the control), and was sustained up to 5 h post-treatment. This induction preceded the onset of apoptosis, as determined by morphological features and internucleosomal degradation of DNA. Upon treatment of cells with JNK1-inducing doses, ADR caused an elevation of steady-state levels of c-jun and ATF3 mRNAs, as measured by RT-PCR. In contrast, the activity of ERK 1/2 remained unchanged throughout the treatments, indicating that members of MAPK family are differentially regulated in ADR-treated cells. A possible role of JNK1 activation in ADR-induced apoptosis is discussed.
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PMID:Adriamycin activates c-jun N-terminal kinase in human leukemia cells: a relevance to apoptosis. 891 69

We have previously shown that osmotic stress activates both the mitogen-activated protein kinase (MAPK) cascade and the stress-activated protein kinase (SAPK, also known as JNK) cascade in rat fibroblastic 3Y1 cells and rat PC12 cells. Here, we show that treatment of these cells with sodium arsenite, a chemical compound that mimics the effects of heat shock, or anisomycin, a protein synthesis inhibitor, induces activation of SAPKs potently. These chemical compounds also stimulated the activity of SEK1/MKK4/JNKK, SAPK activator, and the activity of MEKK, SEK1 activator. Expression of a dominant negative mutant of Ras blocked the anisomycin-induced activation of SAPK and SEK1, but did not affect markedly the arsenite-induced or heat shock-induced activation in PC12 cells. The osmotic-stress-induced activation of SAPK was insensitive to the expression of a dominant negative Ras, but was partly sensitive to down-regulation of protein kinase C. These results suggest the existence of Ras-dependent and Ras-independent activation pathways for the SAPK cascade triggered by environmental stresses including chemical stress in PC12 cells. Cell staining with a specific anti-SAPK serum showed that SAPKs were present in both the cytoplasm and the nucleus under normal conditions, and became located mainly in the nucleus after osmotic stress or ultraviolet treatment, suggesting the nuclear translocation of SAPKs.
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PMID:Ras-dependent and Ras-independent activation pathways for the stress-activated-protein-kinase cascade. 891 25

The stress-activated protein kinases JNK and p38 mediate increased gene expression and are activated by environmental stresses and proinflammatory cytokines. Using an in vivo model in which oxidative stress is generated in the liver by intracellular metabolism, rapid protein-DNA complex formation on stress-activated AP-1 target genes was observed. Analysis of the induced binding complexes indicates that c-fos, c-jun, and ATF-2 were present, but also two additional jun family members, JunB and JunD. Activation of JNK precedes increased AP-1 DNA binding. Furthermore, JunB was shown to be a substrate for JNK, and phosphorylation requires the N-terminal activation domain. Unexpectedly, p38 activity was found to be constitutively active in the liver and was down-regulated through selective dephosphorylation following oxidative stress. One potential mechanism for p38 dephosphorylation is the rapid stress-induced activation of the phosphatase MKP-1, which has high affinity for phosphorylated p38 as a substrate. These data demonstrate that there are mechanisms for independent regulation of the JNK and p38 mitogen-activated protein kinase signal transduction pathways after metabolic oxidative stress in the liver.
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PMID:Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver. 891 18

Mammalian cells contain at least three signaling systems which are structurally related to the mitogen-activated protein kinase (MAPK) pathway. Growth factors acting through Ras primarily stimulate the Raf/MEK/MAPK cascade of protein kinases. In contrast, many stress-related signals such as heat shock, inflammatory cytokines, and hyperosmolarity induce the MEKK/SEK(MKK4)/SAPK(JNK) and/or the MKK3 or MKK6/p38(hog) pathways. Physiological agonists of these pathway types are either qualitatively or quantitatively distinct, suggesting few common proximal signaling elements, although past studies performed in vitro, or in cells using transient over-expression, reveal interaction between the components of all three pathways. These studies suggest a high degree of cross-talk apparently not seen in vivo. We have examined the possible molecular basis of the differing agonist profiles of these three MAPK pathways. We report preferential association between MAP kinases and their activators in eukaryotic cells. Furthermore, using the yeast 2-hybrid system, we show that association between these components can occur independent of additional eukaryotic proteins. We show that SAPK(JNK) or p38(hog) activation is specifically impaired by co-expression of cognate dominant negative MAP kinase kinase mutants, demonstrating functional specificity at this level. Further divergence and insulation of the stress pathways occurs proximal to the MAPK kinases since activation of the MAPK kinase kinase MEKK results in SAPK(JNK) activation but does not cause p38(hog) phosphorylation. Therefore, in intact cells, the three MAPK pathways may be independently regulated and their components show specificity in their interaction with cognate cascade members. The degree of intermolecular specificity suggests that mammalian MAPK signaling pathways may remain distinct without the need for specific scaffolding proteins to sequester components of individual pathways.
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PMID:Mammalian mitogen-activated protein kinase pathways are regulated through formation of specific kinase-activator complexes. 893 29

