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)

We examined the molecular mechanism of DT-5461-induced LPS antagonism in human peripheral blood monocytes. Dose-response studies revealed that LPS-induced IL-1 and TNF-alpha production was apparently totally suppressed in a competitive manner by a 10-fold excess of DT-5461. A 10-fold excess of DT-5461 significantly blocked the binding of FITC-LPS to the monocytes. DT-5461 suppressed IL-1 and TNF-alpha mRNA expression in LPS-activated monocytes. Western blots showed that DT-5461 suppressed the LPS-induced tyrosine phosphorylation of p42mapk/ERK2. These results suggested that the competitive binding inhibition and repression of early intracellular signaling involved in DT-5461-mediated LPS antagonism.
 ...
PMID:Endotoxin antagonism by a synthetic lipid A analogue, DT-5461, with low endotoxicity in human peripheral blood monocytes. 748 14

Cross-linking of the dichotomous cell surface receptors for TNF-alpha (CD120a (p55) and CD120b (p75)) induces the activation of a variety of macrophage responses that mediate the role of this cell in inflammation and host defense. Although significant progress has been made in understanding the role that lipid second messengers play in mediating the action(s) of this multifunctional cytokine, less is known about the role of specific kinases in TNF-alpha-initiated signaling. We show that exposure of mouse macrophages to TNF-alpha stimulates a rapid and transient tyrosine phosphorylation and activation of p42mapk/erk2. By contrast, p44mapk/erk1 was found to be constitutively phosphorylated, with minimal further response to TNF-alpha. To investigate the use of CD120a (p55) and CD120b (p75) in the activation of p42mapk/erk2 in mouse macrophages, we determined the effects of blocking Ab on the activation of p42mapk/erk2 in response to TNF-alpha. In addition, we independently cross-linked each receptor with specific agonistic Ab, which have previously been shown to mimic the effects of TNF-alpha. Collectively, the results from these experiments indicate that cross-linking of CD120a (p55), but not that of CD120b (p75), was both necessary and sufficient for the activation of p42mapk/erk2 in mouse macrophages.
 ...
PMID:Activation of p42mapk/erk2 following engagement of tumor necrosis factor receptor CD120a (p55) in mouse macrophages. 763 14

In soluble peptidoglycan (PGN) from staphylococcal cell walls as well as soluble PGN (sPGN) secreted by staphylococci in the presence of beta-lactam antibiotics induced TNF-alpha mRNA and secretion of bioactive TNF-alpha in the murine RAW264.7 macrophage cell line, PGN and sPGN also induced rapid and dose-dependent tyrosine phosphorylation of several cellular proteins, including lyn and mitogen-activated protein kinases (extracellular signal-regulated kinases; but not hck, fgr, or vav) and increased the activities of mitogen-activated protein and rsk kinases. These PGN- and sPGN-induced effects were qualitatively similar to the effects induced by ReLPS, but higher concentrations of PGN and sPGN than ReLPS were required. In contrast to the ReLPS-induced effects, the PGN- and sPGN-induced effects were not inhibited by polymyxin B. All PGN-, sPGN-, and ReLPS-induced effects were serum independent, since they were observed both in RAW264.7 cells grown and stimulated in the presence of serum and in the cells adapted to growth and stimulated in a serum- and albumin-free medium. These results indicate that lyn, extracellular signal-regulated kinase, and rsk signal transduction molecules may be involved in macrophage activation by PGN and further support the idea that PGN and LPS may activate the cells through similar mechanisms.
 ...
PMID:Peptidoglycan induces transcription and secretion of TNF-alpha and activation of lyn, extracellular signal-regulated kinase, and rsk signal transduction proteins in mouse macrophages. 765 Mar 92

