Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although Daxx (death-associated protein) was first reported to mediate the apoptotic signal from Fas to JNK in the cytoplasm, other data suggested that Daxx is mainly located in the nucleus as a transcriptional regulator. Here, we demonstrated that cellular localization of Daxx could be determined by the relative concentration of a proapoptotic kinase, apoptosis signal-regulating kinase 1 (ASK1) by using immunofluorescence and transcriptional reporter assay. ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription. In addition, Daxx was bound to the activated Fas only in the presence of ASK1, accelerating the Fas-mediated apoptosis. These results suggest that Daxx requires ASK1 for its cytoplasmic localization and Fas-mediated signaling. Taken together, we could conclude that ASK1 controls the dual function of Daxx as a transcriptional repressor in the nucleus and as a proapoptotic signal mediator in the cytoplasm.
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PMID:Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm. 1149 19

Apoptosis signal-regulating kinase 1 (ASK1) is a MAP kinase kinase kinase (MAPKKK) that activates the JNK and p38 MAP kinase cascades and is activated in response to oxidative stress such as hydrogen peroxide (H(2)O(2)). A yeast two-hybrid screening identified a serine/threonine protein phosphatase 5 (PP5) as a binding partner of ASK1. PP5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ASK1 and thereby inactivated ASK1 activity in vitro and in vivo. The interaction between PP5 and ASK1 was induced by H(2)O(2) treatment and was followed by the decrease in ASK1 activity. PP5 inhibited not only H(2)O(2)-induced sustained activation of ASK1 but also ASK1-dependent apoptosis. Thus, PP5 appears to act as a physiological inhibitor of ASK1-JNK/p38 pathways by negative feedback.
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PMID:Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress. 1168 43

Apoptosis signal-regulating kinase 1 (ASK1) is a MAPKKK family member which activates c-Jun N-terminal kinase (JNK) and p38. In non-stressed cells, ASK1 exists as an inactive complex with the reduced form of thioredoxin. Oxidative stress such as hydrogen peroxide (H2O2) disrupts the ASK1-thioredoxin complex by oxidization of thioredoxin and thereby activates ASK1. The precise mechanism by which ASK1 is activated after its release from thioredoxin is unknown. Here we show that phosphorylation of Thr845 at the activation loop is essential for ASK1 to be activated by H2O2. ASK1 appears to form a silent homo-oligomer through its C-terminal coiled-coil region in non-stressed cells. Following H2O2 treatment, pre-existing ASK1 oligomer undergoes conformational change and creates a new interface within an oligomer, which ultimately leads to trans-autophosphorylation of Thr845. Thus, direct interaction via the coiled-coil region is required for self-scaffolding but not sufficient for activation of ASK1. Importantly, Thr845 of ASK1 can also be trans-phosphorylated by an unidentified Thr845 kinase in response to H2O2 treatment. We propose that this potential Thr845 kinase may be an ignition kinase that triggers Thr845 phosphorylation in oligomerized and activation-competent forms of ASK1.
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PMID:Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer. 1192 Jun 85

Daxx has been reported to mediate the Fas/JNK-dependent signals in the cytoplasm. However, several lines of evidence have suggested that Daxx is located mainly in the nucleus and functions as a transcriptional regulator. Recent studies have further indicated that Daxx-elicited transcriptional repression can be inhibited by the nuclear body-associated promyelocytic leukemia protein and apoptosis signal-regulating kinase 1 by sequestering Daxx to the nuclear bodies and the cytoplasm, respectively. Here, we further investigated the coordinated molecular mechanism by which Daxx function is regulated through protein-protein interaction. Using yeast two-hybrid screens to identify Daxx-interacting protein(s), three independent clones encoding the 58-kDa microspherule protein (MSP58) fragments were identified. Furthermore, we have demonstrated that Daxx interacts in vitro and in vivo with MSP58 via its NH(2)-terminal segment, which is distinct from the binding region of Fas, apoptosis signal-regulating kinase 1, and promyelocytic leukemia protein, suggesting a unique modulatory role of MSP58 on Daxx function. Transient transfection experiments revealed that MSP58 relieves the repressor activity of Daxx in a dose-dependent manner in COS-1 and 293 cells but not in HeLa cells, implicating cell type-specific modulation of Daxx function by MSP58. Moreover, immunofluorescence analysis unequivocally demonstrated that MSP58 overexpression results in a translocation of Daxx to the enlarged nucleoli in COS-1 or 293 cells, whereas Daxx exhibited a diffuse nuclear pattern in HeLa cells. Taken together, these findings delineate a network of regulatory signaling pathways that converges on MSP58/Daxx interaction, causally associating Daxx nucleolus targeting with its transcriptional activation function.
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PMID:Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration. 1194 83

