Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Fas ligand and tumor necrosis factor alpha (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis.
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PMID:Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor alpha. 955 74

We previously demonstrated that p38 MAPK is a crucial mediator in the NF-kappaB-dependent gene activation induced by TNF. Here, we have studied the role of several TNF receptor-associated proteins and caspases in p38 MAPK activation by TNF. The latter appears to be dependent on TRAF2, but independent of FADD or caspases. Remarkably, p38 MAPK activation by TNF proceeds independently of the TRAF2-associated NF-kappaB-inducing kinase NIK, which is known to bind and activate two recently identified IkappaB kinases. These results demonstrate that two kinase pathways involved in NF-kappaB regulation, viz. NIK and p38 MAPK-mediated, diverge at the level of TRAF2.
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PMID:TRAF2 plays a dual role in NF-kappaB-dependent gene activation by mediating the TNF-induced activation of p38 MAPK and IkappaB kinase pathways. 955 46

CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on T, B, and NK cells. The signal via CD27 plays pivotal roles in T-T and T-B cell interactions. Here we demonstrate that overexpression of CD27 activates NF-kappaB and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). Deletion analysis of the cytoplasmic domain of CD27 revealed that the C-terminal PIQEDYR motif was indispensable for both NF-kappaB and SAPK/JNK activation and was also required for the interaction with TNF receptor-associated factor (TRAF) 2 and TRAF5, both of which have been implicated in NF-kappaB activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-kappaB and SAPK/JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-kappaB-inducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-kappaB and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-kappaB and SAPK/JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-kappaB and SAPK/JNK activation.
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PMID:CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase. 958 83

The subcellular localization of the TNF receptor-associated factor-2 (TRAF2) adaptor protein in human endothelial cells, which mediates proinflammatory responses of TNF, has been analyzed by confocal immunofluorescence microscopy and by Western blotting of fractionated cell extracts. Rabbit antisera reactive with either amino- or carboxyl-terminal TRAF2 peptides frequently but not uniformly stain nuclei of cultured HUVEC or the established human endothelial cell line, ECV304. However, Western blotting reveals significant heterogeneity in the reactivities of these polyclonal Abs. Transiently transfected HUVEC expressing FLAG epitope-tagged TRAF2 consistently show prominent nuclear localization, and deletion mutants of TRAF2 identify the portion of the molecule responsible for nuclear localization as the amino-terminal ring finger domain. TNF treatment does not appear to influence the localization of endogenous or transfected TRAF2 protein. Transfection of the amino-terminal half of the TRAF2 molecule, containing the ring and zinc finger domains, which localizes to the nucleus, results in activation of E-selectin but not of NF-kappaB promoter-reporter gene transcription or of c-Jun N-terminal kinase activation. These observations suggest that TRAF2 may reside in the nucleus and directly regulate transcription, independent of its role in cytoplasmic signal transduction.
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PMID:The N-terminal domains target TNF receptor-associated factor-2 to the nucleus and display transcriptional regulatory activity. 964 39

Ceramide has been implicated in the activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK). Binding of tumour necrosis factor (TNF) to its 55 kDa receptor (TR55) leads to the generation of ceramide through activation of either acid or neutral sphingomyelinase (A/N-SMase) as well as to potent activation of SAPK/JNK. We have examined a putative role of both N- and A-SMase in the TR55-dependent activation of SAPK/JNK. The analysis of TR55 deletion mutants expressed in 70Z/3 pre-B cells revealed that activation of SAPK/JNK occurs independently of N-SMase. Although both SAPK/JNK and A-SMase are activated by the death domain of TR55, pharmacological prevention of the TR55-dependent activation of A-SMase, or proteolytic degradation of A-SMase in 70Z/3 cells, did not impair SAPK/JNK activation, indicating that SAPK/JNK are not secondary to A-SMase. In addition, proteolytic degradation of A-SMase also did not affect SAPK/JNK activation by ultraviolet (UV-C) irradiation, arguing against a general role of A-SMase in stress-mediated responses. Furthermore, fibroblasts from Niemann-Pick A patients deficient in A-SMase did not show altered activation of SAPK/JNK in response to either TNF or UV-C. These results suggest that TR55 can activate SAPK/JNK without direct participation of sphingomyelinases or ceramide.
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PMID:Induction of stress-activated protein kinases/c-Jun N-terminal kinases by the p55 tumour necrosis factor receptor does not require sphingomyelinases. 965 74

