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

A stress-activated, serine/threonine kinase, p38 (also known as HOG1 or MPK2) belongs to a subgroup of mitogen-activated protein kinase (MAPK) superfamily molecules. An activity to activate p38 (p38 activator activity) as well as p38 activity itself were greatly stimulated by hyperosmolar media in mouse lymphoma L5178Y cells. The activator activity has been purified by sequential chromatography. A 36-kDa polypeptide that was coeluted with the activity in the final chromatography step was identified as MAPK kinase 6 (MAPKK6) by protein microsequencing analysis. Monoclonal and polyclonal antibodies raised against recombinant MAPKK6 recognized specifically the 36-kDa MAPKK6 protein but did not cross-react with MKK3 proteins. The use of these anti-MAPKK6 antibodies revealed that two major peaks of the p38 activator activity in the first chromatography step reside in the activated MAPKK6. Using a genetic screen in yeast, we isolated MKK3b, an alternatively spliced form of MKK3. Like MKK3 and MAPKK6, MKK3b was shown to be a specific activator for p38 and was activated by osmotic shock when expressed in COS7 cells. Immunoblotting analysis revealed that MAPKK6 is expressed highly in HeLa and KB cells and scarcely in PC12 cells, whereas MKK3 and MKK3b are expressed in all cells examined. Immunodepletion of MAPKK6 from the extracts obtained from L5178Y cells and KB cells exposed to hyperosmolar media depleted them of almost all of the p38 activator activity, indicating that MAPKK6 is a major activator for p38 in an osmosensing pathway in these cells. In addition, MAPKK6 was activated strongly by tumor necrosis factor-alpha, H2O2, and okadaic acid and moderately by cycloheximide in KB cells. Thus, there are at least three members of p38 activator, MKK3, MKK3b, and MAPKK6, and MAPKK6 may function as a major activator for p38 when expressed.
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PMID:Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2. 890 Jan 84

Despite intensive efforts, the intracellular signaling pathways that mediate apoptosis remain unclear. The human B lymphoma cell line, B104, possesses characteristics that make it an attractive model for analysis of receptor-mediated apoptosis. Although these cells express both membrane IgM (mIgM) and membrane IgD (mIgD) crosslinking mIgM results in significant apoptosis while crosslinking mIgD does not. Our results show that crosslinking mIgM but not mIgD induced a delayed and sustained activation of the mitogen-activated protein kinase (MAPK) family members stress-activated protein kinase (SAPK) and p38 MAPK. The calcium ionophore ionomycin, which also induces apoptosis in B104 cells, stimulated a similar SAPK and p38 MAPK response. Cyclosporin A, a potent inhibitor of apoptosis induced by either mIgM or ionomycin, inhibited activation of both SAPK and p38 MAPK, suggesting that stimulation of these kinases may be required for induction of apoptosis. Collectively, our results indicate that SAPK and p38 MAPK may be downstream targets during mIgM-induced, calcium-mediated, apoptosis in human B lymphocytes.
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PMID:Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes. 894 18

IL-6 is a multifunctional cytokine involved in hemopoiesis, immune regulation, inflammation, neural development, and infection. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor, oncostatin M, IL-11, ciliary neurotropic factor, and cardiotropin-1, all of which initiate signaling through a receptor-associated gp130. IL-6 induces homodimerization of gp130 and activates the Jak/STAT pathway of signal transduction. In addition, IL-6 stimulates the mitogen-activated protein kinases designated ERK (extracellular signal-regulated kinase)-1 and -2. Activation of ERK-1 and -2 may involve the Src homology-2 containing proteins Shc and Grb2. Here we provide evidence that Shc could function as signaling molecules for IL-6 in DeFew-IL-6R/gp130 cells, a human B lymphoma cell line engineered to express high levels of both the IL-6R (p80) and the gp130 subunit. IL-6 was shown to promote the rapid tyrosine phosphorylation of gp130, Jak2, and Shc proteins. Moreover, Shc associated both in vivo and in vitro with phosphorylated gp130 through the Shc-Src homology-2 domain. We also report that Shc bound to activated Jak2 by using the Shc amino terminal phosphotyrosine interaction domain. Following IL-6 stimulation, Shc physically associated with Grb2. Thus, the data point to Shc proteins as a functional link between the Jak2 and Ras pathways of IL-6 signal transduction.
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PMID:Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. 912 68