Stress-activated protein kinase (SAPK) pathway-regulating phosphatase 1 (SKRP1) has been identified as a member of the mitogen-activated protein kinase (MAPK) phosphatase (MKP) family that interacts physically with the MAPK kinase (MAPKK) MKK7, a c-Jun N-terminal kinase (JNK) activator, and inactivates the MAPK JNK pathway. Although these findings indicated that SKRP1 contributes to the precise regulation of JNK signaling, it remains to be elucidated how SKRP1 is integrated into this pathway. We report that SKRP1 also plays a scaffold role for the JNK signaling, judged by the following observations. SKRP1 selectively formed the stable complexes with MKK7 but not with MKK4 and biphasically regulated the MKK7 activity and MKK7-induced gene transcription in vivo. Co-precipitation analysis between SKRP1 and MKK7-activating MAPKK kinases (MAPKKKs) revealed that SKRP1 also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 (ASK1), but not with MAP kinase kinase kinase 1 (MEKK1). Consistent with these findings, SKRP1 expression increased the ASK1-MKK7 complexes in a dose-dependent manner and specifically enhanced the activation of MKK7 by ASK1. Thus, our findings are, to our knowledge, the first evidence to show that an MKP also functions as a scaffold protein for the particular MAPK signaling.
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PMID:Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway. 1195 62

Glutathione S-transferase pi (GSTpi) protects cells from death by altering intracellular oxidative stress. In order to understand the mechanism of GSTpi protection, a cell death model induced by serum depletion as the stress was established. Cotransfection of apoptosis signal-regulating kinase 1 (ASK1) and GSTpi cDNA was performed to elucidate the impact of GSTpi on ASK1 activity, as well as on its downstream signals, MKK7 and JNK, and to elucidate the potential protection of GSTpi on 293 cell death induced by serum depletion. The dominant negative mutant of JNK was used to explore if the blocking of the JNK pathway led to cell death inhibition. It was found that GSTpi had a dose-dependent inhibitory effect on activation induced by serum depletion, and also on inhibition both on MKK7 and JNK. Intracellular expression of GSTpi significantly inhibited serum depletion-induced cell death. Blocking the JNK pathway by transfection of a dominant negative form of JNK (JNK (APF)) brought about significant inhibition of cell death induced by serum depletion with an inhibiting rate as high as 15%. All the results suggest that the mechanism of GSTpi protection on serum depletion-induced cell death works through an ASK1-MKK7-JNK pathway.
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PMID:Glutathione S-transferase pi Protects Serum Depletion-induced Cell Death by Inhibiting ASK1-MKK7-JNK Pathway in the 293 Cells. 1205 Aug 8

The role of regulation of nitric oxide synthase (NOS) activity in mitigating oxidative stress in neonatal lungs and contributing to pulmonary vasodilation at birth is still unclear. Furthermore, it is known that, depending on interactions between the individual components of the mitogen-activated protein kinase (MAPK) signaling cascades, many biological consequences, including apoptosis, are initiated. Although the importance of nitric oxide (NO) in apoptosis is controversial and likely depends on NO concentrations and cell types, this highly reactive free radical can activate the p38 MAPK signal cascade. Recent studies have suggested that thioredoxin may play an important role as an effector for some of these functions. Thioredoxin is a major redox protein for many enzymes/transcription factors and is involved in cellular functions, such as viability, activation, and proliferation. In addition to its redox regulation, thioredoxin binds directly to the apoptosis signal-regulating kinase 1 (ASK1), thus inhibiting the activation of stress-induced MAPK signaling cascades that lead to apoptosis. Furthermore, NO produced from newly induced neuronal NOS was reported to induce expression of thioredoxin and several other genes for preconditioning-induced neuroprotection. Moreover, although exposure of endothelial cells to NO decreases NOS activity, this inhibition was shown to be reversed by thioredoxin. Finally, the correlation of expression of thioredoxin with endothelial NOS activity seems to suggest an important role played by this protein in perinatal changes of pulmonary artery functions. Therefore, thioredoxin may participate in the regulation of NOS activity and be involved in NO functions via multiple mechanisms.
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PMID:Thioredoxin-related regulation of NO/NOS activities. 1207 71

