UNIPROT:P51812 - FACTA Search

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Query: UNIPROT:P51812 (mitogen-activated protein)
10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recently described downstream target of mitogen-activated protein kinases (MAPKs) is the MAPK-activated protein (MAPKAP) kinase 2 which has been shown to be responsible for small heat shock protein phosphorylation. We have analyzed the mechanism of MAPKAP kinase 2 activation by MAPK phosphorylation using a recombinant MAPKAP kinase 2-fusion protein, p44MAPK and p38/40MAPK in vitro and using an epitope-tagged MAPKAP kinase 2 in heat-shocked NIH 3T3 cells. It is demonstrated that, in addition to the known phosphorylation of the threonine residue carboxyl-terminal to the catalytic domain, Thr-317, activation of MAPKAP kinase 2 in vitro and in vivo is dependent on phosphorylation of a second threonine residue, Thr-205, which is located within the catalytic domain and which is highly conserved in several protein kinases. Constitutive activation of MAPKAP kinase 2 is obtained by replacement of both of these threonine residues by glutamic acid. A constitutively active form of MAPKAP kinase 2 is also obtained by deletion of a carboxyl-terminal region containing Thr-317 and the A-helix motif or by replacing the conserved residues of the A-helix. These data suggest a dual mechanism of MAPKAP kinase 2 activation by phosphorylation of Thr-205 inside the catalytic domain and by phosphorylation of Thr-317 outside the catalytic domain involving an autoinhibitory A-helix motif.
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PMID:Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif. 759 79

We report the identification of 16 of the 30 cellular proteins which are rapidly phosphorylated in tumour-necrosis-factor-(TNF)-treated or interleukin-1-(IL-1)-treated primary human fibroblasts. Phosphorylation assays of proteins found in the cytosolic extract of human fibroblasts by in vitro assays indicate that at least 12 of these proteins are likely to be substrates for mitogen-activated protein kinase(s) (MAP kinase), mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAP kinase 2), a pp60c-src-like tyrosine kinase as well as for a putative dual nucleotide protein kinase (DNK) in TNF-treated or IL-1-treated cells. Comparison of the phosphorylation of cytosolic proteins in vitro by exogenously added protein kinases with that observed in cells treated with TNF or IL-1 enabled the identification of cellular substrates of TNF-activated and IL-1-activated cellular protein kinases. Comparison of protein kinase activities of cytosolic extracts derived from TNF-treated or IL-1-treated and control fibroblasts also show the activation of MAP kinase, MAPKAP kinase 2, a putative DNK and a pp60src-like tyrosine kinase 3-19 fold. The data suggest TNF or IL-1 signal transduction may involve the phosphorylation of protein phosphatase type 2A by a pp60src-like tyrosine kinase, followed by the activation of MAP kinase, MAPKAP kinase 2 and the putative DNK. However, the activation of MAP kinase and MAPKAP kinase 2 may be independent of the earlier activation of pp60src-like tyrosine kinase and the inactivation of protein phosphatase type 2A.
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PMID:Activation of protein kinases and the inactivation of protein phosphatase 2A in tumour necrosis factor and interleukin-1 signal-transduction pathways. 774 73

Interleukin (IL)-1 plays a central role in human host defense. Binding of IL-1 to its receptor is associated with phosphorylation of various cellular target proteins, most of which are unidentified. The kinases responsible for target protein phosphorylation after IL-1 stimulation are also still not completely understood. We report here that IL-1 induced activation of mitogen-activated protein (MAP) kinase in primary monocytes and in the human monocytic leukemia cell line U-937. Activation of MAP kinase was followed by activation of MAP kinase-activated protein (MAPKAP) kinase 2, a serine/threonine kinase, leading to subsequent phosphorylation of the small heat shock protein [27-kDa heat shock protein (Hsp27)]. Phosphorylation of Hsp27 triggered by IL-1 was both dose and time dependent. IL-1 failed to phosphorylate Hsp27 when cells had been previously deactivated with tyrosine kinase inhibitors such as genistein. In those cells, however, Hsp27 phosphorylation could be reconstituted when activated immunoprecipitated MAP kinase or purified MAPKAP kinase 2 was added. Phosphorylation of Hsp27 could also be inhibited when NaF, a serine/threonine phosphatase inhibitor, was omitted. Taken together, our findings indicate that IL-1-induced intracellular signaling pathways converge in the activation of MAP kinase and MAPKAP kinase 2 and the subsequent phosphorylation of Hsp27.
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PMID:Interleukin-1-induced intracellular signaling pathways converge in the activation of mitogen-activated protein kinase and mitogen-activated protein kinase-activated protein kinase 2 and the subsequent phosphorylation of the 27-kilodalton heat shock protein in monocytic cells. 780 27