Prolactin (PRL) stimulates mitogenesis and differentiative processes in a variety of cell types. Not all of the molecules involved in PRL signaling, which follows an initial PRL-receptor interaction, have been identified. In the present studies, PRL is shown to stimulate the differential tyrosyl phosphorylation of three isoforms (ERK-1, 2, and 4) of mitogen-activated protein kinases (MAP kinase) in a rat pre-T lymphoma cell line (Nb2). Evidence also suggests that PRL stimulates the tyrosyl phosphorylation of ERK-3, a MAP kinase isoform recently identified. When G1-arrested Nb2 cells are treated with 50 ng/ml oPRL, ERK-1 through 3 become tyrosyl phosphorylated within minutes (an indication of enzyme activation) and then become dephosphorylated within 30 min. Conversely, ERK-4 is rapidly tyrosyl phosphorylated by 5 min, and remains in this state for at least 1 hr.
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PMID:Differential tyrosyl-phosphorylation of multiple mitogen-activated protein kinase isoforms in response to prolactin in Nb2 lymphoma cells. 916 49

The signal transduction pathway from heterotrimeric G proteins to the mitogen-activated protein kinase (MAPK) cascade is best understood in the yeast mating pheromone response, in which a serine/threonine protein kinase (STE20) serves as the critical linking component. Little is known in metazoans on how G proteins and the MAPK cascade are coupled. Here we provide genetic and biochemical evidence that a tyrosine kinase cascade bridges G proteins and the MAPK pathway in vertebrate cells. Targeted deletion of tyrosine kinase Csk in avian B lymphoma cells blocks the stimulation of MAPK by Gq-, but not Gi-, coupled receptors. In cells deficient in Bruton's tyrosine kinase (Btk), Gi-coupled receptors failed to activate MAPK, while Gq-coupled receptor-mediated stimulation is unaffected. Taken together with our previous data on tyrosine kinases Lyn and Syk, the Gq-coupled pathway requires tyrosine kinases Csk, Lyn, and Syk, while the Gi-coupled pathway requires tyrosine kinases Btk and Syk to feed into the MAPK cascade in these cells. The central role of Syk is further strengthened by data showing that Syk can bind to purified Lyn, Csk, or Btk.
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PMID:Genetic evidence for a tyrosine kinase cascade preceding the mitogen-activated protein kinase cascade in vertebrate G protein signaling. 920 44

Contact with bone marrow stromal cells is crucial for the normal growth and development of B-cell precursors. We have previously shown that human bone marrow stromal cell tyrosine kinase activity can be activated by direct contact with B-lymphoid cells (J Immunol 155:2359, 1995). In the present study, we show that increased tyrosine phosphorylation of focal adhesion kinase, paxillin, and extracellular-related kinase 2 (or p42 MAP kinase) accounted for the major changes occurring in stromal cell tyrosine phosphorylation after 5 to 10 minutes of contact with the RAMOS B-lymphoma cell line. Although adhesion of B-cell precursors to stromal cells is primarily mediated by very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), VLA-4-deficient and adhesion-deficient RAMOS cells were equally capable of stimulating stromal cell tyrosine phosphorylation. Similar changes in the tyrosine phosphorylation pattern of stromal cells were induced by contact with normal human B-cell precursors and several other B-lineage cell lines. After 5 to 30 minutes of contact with stromal cells, no change in protein tyrosine phosphorylation was detected in RAMOS or normal human B-cell precursors removed from stromal cells. Pretreatment of stromal cells with cytochalasin D abrogated contact-mediated enhancement of stromal cell tyrosine phosphorylation, suggesting that an intact cytoskeleton was essential. These results suggest that B-cell contact activates stromal cell signaling cascades that regulate cytoskeletal organization and transcription, independent of the interaction mediated by VLA-4 and VCAM-1.
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PMID:Contact between human bone marrow stromal cells and B lymphocytes enhances very late antigen-4/vascular cell adhesion molecule-1-independent tyrosine phosphorylation of focal adhesion kinase, paxillin, and ERK2 in stromal cells. 926 82

We showed in a previous study that the expression, in Gs-deficient S49 cyc- cells, of a fusion gene encoding the beta 2-adrenergic Receptor (beta 2AR) and the alpha subunit of the Gs protein (Gs alpha) restored beta 2AR-dependent activation of adenylyl cyclase. We report here the extensive characterization of short- and long-term regulation of the beta 2AR/Gs alpha fusion protein activity and its pharmacological effect after expression in two cancer cell lines. In contrast with native beta 2ARs and Gs, the receptor and the alpha s subunit moieties of the beta 2AR/Gs alpha fusion protein did not undergo functional uncoupling. After a sustained incubation with isoproterenol or forskolin, the accumulation of cAMP could still be observed in S49 beta Gs cells, expressing the fusion gene, which showed, in addition, an up-regulation of their beta 2AR binding sites, while in S49 wt cells, the same treatments completely abolished the rise of cAMP and markedly reduced the number of receptors. cAMP-activation of protein kinase A (PKA) is known to modulate proliferation of most cells. We studied the effect of long term beta 2AR/Gs alpha activation on the growth rate of S49 lymphoma cells and carcinoma carB cells, a highly proliferative cancer cell line expressing oncogenic ras protein. The beta 2AR agonist salmeterol blocked the proliferation of both S49 and carB beta 2Gs cells, while this treatment did not change the growth of wild-type cells. In carB beta 2Gs cells, this effect may be reinforced by a significant basal activity of the fusion protein and by agonist-promoted MAP kinase inhibition. In conclusion, the stimulatory overload provided by the beta 2AR/Gs alpha fusion protein led to the inhibition of cAMP-sensitive cancer cell proliferation in vitro.
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PMID:Activation of a beta 2-adrenergic receptor/Gs alpha fusion protein elicits a desensitization-resistant cAMP signal capable of inhibiting proliferation of two cancer cell lines. 927 75