The early growth response 1 (EGR-1) gene is induced by mitogenic and differentiating signals in diverse cell types. The present studies have examined the effects of TNF-alpha on the induction of EGR-1 expression in human myeloid leukemia cells and the potential cytoplasmic signaling cascades that transduce TNF-induced signals to the nucleus. The results demonstrate that treatment of HL-60 cells with TNF is associated with the transient induction of the EGR-1 gene. The results also demonstrate that TNF treatment is associated with activation of the serine/threonine kinase, pp90rsk, which acts upstream to EGR-1 gene induction. Partial purification of pp90rsk by affinity chromatography demonstrated an increase in S6 peptide phosphorylation in response to TNF treatment. Because TNF activates sphingomyelin hydrolysis, we also studied the effects of sphingomyelinase (SMase) on induction of EGR-1 and pp90rsk. The results demonstrate that SMase also activates pp90rsk and induces EGR-1 gene expression. Previous work has demonstrated that mitogen-activated protein (MAP) kinase activates pp90rsk. The present studies further show that treatment with TNF or SMase is associated with induction of both the pp42/44 MAP and the related Jun kinases. Induction of pp42/44 MAP kinase activity is temporally related to activation of pp90rsk and the EGR-1 gene. These findings support the involvement of an MAP kinase/pp90rsk/EGR-1 cascade in the response of myeloid leukemia cells to TNF.
 ...
PMID:Activation of serine/threonine protein kinases and early growth response 1 gene expression by tumor necrosis factor in human myeloid leukemia cells. 770 52

Recombinant human TNF-alpha induces increased tyrosine phosphorylation of several proteins in human neutrophils (PMN) adhered to serum-coated plastic. When PMN are kept in suspension, TNF does not induce significant tyrosine phosphorylation. In adherent PMN, a 42-kDa protein (p42) displayed the most striking increase in tyrosine phosphorylation after TNF stimulation. Cell lysates of TNF-stimulated PMN were separated by two-dimensional gel electrophoresis and were immunoblotted with either anti-phosphotyrosine (alpha-PY) mAb or anti-mitogen-activated protein kinase (alpha-MAPK) mAb. Both Abs detected p42, and the spots were superimposable. Cell lysates were immunoprecipitated with agarose-conjugated alpha-PY mAb, electrophoresed, and then immunoblotted with alpha-MAPK Ab; alternatively, cell lysates were immunoprecipitated with agarose-conjugated alpha-MAPK Ab, electrophoresed, and then immunoblotted with alpha-PY mAb. In both cases, p42 was detected. These results demonstrate that p42 is a member of the MAPK family. TNF induces a time-and dose-dependent increase in tyrosine phosphorylation of p42 and MAPK activity. The degree of p42 tyrosine phosphorylation parallels the level of MAPK activity. MAPK activity was determined by measuring 32P phosphorylation of a synthetic peptide containing the recognition site on myelin basic protein for MAPK. PMN pretreatment with genistein, a tyrosine kinase inhibitor, inhibited the TNF-induced increase in tyrosine phosphorylation and MAPK activity. These results indicate that TNF signaling involves activation of MAPK.
 ...
PMID:TNF-alpha induces tyrosine phosphorylation of mitogen-activated protein kinase in adherent human neutrophils. 772 27

Although tumor necrosis factor (TNF)-alpha stimulation of human neutrophils does not result in a significant release of arachidonic acid, it primes the cell for arachidonic acid release when cells are further stimulated by agents that induce an intracellular calcium increase. We demonstrate that TNF-alpha stimulation of neutrophils induces the phosphorylation of cytosolic phospholipase A2 (cPLA2) and also increases its activity. These results indicate that although TNF-alpha, by itself, does not cause the release of arachidonic acid in intact cells, it increases the phosphorylation and activation of the enzyme cPLA2. Since we recently found that TNF-alpha stimulation of neutrophils does not increase the tyrosine phosphorylation or activation of the p42erk2 and p44erk1 mitogen-activated protein kinases (MAPKs), the present studies demonstrate the involvement of a MAPK independent pathway in the phosphorylation and activation of cPLA2.
 ...
PMID:A mitogen-activated protein kinase independent pathway involved in the phosphorylation and activation of cytosolic phospholipase A2 in human neutrophils stimulated with tumor necrosis factor-alpha. 772 46