Despite the importance of the stress-activated protein kinase pathways in cell death and survival, it is unclear how stressful stimuli lead to their activation. In the case of heat shock, the existence of a specific mechanism of activation has been evidenced, but the molecular nature of this pathway is undefined. Here, we found that Ask1 (apoptosis signal-regulating kinase 1), an upstream activator of the stress-activated protein kinase p38 during exposure to oxidative stress and other stressful stimuli, was also activated by heat shock. Ask1 activity was required for p38 activation since overexpression of a kinase dead mutant of Ask1, Ask1(K709M), inhibited heat shock-induced p38 activation. The activation of Ask1 by oxidative stress involves the oxidation of thioredoxin, an endogenous inhibitor of Ask1. A different activation mechanism takes place during heat shock. In contrast to p38 induction by H(2)O(2), induction by heat shock was not antagonized by pretreatment with the antioxidant N-acetyl-l-cysteine or by overexpressing thioredoxin and was not accompanied by the dissociation of thioredoxin from Ask1. Instead, heat shock caused the dissociation of glutathione S-transferase Mu1-1 (GSTM1-1) from Ask1 and overexpression of GSTM1-1-inhibited induction of p38 by heat shock. We concluded that because of an alternative regulation by the two distinct repressors thioredoxin and GSTM1-1, Ask1 constitutes the converging point of the heat shock and oxidative stress-sensing pathways that lead to p38 activation.
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PMID:Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. 1207 34

It has been shown that thioredoxin (Trx) in a reduced form binds to and inhibits apoptosis signal-regulating kinase 1 (ASK1). Apoptotic stimuli such as tumor necrosis factor (TNF) and reactive oxygen species (ROS) activate ASK1 in part by oxidizing Trx (forming intramolecular disulfide between C32 and C35) to release Trx from ASK1. In the present study, we examined if Trx affects ASK1 protein stability and whether the redox activity of Trx is critical in regulating ASK1 activity. First, we showed that overexpression of the wild-type Trx (Trx-WT) in endothelial cells induced ASK1 ubiquitination and degradation. Trx-induced ASK1 ubiquitination/degradation could be blocked by ASK1 activators TNF and TRAF2. We then tested the single-mutation of Trx at the catalytic site C32 or C35 (Trx-C32S or Trx-C35S) and the double-mutation (Trx-CS). The results showed that the single mutants (but not Trx-CS) retained the binding activity for ASK1 and the ability to induce ASK1 ubiquitination/degradation. Unlike Trx-WT, Trx-C32S and Trx-C35S mutants constitutively bind to ASK1 even in the presence of hydrogen peroxide in vitro and TNF in vivo. Finally, we showed that the single mutants (not Trx-WT) significantly (n=4 and P<0.05) inhibited ASK1-induced JNK activation, caspase 3 activity, and apoptosis in TNF/ROS-resistant manner. Our data suggest that association of Trx with ASK1 through a single Cysteine (C32 or C35) is necessary and sufficient for Trx activity in inducing ASK1 ubiquitination/degradation leading to inhibition of ASK1-induced apoptosis.
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PMID:Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. 1208 59

The p38 mitogen activated kinase (MAPK) signaling pathway plays an essential role in regulating many cellular processes, including inflammation, cell differentiation, and cell death. Here, we report that the hepatitis C virus (HCV) core inhibits the Fas-mediated p38 signaling pathway. The Fas-mediated p38 activation is suppressed in core-expressing HepG2 cell lines, as well as in the hepatocytes of transgenic mice. In addition, core protein blocked the Fas-mediated activation of apoptosis signal-regulating kinase 1 (ASK1), a major upstream MAPKKK of p38. Treatment of a specific p38 inhibitor (SB203580) or overexpression of a kinase-defective mutant, ASK1 (K709R), promoted Fas-mediated cell death in HepG2 cells. This suggests that the p38 and ASK1 activation is required for cell survival against Fas-mediated cell death. In addition, we observed that the HCV core protein enhances Fas-mediated liver injury and lethality in transgenic mice. Collectively, our findings suggest that the HCV core inhibits the Fas-mediated p38 signaling pathway, which results in accelerated Fas-mediated cell death.
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PMID:Hepatitis C virus core inhibits the Fas-mediated p38 mitogen activated kinase signaling pathway in hepatocytes. 1213 86


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