Various members of the tumor necrosis factor (TNF) receptor superfamily interact directly with signaling molecules of the TNF receptor-associated factor (TRAF) family to activate nuclear factor kappaB (NF-kappaB) and the c-Jun N-terminal kinase (JNK) pathway. The receptor activator of NF-kappaB (RANK), a recently described TNF receptor family member, and its ligand, RANKL, promote survival of dendritic cells and differentiation of osteoclasts. RANK contains 383 amino acids in its intracellular domain (residues 234-616), which contain three putative TRAF-binding domains (termed I, II, and III). In this study, we set out to identify the region of RANK needed for interaction with TRAF molecules and for stimulation of NF-kappaB and JNK activity. We constructed epitope-tagged RANK (F-RANK616) and three C-terminal truncations, F-RANK330, F-RANK427, and F-RANK530, lacking 85, 188, and 285 amino acids, respectively. From this deletion analysis, we determined that TRAF2, TRAF5, and TRAF6 interact with RANK at its C-terminal 85-amino acid tail; the binding affinity appeared to be in the order of TRAF2 > TRAF5 > TRAF6. Furthermore, overexpression of RANK stimulated JNK and NF-kappaB activation. When the C-terminal tail, which is necessary for TRAF binding, was deleted, the truncated RANK receptor was still capable of stimulating JNK activity but not NF-kappaB, suggesting that interaction with TRAFs is necessary for NF-kappaB activation but not necessary for activation of the JNK pathway.
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PMID:Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. 968 12

CD40 engagement induces a variety of functional outcomes following association with adaptor molecules of the TNF receptor-associated factor (TRAF) family. Whereas TRAF2, -5, and -6 initiate NF-kappaB activation, the outcomes of TRAF3-initiated signaling are less characterized. To delineate CD40-induced TRAF3-dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154/CD40 ligand. In the absence of TRAF3 signaling, activation of p38 and control of Ig production were abrogated, whereas Jun N-terminal kinase activation and secretion of IL-10, lymphotoxin-alpha, and TNF-alpha were partially blocked. By contrast, induction of apoptosis, activation of NF-kappaB, generation of granulocyte-macrophage CSF, and up-regulation of CD54, MHC class II, and CD95 were unaffected by the TRAF3 dominant negative. Together, these results indicate that TRAF3 initiates independent signaling pathways via p38 and JNK that are associated with specific functional outcomes.
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PMID:TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells. 968 78

The diverse biological effects of the tumor necrosis factor (TNF) receptor superfamily are believed to be mediated in part through TNF receptor-associated factors (TRAFs), a family of cytoplasmic adaptor proteins which can activate intracellular signaling pathways, including the nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) pathways. TRAFs 2, 5, and 6 strongly activate both pathways when overexpressed; however, TRAF 3 (a close homologue of TRAF 5) does not significantly activate either pathway. The current study addresses the structural basis for this difference by substituting corresponding domains of TRAF 5 into TRAF 3 and testing activation of both pathways. A small region of TRAF 5 (the first zinc finger and 10 residues of the second zinc finger) is sufficient to convert TRAF 3 into an activator of both pathways. Also, an intact zinc ring finger is required for NF-kappaB activation but not JNK activation. In agreement with this finding, TRAF 2A, a TRAF 2 splice variant with an altered ring finger, is a specific activator of JNK. These findings suggest that different domains of TRAFs may be involved in NF-kappaB and JNK signaling. Also, alternative splicing of TRAFs may represent a novel mechanism whereby TNF family receptors can mediate distinct downstream effects in different tissues.
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PMID:An intact zinc ring finger is required for tumor necrosis factor receptor-associated factor-mediated nuclear factor-kappaB activation but is dispensable for c-Jun N-terminal kinase signaling. 973 79