The lymphocyte integrin alpha 4 beta 7 is a cell surface adhesion receptor involved in initiating lymphocyte homing to gut-associated/mucosal lymphoid tissues by binding the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Other known ligands are vascular cell adhesion molecule-1, fibronectin, and the alpha 4 integrin chain itself. Here, we demonstrate that stimulation of the alpha 4 beta 7 integrin through its alpha 4 subunit (mAb R1-2), beta 7 subunit (mAb M293), or the combinatory epitope (mAb DATK32) enhances tyrosine phosphorylation of several cellular proteins in the murine TK1 lymphoma cell line. The two src-kinases p56lck and p59fyn were identified as possible mediators and substrates of the detected tyrosine phosphorylation. Furthermore, we observed activation of the MAP-kinases ERK1/2.
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PMID:Stimulation of TK1 lymphoma cells via alpha 4 beta 7 integrin results in activation of src-tyrosine- and MAP-kinases. 934 71

We evaluated induction of lymphomas by the methylating carcinogen, N-methylnitrosourea [MNU], in transgenic mice expressing both LMO1 and the DNA repair gene, MGMT, in the thymus. The goal was to determine whether environmental mutagens shorten the latency or increase the incidence of LMO1 + lymphomas and whether mice transgenic for both LMO1 and MGMT, and thereby able to repair O6-methylguanine DNA adducts induced by MNU, would be protected. Mice heterozygous for LMO1 or MGMT were crossed and offspring treated with MNU at 6 weeks of age. MNU induced lymphoma incidence was highest in the LMO1 mice, 91% and lowest in the hMGMT + mice, 15%. MNU induced K-ras mutations in codon 12 in non-MGMT transgenics resulted in a shorter latency of tumors and accounting for half of the early lymphomas in LMO1 mice. The effect of MNU was abrogated in the LMO1/hMGMT transgenic mice, indicating the ability of MGMT expression to block the carcinogenic effect of MNU even in cancer prone mice. Thus, methylating agents potentiate lymphomagenesis of LMO1, in part through activation of K-ras and the MAPK pathway, a process which appear to synergize with LMO1 mediated transcription activation. O6-alkylguanine DNA-alkyltransferase mediated DNA repair effectively blocks chemical carcinogenesis in mice carrying the LMO1 oncogene.
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PMID:Potentiation of lymphomagenesis by methylnitrosourea in mice transgenic for LMO1 is blocked by O6-alkylguanine DNA-alkyltransferase. 936 29

Perillic acid, a major metabolite of d-limonene, substantially suppressed interleukin-2 (IL-2) and IL-10 production in mitogen-activated T lymphocytes. The effects of perillic acid on cytokine secretion were selective: IL-6 and transforming growth factor-beta 1 (TGF-beta 1) generation were unchanged. In H9 T lymphoma cells, exposure to perillic acid resulted in a dose-dependent depletion of membrane-bound Ras proteins. Unlike hydroxymethyl-glutaryl-CoA reductase or protein farnesyltransferase inhibitors, perillic acid did not induce a shift of membrane-bound into cytosolic p21ras but depleted total cellular Ras proteins. Triggering of the T cell receptor (TCR) perturbs the guanine nucleotide binding cycle of p21ras and in turn induces phosphorylation and activation of mitogen-activated protein kinases (MAPK). In perillic acid-treated cells, the levels of phosphorylated but not total MAPK were also decreased in a dose-dependent manner. Taken together, we provide evidence that perillic acid interrupts signalling via the Ras/MAP kinase pathway by depleting farnesylated Ras levels, an effect which may contribute to its inhibition of IL-2 production and T cell activation.
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PMID:Perillic acid inhibits Ras/MAP kinase-driven IL-2 production in human T lymphocytes. 943 75


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