Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by phosphorylation on Thr and Tyr. Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK. In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway. MKK7 is therefore established to be a novel component of the JNK signal transduction pathway.
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PMID:Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. 920 92

Exposure of mammalian cells to stressful stimuli results in activation of the c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinases (SAPKs), a family of protein kinases related to mitogen-activated protein (MAP) kinase. JNK/SAPKs are activated by specific MAP kinase kinases (MKKs), one of which, MKK4/SEK1, has been characterized extensively. In Drosophila, the JNK/SAPK Basket (Bsk) and the MKK Hemipterous (Hep), are important for embryonic development. Loss of function of either gene inhibits dorsal closure, a morphogenetic movement in which the edges of the embryonic ectoderm move together over the amnioserosa. There is evidence that the Rho GTPases Rac and Cdc42 are also required for dorsal closure, suggesting that Rac or Cdc42 may regulate Hep and Bsk. We have identified MKK7, a murine homolog of Hep. MKK7 functionally rescues hep mutant flies. In fibroblasts, MKK7 is activated by stress and by the GTPase Rac1. MKK7 directly phosphorylates and activates JNK/SAPK. Thus, MKK7 is a homolog of hep and functions in a conserved signaling pathway involving JNK/SAPK and the GTPase Rac1.
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PMID:MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. 931 5

Activation of stress-activated protein kinases, including the p38 and the c-Jun NH2-terminal kinases (JNK), have been associated with the onset of cardiac hypertrophy and cell death in response to hemodynamic overload and ischemia/reperfusion injury. Upon infection of cultured neonatal rat cardiac myocytes with recombinant adenoviral vectors expressing a wild type and a constitutively active mutant of MKK7 (or JNKK2), JNK was specifically activated without affecting other mitogen-activated protein kinases, including extracellular signal-regulated protein kinases and p38. Specific activation of the JNK pathway in cardiac myocytes induced characteristic features of hypertrophy, including an increase in cell size, elevated expression of atrial natriuretic factor, and induction of sarcomere organization. In contrast, co-activation of both JNK (by MKK7) and p38 (by MKK3 or MKK6) in cardiomyocytes led to an induction of cytopathic responses and suppression of hypertrophic responses. These data provide the first direct evidence that activation of JNK alone is sufficient to induce characteristic features of cardiac hypertrophy, thereby supporting an active role for the JNK pathway in the development of cardiac hypertrophy. The cytopathic response, as a result of co-activation of both JNK and p38, may contribute to the loss of contractile function and viability of cardiomyocytes following hemodynamic overload and cardiac ischemia/reperfusion injury.
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PMID:Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. 948 59

MKN28-derived nonreceptor type of serine/threonine kinase/mixed lineage kinase 2 (MST/MLK2) directly phosphorylates and activates SEK1/MKK4/JNKK1/SKK1 in vitro, thereby acting as a mitogen-activated protein (MAP) kinase kinase kinase in the JNK/SAPK pathway (Hirai, S. -i., Katoh, M., Terada, M., Kyriakis, J. M., Zon, L. I., Rana, A., Avruch, J., and Ohno, S. (1997) J. Biol. Chem. 272, 15167-15173). The in vitro reconstitution system for the kinase cascade allowed us now to identify JNK/SAPK activators involved in the MST/MLK2-dependent activation of JNK/SAPK in vivo. We show that at least two distinct MST/MLK2-dependent JNK/SAPK activators are present in the fractionated COS-1 cell lysate, and that they appear to be SEK1/MKK4/JNKK1/SKK1 and MKK7/JNKK2/SKK4 by Western blot analysis. Notably, a majority of the MST/MLK2-dependent JNK/SAPK-activating activity is found in MKK7-containing fractions, whereas the MEKK1-dependent activity is comparably distributed in SEK1- and MKK7-containing fractions. Moreover, MST/MLK2 activates recombinant MKK7 more effectively than recombinant SEK1, whereas MEKK1 activates both to a similar extent. In addition, the deletion analysis on MST/MLK2 showed that the kinase domain is responsible for the determination of substrate specificity. These results provide a molecular aspect to the differential regulation of the two JNK activators by a variety of cellular stimuli.
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PMID:Differential activation of two JNK activators, MKK7 and SEK1, by MKN28-derived nonreceptor serine/threonine kinase/mixed lineage kinase 2. 951 38

