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)

Nuclear factor kappaB (NF-kappaB) is a eukaryotic member of the Rel family of transcription factors whose biological activity is post-translationally regulated by its assembly with various ankyrin-rich cytoplasmic inhibitors, including IkappaBalpha. Expression of NF-kappaB in the nucleus occurs after signal-induced phosphorylation, ubiquitination, and proteasome-mediated degradation of IkappaBalpha. The induced proteolysis of IkappaBalpha unmasks the nuclear localization signal within NF-kappaB, allowing its rapid migration into the nucleus, where it activates the transcription of many target genes. At present, the identity of the IkappaBalpha kinase(s) that triggers the first step in IkappaBalpha degradation remains unknown. We have investigated the potential function of the 90-kDa ribosomal S6 kinase, or pp90(rsk), as a signal-inducible IkappaBalpha kinase. pp90(rsk) lies downstream of mitogen-activated protein (MAP) kinase in the well characterized Ras-Raf-MEK-MAP kinase pathway that is induced by various growth factors and phorbol ester. We now show that pp90(rsk), but not pp70(S6K) or MAP kinase, phosphorylates the regulatory N terminus of IkappaBalpha principally on serine 32 and triggers effective IkappaBalpha degradation in vitro. When co-expressed in vivo in COS cells, IkappaBalpha and pp90(rsk) readily assemble into a complex that is immunoprecipitated with antibodies specific for either partner. While phorbol 12-myristate 13-acetate produced rapid activation of pp90(rsk), in vivo, other potent NF-kappaB inducers, including tumor necrosis factor alpha and the Tax transactivator of human T-cell lymphotrophic virus, type I, failed to activate pp90(rsk). These data suggest that more than a single IkappaBalpha kinase exists within the cell and that these IkappaBalpha kinases are differentially activated by different NF-kappaB inducers.
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PMID:The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro. 926 Nov 39

Transcription factor NF-kappa B plays a crucial role in the regulation of numerous genes involved in the inflammatory response and control of cell death. Activation of NF-kappa B is mediated through the phosphorylation of its inhibitory subunit I kappa B, followed by the subsequent degradation of I kappa B at the proteasome. A second level of control involves phosphorylation events of NF-kappa B in the cell nucleus. The kinases that regulate these processes are rather undefined. NF-kappa B activation is induced by a great variety of predominantly pathogenic and noxious stimuli. A similar spectrum of conditions triggers the activation of two mitogen-activated protein (MAP) kinase cascades, designated as the JNK and p38 kinase pathways. Several points of evidence suggest that MAP kinases can participate in the regulation of NF-kappa B transcriptional activity. Here, we will review very recent data demonstrating that both the JNK and the p38 pathways are involved in the activation of NF-kappa B in the cytoplasm as well as in modulation of its transactivating potential in the nucleus.
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PMID:Regulation of NF-kappa B activation by MAP kinase cascades. 944 76

Protein kinases of the Raf family act as signal-transducing elements downstream of activated cell surface receptors and are involved in the regulation of proliferation, differentiation, and cell survival. Whereas the role of c-Raf-1 as a mitogen-activated protein/extracellular signal-regulated kinase activator within the mitogenic cascade is well established, less is known about the mammalian Raf isoforms A-Raf and B-Raf. Here we report that B-Raf binds to PA28alpha, one of two subunits of the 11S regulator of proteasomes. PA28alpha was isolated as a B-Raf-binding protein in a yeast two-hybrid screen of a PC12 cDNA library. Both proteins can be coimmunoprecipitated after transient expression in 293 cells. No association could be found between PA28alpha and A-Raf or c-Raf-1. B-Raf binds to a region in PA28alpha that is important for its proteasome-activating function.
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PMID:Interaction between the protein kinase B-Raf and the alpha-subunit of the 11S proteasome regulator. 967 60