The zeta isotype of protein kinase C (zeta PKC), a distinct PKC unable to bind phorbol esters, is required during NF-kappa B activation as well as in mitogenic signalling in Xenopus oocytes and mammalian cells. To investigate the mechanism(s) for control of cellular functions by zeta PKC, this enzyme was expressed in Escherichia coli as a fusion protein with maltose binding protein (MBP), to allow immobilization on amylose beads to study signalling proteins in cell extracts that might form complex(es) with zeta PKC. The following evidence for interaction with the NF-kappa B/I kappa B pathway was obtained. MBP-zeta PKC, but not MBP, bound and activated a potentially novel I kappa B kinase of approximately 50 kDa molecular weight able to regulate I kappa B-alpha function. Activation of the I kappa B kinase was dependent on zeta PKC enzymatic activity and ATP, suggesting that zeta PKC controls, directly or indirectly, the activity of a functionally significant I kappa B kinase. Importantly, zeta PKC immunoprecipitates from TNF-alpha-stimulated NIH-3T3 fibroblasts displayed a higher I kappa B phosphorylating activity than untreated controls, indicating the in vivo relevance of these findings. We also show here that zeta PKC associates with and activates MKK-MAPK in vitro, suggesting that one of the mechanisms whereby overexpression of zeta PKC leads to deregulation of cell growth may be accounted for at least in part by activation of the MKK-MAPK complex. However, neither MKK nor MAPK is responsible for the putative I kappa B phosphorylating activity. These data provide a decisive step towards understanding the functions of zeta PKC.
 ...
PMID:zeta PKC induces phosphorylation and inactivation of I kappa B-alpha in vitro. 802 69

Previous studies have shown that macrophages play an important role in both the initiation of protective responses and the effector mechanism of immunity to Toxoplasma gondii. The purpose of this investigation was to characterize the responses of macrophages to a soluble antigen extract of T. gondii tachyzoites (STAg) in comparison with a prototypic macrophage-activating agent, lipopolysaccharide (LPS), and to determine whether STAg-induced signaling requires a functional Lps gene. Toward this end, tumor necrosis factor (TNF) secretion, a panel of six LPS-inducible genes, and protein tyrosine phosphorylation were examined to gain insights into macrophage responses to STAg. STAg stimulated both C3H/OuJ (Lpsn) and C3H/HeJ (Lpsd) macrophages to secrete bioactive TNF-alpha and to express a subset of LPS-inducible genes (encoding TNF-alpha, TNF receptor 2, and interleukin-1 beta). In contrast to LPS, STAg failed to stimulate Lpsn or Lpsd macrophages to express genes encoding IP-10, D3, or D8. STAg also induced a pattern of tyrosine phosphorylation identical to that induced by LPS; mitogen-activated protein kinase 47-kDa and 43-kDa isoforms and a 41-kDa protein of undetermined identity were inducibly phosphorylated. The ability of STAg to induce TNF-alpha, encoded by a subset of LPS-inducible genes, and tyrosine phosphoproteins was not affected by LPS inhibitors, confirming that the macrophage response to the parasite extract could not be attributed to LPS contamination. We propose that STAg, while differing from LPS in the pattern of macrophage genes induced, may share with LPS two signaling pathways that are intact in Lpsd macrophages.
 ...
PMID:Toxoplasma gondii soluble antigen induces a subset of lipopolysaccharide-inducible genes and tyrosine phosphoproteins in peritoneal macrophages. 803 14

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal-regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF-alpha and IL-1-beta, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the "stress activated' protein kinases (SAPKs, also termed Jun N-terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF-alpha actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells.
 ...
PMID:Protein kinase cascades activated by stress and inflammatory cytokines. 875 35

The mechanism of TNF-alpha to regulate glucose metabolism remains unclear. To further delineate the TNF-alpha signal transduction pathway mediating glucose metabolism, we utilized L6 rat myoblasts which contain the receptors for the insulin-like growth factor-I (IGF-I) and TNF-alpha, and the ability of both ligands to stimulate glucose uptake was compared. IGF-I (6.5 nM) maximally stimulated glucose uptake 7-fold after 24 h incubation, while 23 nM TNF-alpha maximally stimulated glucose uptake 3-fold only after 48 h incubation. IGF-I receptor beta-subunit, insulin receptor substrate-1 (IRS-1), and mitogen-activated protein (MAP) kinase were all phosphorylated in response to 6.5 nM IGF-I after 10 min incubation. In contrast, the treatment with 23 nM TNF-alpha failed to phosphorylate either IGF-I receptor beta-subunit or IRS-1 but did phosphorylate MAP kinase as much as IGF-I did. Despite a similar extent to which TNF-alpha induced MAP kinase phosphorylation as IGF-I did, TNF-alpha stimulated glucose uptake less compared to IGF-I. The results indicate that MAP kinase phosphorylation is not sufficient for glucose uptake in L6 myoblasts. TNF-alpha-elicited signal transduction to glucose uptake may utilize a different pathway from that seen with IGF-I.
 ...
PMID:TNF-alpha stimulates glucose uptake in L6 myoblasts. 880 77


1 2 3 4 5 6 7 8 9 10 Next >>