The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by the exposure of cells to multiple forms of stress. A putative scaffold protein was identified that interacts with multiple components of the JNK signaling pathway, including the mixed-lineage group of MAP kinase kinase kinases (MLK), the MAP kinase kinase MKK7, and the MAP kinase JNK. This scaffold protein selectively enhanced JNK activation by the MLK signaling pathway. These data establish that a mammalian scaffold protein can mediate activation of a MAP kinase signaling pathway.
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PMID:A mammalian scaffold complex that selectively mediates MAP kinase activation. 976 29

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAP kinases) is activated by exposure of cells to environmental stress and by the treatment of cells with cytokines. The mechanism of activation of JNK is mediated by dual phosphorylation within kinase subdomain VIII on the motif Thr-Pro-Tyr. This phosphorylation is mediated by the MAP kinase kinases MKK4 and MKK7. These MAP kinase kinases serve as signalling molecules that integrate a wide array of stimuli into the activation of the JNK signalling pathway. Studies of the physiological function of JNK have been facilitated by the molecular genetic analysis of JNK signalling in Drosophila and by the creation of mice with targeted disruption of components of the JNK pathway. These studies demonstrate that the JNK pathway regulates AP-1 (activator protein-1) transcriptional activity in vivo and indicate that JNK is required for embryonic morphogenesis, the regulation of cellular proliferation and apoptosis, and the response of cells to immunological stimuli.
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PMID:Signal transduction by the c-Jun N-terminal kinase. 1020 17

Tumor necrosis factor (TNF) exerts many actions through activation of the transcription factor NF-kappaB. NF-kappaB is sequestered in the cytosol by an inhibitory subunit IkappaB, which is inducibly phosphorylated by an IkappaB kinase complex and subsequently degraded. Sodium salicylate (NaSal) can block NF-kappaB activation by inhibiting IkappaBalpha phosphorylation. Recently, we used the specific p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 to demonstrate that inhibition of TNF-induced IkappaBalpha phosphorylation requires NaSal-induced p38 activation. We demonstrate that NaSal similarly inhibits TNF-induced IkappaBbeta degradation in a p38-dependent manner. To further examine the role of p38, we determined whether other agents that activate p38 can block TNF-induced IkappaB phosphorylation and degradation. Sorbitol, H(2)O(2), and arsenite each blocked IkappaBalpha phosphorylation induced by TNF, and SB203580 reversed the inhibitory effects of sorbitol and H(2)O(2), but not arsenite. In addition, sorbitol and H(2)O(2) blocked TNF-induced but not interleukin-1-induced IkappaBalpha phosphorylation, whereas arsenite inhibited IkappaBalpha phosphorylation induced by TNF and interleukin-1. Transient expression of MAP kinase kinase (MKK) 6b(E), a constitutive activator of p38, reduced both TNF-induced phosphorylation of IkappaBalpha and NF-kappaB-dependent reporter activity. However, MKK7(D), a constitutive activator of c-Jun N-terminal kinases, failed to inhibit these TNF actions. Thus, sustained p38 activation by various stimuli inhibits TNF-induced IkappaB phosphorylation and NF-kappaB activation.
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PMID:Cell stress and MKK6b-mediated p38 MAP kinase activation inhibit tumor necrosis factor-induced IkappaB phosphorylation and NF-kappaB activation. 1042 82