The human immunodeficiency virus, type 1 (HIV-1) promoter is known to be activated by proinflammatory cytokines and UV light. These stimuli also activate various members of the mitogen-activated protein kinase family, including JNK/SAPK and CSBP/p38. In HeLa cells containing an integrated HIV-1 long terminal repeat (LTR) -driven reporter, we now show that the specific p38 inhibitor, SB203580, inhibits activation of the HIV-1 LTR by interleukin-1, tumor necrosis factor, UV light, and osmotic stress. Inhibition was 70-90% in all but the case of tumor necrosis factor stimulation, where inhibition was 50%. Each of these stimuli activated p38, which was inhibited by SB203580 in vitro and in vivo with an IC50 (between 0.1 and 1 microM) similar to that required to inhibit transcription. In contrast, SB203580 had no effect on JNK, which was also activated by these stimuli. The NFkappaB sites in the HIV-1 LTR were required for a response to cytokines but not to UV, and SB203580 remained capable of inhibiting UV activation in the absence of the NFkappaB sites. Studies in which SB203580 was added at different times relative to UV stimulation suggested that the critical p38-mediated phosphorylation event occurred between 2 and 4 h after UV treatment. These data indicate that p38 is required for HIV-1 LTR activation but that the action of p38 is delayed, presumably due to substrate unavailability or inaccessibility.
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PMID:Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase. 894 70

We have isolated two novel human cDNAs, gps1-1 and gps2, that suppress lethal G-protein subunit-activating mutations in the pheromone response pathway of the yeast Saccharomyces cerevisiae. Suppression of other pathway-activating events was examined. In wild-type cells, expression of either gps1-1 or gps2 led to enhanced recovery from cell cycle arrest induced by pheromone. Sequence analysis indicated that gps1-1 contains only the carboxy-terminal half of the gps1 coding sequence. The predicted gene product of gps1 has striking similarity to the protein encoded by the Arabidopsis FUS6 (COP11) gene, a negative regulator of light-mediated signal transduction that is known to be essential for normal development. A chimeric construct containing gps1 and FUS6 sequences also suppressed the yeast pheromone pathway, indicating functional conservation between these human and plant genes. In addition, when overexpressed in mammalian cells, gps1 or gps2 potently suppressed a RAS- and mitogen-activated protein kinase-mediated signal and interfered with JNK activity, suggesting that signal repression is part of their normal function. For gps1, these results are consistent with the proposed function of FUS6 (COP11) as a signal transduction repressor in plants.
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PMID:Two human cDNAs, including a homolog of Arabidopsis FUS6 (COP11), suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction in yeast and mammalian cells. 894 24

We cloned and characterized the Drosophila homolog of mammalian Jun-N-terminal kinases (DJNK). We show that DJNK is encoded by basket (bsk). Like hemipterous (hep), which encodes the Drosophila JNK kinase, bsk is required in the embryo for dorsal closure, a process involving coordinate cell shape changes of ectodermal cells. Dorsal closure can also be blocked by dominant negative Drosophila cdc42, which has been shown to act upstream of JNKK in vertebrates. Therefore it appears that the JNK pathway is conserved and that it is involved in controlling cell morphogenesis in Drosophila. Although DJNK efficiently phosphorylates DJun in vitro, bsk function is not required for the specification of cell fate in the developing eye, a process that requires MAP kinase and DJun function.
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PMID:The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. 894 16

The disruption of interactions between extracellular matrix and specific cognate integrins triggers apoptosis in epithelial cells, in a process termed "anoikis." To understand anoikis, the connections between epithelial cell integrin signaling and the apoptosis-regulatory proteins are being explored. We report herein that early after detachment from matrix, epithelial cells activate Jun-N-Terminal Kinases (JNKs; alternatively known as Stress-activated Protein Kinases), which are also activated by other apoptotic stimuli. The activity of this pathway was required for anoikis. Another early response to cell suspension was the activation of the ICE-related cysteine protease, ICE/LAP3; this activation and anoikis were suppressed by the ICE-protease inhibitor, crmA. The overexpression of bcl-2 suppressed ICE/LAP3 activation as well. Surprisingly, bcl-2 and crmA attenuated the activation of JNKs following cell suspension, suggesting that the JNK pathway is regulated directly or indirectly by proteolysis. In addition, the blockage of the JNK pathway attenuated the activation of ICE/LAP3, suggesting a positive feedback loop between the ICE and JNK systems. These results indicate the following sequence of information flow in anoikis: integrins-->bcl-2/bax-->(ICE-proteases<-->JNK)-->apopt osis. Cell-cell interactions, which were previously shown to sensitize cells to anoikis, caused bcl-2 mRNA to be downregulated, a permissive event for downstream apoptotic signaling.
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PMID:A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. 894 58

Neutral sphingomyelinase (SMase) can be activated by extracellular signals to produce ceramide, which may affect mitogen-activated protein kinase (MAPK) activities. Neutral SMase activity was assessed in membranes from Jurkat, a human T-cell line, and EL4, a murine T-cell line. Ara-C activated SMase with 10 minutes in both Jurkat and EL4 cells, while phorbol ester (PMA) had no effect. PMA, but not Ara-C or ceramides, activated ERK MAPKS, in Jurkat and EL4. PMA acted synergistically with ionomycin to activate JNK MAPKs in Jurkat and EL4 within 10 minutes. Ara-C activated JNKs only after prolonged incubation (90-120 minutes). Thus, ceramide is not a positive signal for ERK activation in T-cell lines. The effects of Ara-C on JNK activity may be mediated through secondary response pathways.
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PMID:Effects of Ara-C on neutral sphingomyelinase and mitogen- and stress-activated protein kinases in T-lymphocyte cell lines. 895 29


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