Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase
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Abstract:
A search of the National Cancer Institute's Anti‐Neoplastic Drug Screen for compounds with an inhibitory profile similar to that of the mitogen‐activated protein kinase kinase (MAPKK) inhibitor PD098059 yielded anthrax lethal toxin. Anthrax lethal factor was found to inhibit progesterone‐induced meiotic maturation of frog oocytes by preventing the phosphorylation and activation of mitogen‐activated protein kinase (MAPK). Similarly, lethal toxin prevented the activation of MAPK in serum stimulated, ras‐transformed NIH3T3 cells. In vitro analyses using recombinant proteins indicated that lethal factor proteolytically modified the NH2‐terminus of both MAPKK1 and 2, rendering them inactive and hence incapable of activating MAPK. The consequences of this inactivation upon meiosis and transformed cells are also discussed.Keywords:
Protein kinase R
The double-stranded RNA (dsRNA)-activated protein kinase R (PKR) has been invoked in different signaling pathways. In cells pre-exposed to the PKR inhibitor 2-aminopurine or in PKR-null cells, the activation of p38 mitogen-activated protein kinase (MAPK) following dsRNA stimulation is attenuated. We found that the p38 MAPK activator MKK6, but not its close relatives MKK3 or MKK4, exhibited an increased affinity for PKR following the exposure of cells to poly(rI:rC), a dsRNA analog. In vitro kinase assays revealed that MKK6 was efficiently phosphorylated by PKR, and this could be inhibited by 2-aminopurine. Expression of kinase-inactive PKR (K296R) in cells inhibited the poly(IC)-induced phosphorylation of MKK3/6 detected by phosphospecific antiserum but did not affect the poly(IC)-induced gel migration retardation of MKK3. This suggests that poly(IC)-mediated in vivo activation of MKK6, but not MKK3, is through PKR. Consistent with this observation, PKR was capable of activating MKK6 as assessed in a coupled kinase assay containing the components of the p38 MAPK pathway. Our results indicate that the interaction of MKK6 and PKR provides a mechanism for regulating p38 MAPK activation in response to dsRNA stimulation.
Protein kinase R
Cyclin-dependent kinase 9
ASK1
EIF-2 kinase
MAP2K7
c-Raf
RNA Silencing
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Objective: We investigated whether angiotensin (Ang) III induces ERK1/2 and p38 mitogen activated protein (MAP) kinases protein phosphorylation in isolated rat vascular smooth muscle cells (VSMCs). Background The molecular mechanisms by which Ang III induces various biological effects have not been fully investigated. Most studies have shown that MAP kinases mediate Ang II apoptosis and growth promoting effects in VSMCs.Moreover, Ang II induces vascular remodeling in these cells leading to increases in blood pressure. MAP kinases regulate or induce two crucial actions in VSMCs, proliferation and migration, which are associated with atherosclerosis and restenosis. Methods: Primary cultures of VSMCs were isolated from the thoracic aorta of adult Wistar rats by the explant technique. VSMCs were treated with Ang III ranging in concentration from 0.1 nM to 1000 nM for 10 minutes or with 100 nM Ang III for 1 minute to 30 minutes. Western blotting technique was used to determine whether Ang III induces ERK1/2 and p38 MAP kinases protein phosphorylation. Results: Concentration studies showed that Ang III caused a dose-dependent increase in ERK1/2 and p38 MAP kinases protein phosphorylation. The effects of Ang III on both MAP kinases phosphorylation were maximal between 10 nM and 100 nM concentrations. The peptide effects were rapid and significant, occurring within minutes of treatment and the maximal effects on MAP kinases phosphorylation was observed by 10 min. Conclusion These findings provide insight into the molecular nature of the actions of Ang III and offer possible mechanism by which Ang III physiological and possibly pathological actions occur in VSMCs.
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MAPK14
Tyrosine-protein kinase CSK
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MAPK14
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MAPK14
MAPK7
MAPKAPK2
MAP2K7
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Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia-reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.
Inflammatory response
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Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia–reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.
Inflammatory response
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Double‐stranded RNA‐activated protein kinase (PKR), a serine/threonine kinase, is activated in virus‐infected cells and acts as an antiviral machinery of type I interferons. PKR controls several stress response pathways induced by double‐stranded RNA, tumor necrosis factor‐α or lipopolysaccharide, which result in the activation of stress‐activated protein kinase/c‐Jun NH 2 ‐terminal kinase and p38 of the mitogen‐activated protein kinase family. Here we showed a novel interaction between PKR and apoptosis signal‐regulating kinase 1 (ASK1), one of the members of the mitogen‐activated protein kinase kinase kinase family, which is activated in response to a variety of apoptosis‐inducing stimuli. PKR and ASK1 showed predominant cytoplasmic localization in COS‐1 cells transfected with both cDNAs, and coimmunoprecipitated from the cell extracts. A dominant negative mutant of PKR (PKR‐KR) inhibited both the apoptosis and p38 activation induced by ASK1 in vivo . Consistently, PKR‐KR inhibited the autophosphorylation of ASK1 in vitro , and exposure to poly(I)–poly(C) increased the phosphorylation of ASK1 in vivo . These results indicate the existence of a link between PKR and ASK1, which modifies downstream MAPK.
Protein kinase R
ASK1
Cyclin-dependent kinase 9
MAP2K7
c-Raf
EIF-2 kinase
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