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have previously been reported to induce rapid phosphorylation of the mitogen-activated protein (MAP) kinase. However, little is known about signaling events initiated by both hematopoietins that occur downstream of the MAP kinase. MAP kinase has been shown to phosphorylate the AP-1 transcription factor and also to activate two kinases designated insulin-stimulated protein kinase-1 and MAP kinase-activated protein (MAP-KAP) kinase 2. We show here that IL-3 and GM-CSF induce MAPKAP kinase 2 activity in the human megakaryoblastic leukemia cell line MO7 and phosphorylate the human small heat shock protein Hsp 27 on serine residues in vitro. GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2-mediated Hsp 27 activation occurs independently of proliferation. Hsp 27 phosphorylation was dose-dependent, occurred as early as 5 minutes after factor exposure, and was inhibited by the tyrosine kinase inhibitors genistein and herbimycin A. Furthermore, the protein phosphatase A2 abolished IL-3- and GM-CSF-induced serine phosphorylation of Hsp 27. Taken together, our findings indicate that tyrosine phosphorylation of MAP kinase is a prerequisite for serine phosphorylation of Hsp 27, which is mediated by MAPKAP kinase 2. Hsp 27 has shown activation-dependent translocation from the cytosolic to the nuclear region and has been linked to the cellular stress response. However, its precise function is largely unknown. Our data identify Hsp 27 as a target of the IL-3/GM-CSF stimulation pathway that involves MAP kinase and MAPKAP kinase 2. In addition, our results indicate that Hsp 27 may be target of phosphorylation events not only in the stress response but also in unstressed cells responding to cytokine stimulation.
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PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor induce activation of the MAPKAP kinase 2 resulting in in vitro serine phosphorylation of the small heat shock protein (Hsp 27). 1101 49

The presence of a novel 38 kDa protein that is tyrosine phosphorylated in human neutrophils, a terminally differentiated cell, upon stimulation of these cells with low concentrations of lipopolysaccharide (LPS) in combination with serum has been demonstrated. This 38 kDa protein was identified as the mammalian homologue of HOG1 in yeast, the p38 mitogen-activated protein (MAP) kinase. This conclusion is based on the experimental findings that anti-phosphotyrosine (anti-PY) antibody immunoprecipitates a 38 kDa protein that is recognized by anti-p38 MAP kinase antibody, and conversely, anti-p38 MAP kinase antibody immunoprecipitates a 38 kDa protein that can be recognized by anti-PY antibody. Moreover, this tyrosine phosphorylated protein is found associated entirely with the cytosol. It was also found that this p38 MAP kinase is activated following stimulation of these cells with low concentrations of LPS in combination with serum. This conclusion is based on three experimental findings. First, soluble fractions isolated from LPS-stimulated cells phosphorylate heat shock protein 27 (hsp27) in an in vitro assay, and this effect is not inhibited by protein kinase C and protein kinase A inhibitor peptides. This effect is similar to the effect produced by the commercially available phosphorylated and activated MAPKAP kinase-2 (MAP kinase activated protein kinase-2). Secondly, a 27 kDa protein that aligns with a protein recognized by anti-hsp27 antibody is phosphorylated upon LPS stimulation of intact human neutrophils prelabelled with radioactive phosphate. Lastly, immune complex protein kinase assays, using [gamma-32P]ATP and activating transcription factor 2 (ATF2) as substrates, showed increased p38 MAP kinase activity from LPS-stimulated human neutrophils. The phosphorylation and activation of this p38 MAP kinase can be affected by both G-protein-coupled receptors such as platelet-activating factor (PAF) and non-G-protein-coupled receptors such as the cytokine-coupled receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha). The effect of low concentrations of PAF is greatly increased in cells pretreated with LPS. The tyrosine phosphorylation of the p38 MAP kinase is not restricted to stimuli that mediate their actions through membrane-associated receptors, but it can be affected by agents that bypass membrane-associated receptors such as the protein translation blocker anisomycin. While anisomycin is known to increase the tyrosine phosphorylation of the 54 kDa SAPK (stress-activated protein kinase), this is the first report that shows that anisomycin also tyrosine phosphorylates the p38 MAP kinase. Cytokine receptors that increase the tyrosine phosphorylation and activation of the erk1 and erk2 MAP kinases have less effect on this p38 MAP kinase than those that do not affect the erk1 and erk2 MAP kinases. The possible role of the p38 MAP kinase in the phosphorylation of cytosolic phospholipase A2 is discussed.
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PMID:Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists. 876 79