Axin negatively regulates the Wnt pathway during axis formation and plays a central role in cell growth control and tumorigenesis. We found that Axin also serves as a scaffold protein for mitogen-activated protein kinase activation and further determined the structural requirement for this activation. Overexpression of Axin in 293T cells leads to differential activation of mitogen-activated protein kinases, with robust induction for c-Jun NH(2)-terminal kinase (JNK)/stress-activated protein kinase, moderate induction for p38, and negligible induction for extracellular signal-regulated kinase. Axin forms a complex with MEKK1 through a novel domain that we term MEKK1-interacting domain. MKK4 and MKK7, which act downstream of MEKK1, are also involved in Axin-mediated JNK activation. Domains essential in Wnt signaling, i. e. binding sites for adenomatous polyposis coli, glycogen synthase kinase-3beta, and beta-catenin, are not required for JNK activation, suggesting distinct domain utilization between the Wnt pathway and JNK signal transduction. Dimerization/oligomerization of Axin through its C terminus is required for JNK activation, although MEKK1 is capable of binding C terminus-deleted monomeric Axin. Furthermore, Axin without the MEKK1-interacting domain has a dominant-negative effect on JNK activation by wild-type Axin. Our results suggest that Axin, in addition to its function in the Wnt pathway, may play a dual role in cells through its activation of JNK/stress-activated protein kinase signaling cascade.
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PMID:Axin forms a complex with MEKK1 and activates c-Jun NH(2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling. 1057 11

In this study we identified tyrosine-phosphorylated Vav1 as an early point of integration between the signaling routes triggered by the T-cell receptor and CD28 in human T-cell leukemia cells. Costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. T-cell stimulation induced the recruitment of Vav1 to an inducible multiprotein T-cell activation signaling complex at the plasma membrane. Vav1 activated the mitogen-activated protein kinases JNK and p38. The Vav1-mediated activation of JNK employed a pathway involving Rac, HPK1, MLK3, and MKK7. The costimulation-induced activation of p38 was inhibited by dominant negative forms of Vav1, Rac, and MKK6. Here we show that Vav1 also induces transcription factors that bind to the CD28RE/AP element contained in the interleukin-2 promoter. A detailed mutational analysis of Vav1 revealed a series of constitutively active and nonfunctional forms of Vav1. Almost all inactive versions were mutated in their Dbl homology domain and behaved as dominant negative mutants that impaired costimulation-induced activation of JNK, p38, and CD28RE/AP-dependent transcription. In contrast to NF-AT-dependent transcription, Vav1-mediated transcriptional induction of the CD28RE/AP element in the interleukin-2 promoter could only partially be inhibited by cyclosporin A, suggesting a dual role of Vav1 for controlling Ca(2+)-dependent and -independent events.
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PMID:Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription. 1084 38

Cadmium (Cd), a human carcinogen, can induce apoptosis in various cell types. Three major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (ERK), have been shown to regulate apoptosis. In this study we explore the ability of Cd to activate JNK, p38 and ERK, including their effects on Cd-mediated growth inhibition and apoptosis in a human non-small cell lung carcinoma cell line, CL3. The kinase activity of JNK was induced dose-dependently by 30-160 microM CdCl(2). High cytotoxic doses of Cd (130-160 microM) markedly activated p38, but low Cd doses did not. Conversely, the activities of ERK1 and ERK2 were decreased by low cytotoxic doses of Cd (</=80 microM) and moderately activated by high Cd doses. Low cytotoxic doses of Cd transiently activated JNK and simultaneously reduced ERK activity, whereas high cytotoxic doses of Cd persistently activated JNK and p38. PD98059, an inhibitor of ERK upstream activators MAPK kinase (MKK) 1 and MKK2, greatly enhanced cytotoxicity and apoptosis in cells treated with low Cd doses. In contrast, SB202190, an inhibitor of p38, decreased the cytotoxicity and apoptosis induced by high Cd doses. Transient expression of a dominant negative form of JNK1, but not that of JNK2, significantly increased the viability and prevented apoptosis of Cd-treated cells. However, expression of wild-type JNK1 did not affect viability and apoptosis of Cd-treated cells. Transfection of wild-type JNK2 or p38 enhanced apoptosis of cells exposed to low Cd doses but did not affect those exposed to high Cd doses. The JNK activity stimulated by low Cd doses was partially suppressed by expression of a dominant negative form of MKK7, but not a dominant negative form of MKK4, indicating that MKK7 is involved in JNK activation by Cd. Together, the results of this study suggest that JNK and p38 cooperatively participate in apoptosis induced by Cd and that the decreased ERK signal induced by low Cd doses contributes to growth inhibition or apoptosis.
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PMID:Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. 1087 22


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