Injury of the endothelial cells by the induction of apoptotic cell death may play an important role in the pathophysiology of atherosclerosis and the progression of inflammatory diseases. Here, we demonstrate an essential role for the ubiquitin-dependent proteasome complex in stimulus-induced degradation of the antiapoptotic protein Bcl-2. Bcl-2 is specifically degraded after stimulation of human endothelial cells with tumor necrosis factor (TNF)-alpha in a process that is inhibited by specific proteasome inhibitors. In addition, the mutation of the potential ubiquitin-acceptor amino acids of Bcl-2 provides protection against TNF-alpha- and staurosporine-induced degradation in vitro and in vivo. Moreover, mimicking phosphorylation of the putative mitogen-activated protein (MAP) kinase sites of the Bcl-2 protein (Thr 56, Thr 74, and Ser 87) abolishes its degradation, suggesting a link between the MAP kinase pathway to the proteasome pathway. Finally, inhibition of Bcl-2 degradation either by suppressing ubiquitin-dependent proteasomal degradation or by mimicking continuous phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers resistance against induction of apoptosis. Thus, the degradation of Bcl-2 may unleash the inhibitory function of Bcl-2 over the apoptosome and may thereby amplify the activation of the caspase cascade.
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PMID:Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. 1035 85

Long-term facilitation (LTF) of the sensory-to-motor synapses that mediate defensive reflexes in Aplysia requires induction of the transcription factor Aplysia CCAAT/enhancer binding protein (ApC/EBP) as an early response gene. We examined the time course of ApC/ EBP DNA binding during the induction of LTF: Binding activity was detected within 1 h of the sensitization treatment with serotonin, reached a maximum at 2 h, and decreased after 6 h. How are DNA binding and the turnover of ApC/EBP regulated? We find that phosphorylation of ApC/EBP by mitogen-activated protein (MAP) kinase is essential for binding. MAP kinase appears to be activated through protein kinase C. We also showed that ApC/EBP is degraded through the ubiquitin-proteasome pathway but that phosphorylation by MAP kinase renders it resistant to proteolysis. Thus, phosphorylation by MAP kinase is required for ApC/EBP to act as a transcription activator as well as to assure its stability early in the consolidation phase, when genes essential for the development of LTF begin to be expressed.
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PMID:Activation and degradation of the transcription factor C/EBP during long-term facilitation in Aplysia. 1058 1

Proteolysis by the ubiquitin/proteasome pathway regulates the intracellular level of several proteins, some of which control cell proliferation and cell cycle progression. To determine what kinds of signaling cascades are activated or inhibited by proteasome inhibition, we treated PC12 cells with specific proteasome inhibitors and subsequently performed in-gel kinase assays. N-Acetyl-Leu-Leu-norleucinal and lactacystin, which inhibit the activity of the proteasome, induced the activation of p42/p44 mitogen-activated protein (MAP) kinases [extracellular signal-regulated kinases (ERKs) 1 and 2]. In contrast, N-acetyl-Leu-Leu-methional, which inhibits the activity of calpains, but not of the proteasome, failed to induce ERK activation. Uniquely, the kinetics of MAP kinase activation induced by proteasome inhibitors are very slow compared with those resulting from activation by nerve growth factor; ERK activation is detectable only after a 5-h treatment with the inhibitors, and its activity remained unchanged for at least until 27 h. Proteasome inhibitor-initiated ERK activation is inhibited by pretreatment with the ERK kinase inhibitor PD 98059, as well as by overexpression of a dominant-negative form of Ras. Thus, proteasome inhibitors induce sustained ERK activation in a Ras-dependent manner. Proteasome inhibitor-induced neurite outgrowth, however, is not inhibited by PD 98059, indicating that sustained activation of ERKs is not the factor responsible for proteasome inhibitor-induced morphological differentiation. Our data suggest the presence of a novel mechanism for activation of the MAP kinase cascade that involves proteasome activity.
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PMID:Delayed and sustained activation of p42/p44 mitogen-activated protein kinase induced by proteasome inhibitors through p21(ras) in PC12 cells. 1061 9

The mitogen-activated protein (MAP) kinase cascade is inactivated at the level of MAP kinase by members of the MAP kinase phosphatase (MKP) family, including MKP-1. MKP-1 was a labile protein in CCL39 hamster fibroblasts; its degradation was attenuated by inhibitors of the ubiquitin-directed proteasome complex. MKP-1 was a target in vivo and in vitro for p42(MAPK) or p44(MAPK), which phosphorylates MKP-1 on two carboxyl-terminal serine residues, Serine 359 and Serine 364. This phosphorylation did not modify MKP-1's intrinsic ability to dephosphorylate p44(MAPK) but led to stabilization of the protein. These results illustrate the importance of regulated protein degradation in the control of mitogenic signaling.
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PMID:Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. 1061 68