Recently, three mammalian mitogen-activated protein (MAP) kinases, ERK, SAPK/JNK, and p38/HOG-1 have been identified, each with apparently unique signal transduction pathways. The p38 MAP kinase mediates an intracellular stress-activated signaling pathway by regulating down-stream molecules, such as MAP kinase-activated protein (MAPKAP) kinase 2. To study the tissue specificity of MAPKAP kinase 2, mRNA blots containing multiple human tissues were hybridized with a specific oligonucleotide probe corresponding to human MAPKAP kinase 2. The Northern blot analysis revealed that two mRNA species of MAPKAP kinase 2, with sizes of 4.8 and 3.3 kb, were expressed in high levels in both human heart and skeletal muscle tissues. To better understand how MAPKAP kinase 2 is regulated in myocardium, cultured rat cardiac myoblast (H9c2) cells were stimulated with heat shock, H2O2-induced oxidative stress, or phorbol ester (PMA). Enzymatic activity of cellular MAPKAP kinase 2 in the cell lysates was evaluated using an in vitro kinase assay. Exposure of H9c2 cells to heat shock or oxidative stress induced a transient increase of cellular MAPKAP kinase 2 activity, which reached its peak level within 5 min. In contrast, stimulation of H9c2 cells with PMA, a potential myocardial hypertrophic factor, induced a sustained increase of cellular MAPKAP kinase 2 activity that was detectable for over 1 h. In addition, in vitro protein phosphorylation analysis with recombinant MAPKAP kinase 2 showed that small heat shock protein (hsp25) served as a major substrate molecule for the kinase in H9c2 cells and the protein phosphorylation of cellular hsp25 was stimulated by H2O2-induced oxidative stress or PMA treatment in intact H9c2 cells. Moreover, exposure of H9c2 cells to H2O2-induced oxidative stress or PMA rapidly activated cellular p38 MAP kinase as detected by the induced protein phosphorylation of the kinase. Taken together, these results strongly suggest that MAPKAP kinase 2 may be involved in stress-activated signal transduction in myocardium.
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PMID:High expression and activation of MAP kinase-activated protein kinase 2 in cardiac muscle cells. 928 47

"Stress-regulated" mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H2O2) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H2O2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H2O2 in both cases was observed at 0.5 mM. Whereas activation of p38-MAPK by H2O2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H2O2. MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H2O2 to a similar extent as with ischemia or ischemia/reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SR-MAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-alpha-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.
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PMID:Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. 951 15

The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.
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PMID:Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. 952 66