Human orbital fibroblasts play a putative role in the pathogenesis of thyroid-associated ophthalmopathy (TAO). We hypothesize that the hyaluronan accumulation and inflammation in TAO derive from enhanced biosynthetic activities of orbital fibroblasts. CD40, a member of the tumor necrosis factor-alpha receptor superfamily, is a critical signaling molecule expressed by B lymphocytes. Engagement of CD40 with CD154 or CD40 ligand results in the activation of target genes. Orbital fibroblasts also display CD40. Here we report that CD40 engagement leads to substantial increases in hyaluronan synthesis in orbital fibroblasts. The increase is approximately 5-fold above control values, is comparable to the induction elicited by IL-1beta and could be attenuated with dexamethasone but not by SC 58125, a prostaglandin endoperoxide H synthase-2 (PGHS-2)-selective inhibitor. PGHS-2 is also induced by CD40 engagement in a time-dependent manner, and this is mediated through increases in levels of steady-state mRNA. The induction of PGHS-2 leads to a dramatically enhanced prostaglandin E2 production that can be blocked by SC 58125 and dexamethasone. CD40 ligand up-regulates the synthesis of IL-1alpha, and blocking this cytokine with exogenous IL-1 receptor antagonist (IL-1ra) or with IL-1alpha neutralizing antibodies partially attenuates the induction of PGHS-2. In contrast, CD40 ligand up-regulation of hyaluronan synthesis is unaffected by IL-1ra. CD40 cross-linking enhances mitogen-activated protein kinase activation, and interrupting this pathway attenuates the PGHS-2 induction. Thus the CD40/CD40 ligand bridge represents a potentially important activational pathway for orbital fibroblasts that may underlie the cross-talk between these cells and leukocytes. These findings may be relevant to the pathogenesis of TAO and provide insights into previously unrecognized, potential therapeutic targets.
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PMID:Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. 979 71

The activity of tumor necrosis factor (TNF), a proinflammatory cytokine, is regulated by a number of other cytokines, including interleukin (IL)-4. How IL-4 regulates various activities of TNF is not fully understood. In the present report, we investigated the effect of IL-4 on the cell surface TNF receptors in human histiocytic lymphoma U-937 cells. Pretreatment of cells with IL-4 down-regulated TNF receptors in a dose- and time-dependent manner; an almost 90% decrease occurred with 10 ng/ml IL-4 treatment for 24 h. Scatchard analysis revealed that the decrease was due to receptor number and not affinity. IL-13, which shares a common receptor subunit and various biological activities with IL-4, had no effect on TNF receptors. IL-4's effect on TNF receptors was not cell type-specific, since decreases also occurred on various epithelial and T cells. Both the p60 and p80 forms of the TNF receptor were down-regulated to the same extent. Western blot showed that IL-4 induced shedding of the TNF receptors. The decrease of TNF receptors by IL-4 was accompanied by down-regulation of TNF-induced activities, including cytotoxicity, caspase-3 activation, NF-kappaB and AP-1 activation, and c-Jun N-terminal kinase induction. Wortmannin reversed the IL-4-induced TNF receptor down-regulation and all other measured cellular responses, indicating a critical role of phosphatidylinositol 3-kinase. Rapamycin also blocked the effect of IL-4-induced regulation, thus suggesting the role of p70 S6 kinase. Overall, our results suggest that TNF receptor down-regulation by IL-4 plays a critical role in the antagonistic effects of IL-4 on TNF-induced cellular responses and that this mechanism differs from that of IL-13.
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PMID:Interleukin-4 down-regulates both forms of tumor necrosis factor receptor and receptor-mediated apoptosis, NF-kappaB, AP-1, and c-Jun N-terminal kinase. Comparison with interleukin-13. 983 7


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