Ligand-dependent down-regulation that leads to rapid and extensive loss of protein is characteristic of several nuclear steroid receptors, including human progesterone receptors (PRs). In breast cancer cells, >95% of PRs are degraded 6 h after the start of progestin treatment. The mechanism for down-regulation is unknown. We examined the role of PR phosphorylation by mitogen-activated protein kinases (MAPKs) in this process. Lactacystin and calpain inhibitor I, specific inhibitors of the 26S proteasome, blocked progestin-induced down-regulation, and ubiquitinated conjugates of PR accumulated in cells. Ligand-dependent PR degradation was also blocked by specific inhibition of p42 and p44 MAPKs. To define the targets of phosphorylation by this kinase, two serine/proline MAPK consensus sites on PR were mutated. We demonstrate that mutation of PR serine-294 to alanine (S294A) specifically and completely prevents ligand-dependent receptor down-regulation. We also find that rapid, ligand-independent degradation of immature PR intermediates occurs by a proteasome-mediated pathway. These results demonstrate that PR destruction, by either of two alternate routes, is mediated by the 26S proteasome. Specifically, down-regulation of mature PRs occurs by a mechanism in which ligand binding activates PR phosphorylation by MAPKs at a unique serine residue, which then targets the receptors for degradation.
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PMID:Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. 1065 79

The ratio of proapoptotic versus antiapoptotic Bcl-2 members is a critical determinant that plays a significant role in altering susceptibility to apoptosis. Therefore, a reduction of antiapoptotic protein levels in response to proximal signal transduction events may switch on the apoptotic pathway. In endothelial cells, tumor necrosis factor alpha (TNF-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein Bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate Bcl-2 degradation. Mutation of the consensus protein kinase B/Akt site or of potential protein kinase C or cyclic AMP-dependent protein kinase sites does not affect Bcl-2 stability. In contrast, inactivation of the three consensus mitogen-activated protein (MAP) kinase sites leads to a Bcl-2 protein that is ubiquitinated and subsequently degraded by the 26S proteasome. Inactivation of these sites within Bcl-2 revealed that dephosphorylation of Ser87 appears to play a major role. A Ser-to-Ala substitution at this position results in 50% degradation, whereas replacement of Thr74 with Ala leads to 25% degradation, as assessed by pulse-chase studies. We further demonstrated that incubation with TNF-alpha induces dephosphorylation of Ser87 of Bcl-2 in intact cells. Furthermore, MAP kinase triggers phosphorylation of Bcl-2, whereas a reduction in Bcl-2 phosphorylation was observed in the presence of MAP kinase-specific phosphatases or the MAP kinase-specific inhibitor PD98059. Moreover, we show that oxidative stress mediates TNF-alpha-stimulated proteolytic degradation of Bcl-2 by reducing MAP kinase activity. Taken together, these results demonstrate a direct protective role for Bcl-2 phosphorylation by MAP kinase against apoptotic challenges to endothelial cells and other cells.
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PMID:Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. 1066 63

In the process of positive selection, immature CD4+8+ double positive (DP) thymocytes expressing TCR reactive to self-MHC by appropriate avidity develop into mature thymocytes. Positive selection involves not only down-regulation of either CD4 or CD8 but also acquisition of immunocompetent potential such as cell proliferation and cytokine production. To understand the molecular basis for such functional maturation during the positive selection process, we examined whether nonselected DP, selected DP, and CD4+8- single positive thymocytes possess the activation potential for signaling pathways from mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) to AP-1. In response to stimulation, a marked induction of c-Fos protein expression as well as cell proliferation is detected only in CD4+8- single positive cells but not in selected and nonselected DP cells, though mitogen-activated protein kinase activities and c-fos transcripts are equally induced. In the presence of proteasome inhibitors, c-Fos protein became detectable in selected DP cells but still not in nonselected DP cells, suggesting that DP cells receiving positive selection signals acquire the capacity to translate the c-fos gene, but it may not be sufficiently high to overcome the degradation of c-Fos protein. These data indicate that the translating ability of the c-fos gene is up-regulated in the thymic positive selection process, from nonselected DP to CD4+8- single positive cells through positively selected DP cells. The distinguished responsiveness to stimulation in thymocytes with and without positive selection may be a result in part of the distinct regulation of the c-fos gene at the translational level.
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PMID:Molecular basis for functional maturation of thymocytes: increase in c-fos translation with positive selection. 1082 Feb 33


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