We investigated the activation of three subfamilies of mitogen-activated protein kinases (MAPKs), namely the stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs), the extracellularly responsive kinases (ERKs) and p38-MAPK, by oxidative stress as exemplified by H2O2 in primary cultures of neonatal rat ventricular myocytes. The 46 and 54 kDa species of SAPKs/JNKs were activated 5- and 10-fold, respectively, by 0.1 mM H2O2 (the maximally effective concentration). Maximal activation occurred at 15-30 min, but was still detectable after 2 h. Both ERK1 and ERK2 were activated 16-fold by 0.1 mM H2O2 with a similar time course to the SAPKs/JNKs, and this was comparable with their activation by 1 microM PMA, the most powerful activator of ERKs that we have so far identified in these cells. The activation of ERKs by H2O2 was inhibited by PD98059, which inhibits the activation of MAPK (or ERK) kinases, and by the protein kinase C (PKC) inhibitor, GF109203X. ERK activation was also inhibited by down-regulation of PMA-sensitive PKC isoforms. p38-MAPK was activated by 0.1 mM H2O2 as shown by an increase in its phosphorylation. However, maximal phosphorylation (activation) was more rapid (<5 min) than for the SAPKs/JNKs or the ERKs. We studied the downstream consequences of p38-MAPK activation by examining activation of MAPK-activated protein kinase 2 (MAPKAPK2) and phosphorylation of the MAPKAPK2 substrate, the small heat shock protein HSP25/27. As with p38-MAPK, MAPKAPK2 was rapidly activated (maximal within 5 min) by 0.1 mM H2O2. This activation was abolished by 10 microM SB203580, a selective inhibitor of certain p38-MAPK isoforms. The phosphorylation of HSP25/27 rapidly followed activation of MAPKAPK2 and was also inhibited by SB203580. Phosphorylation of HSP25/27 was associated with a decrease in its aggregation state. These data indicate that oxidative stress is a powerful activator of all three MAPK subfamilies in neonatal rat ventricular myocytes. Activation of all three MAPKs has been associated with the development of the hypertrophic phenotype. However, stimulation of p38-MAPK and the consequent phosphorylation of HSP25/27 may also be important in cardioprotection.
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PMID:Stimulation of multiple mitogen-activated protein kinase sub-families by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. 967 16

Myocardial adaptation to ischemia has been shown to activate protein tyrosine kinase, potentiating activation of phospholipase D, which leads to the stimulation of mitogen-activated protein (MAP) kinases and MAP kinase-activated protein (MAPKAP) kinase 2. The present study sought to further examine the signal transduction pathway for the MAPKAP kinase 2 activation during ischemic adaptation. Isolated perfused rat hearts were adapted to ischemic stress by repeated ischemia and reperfusion. Hearts were pretreated with genistein to block tyrosine kinase, whereas SB-203580 was used to inhibit p38 MAP kinases. Western blot analysis demonstrated that p38 MAP kinase is phosphorylated during ischemic stress adaptation. Phosphorylation of p38 MAP kinase was blocked by genistein, suggesting that activation of p38 MAP kinase during ischemic adaptation is mediated by a tyrosine kinase signaling pathway. MAPKAP kinase 2 was estimated by following in vitro phosphorylation with recombinant human heat shock protein 27 as specific substrate for MAPKAP kinase 2. Again, both genistein and SB-203580 blocked the activation of MAPKAP kinase 2 during myocardial adaptation to ischemia. Immunofluorescence microscopy with anti-p38-antibody revealed that p38 MAP kinase is primarily localized in perinuclear regions. p38 MAP kinase moves to the nucleus after ischemic stress adaptation. After ischemia and reperfusion, cytoplasmic striations in the myocytes become obvious, indicating translocation of p38 MAP kinase from nucleus to cytoplasm. Corroborating these results, myocardial adaptation to ischemia improved the left ventricular functions and reduced myocardial infarction that were reversed by blocking either tyrosine kinase or p38 MAP kinase. These results demonstrate that myocardial adaptation to ischemia triggers a tyrosine kinase-regulated signaling pathway, leading to the translocation and activation of p38 MAP kinase and implicating a role for MAPKAP kinase 2.
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PMID:Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. 981 94

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