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)

LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin beta receptor (LTbetaR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTbetaR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTbetaR-mediated activation of both the transcription factor NF-kappaB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-kappaB and JNK activation, which can be blocked by the dominant negative mutant of TRAF2. In these cells, LIGHT causes the recruitment of TRAF2, TRAF3, and IkappaB kinase into the LTbetaR complex. Importantly, while both NF-kappaB and JNK are activated by LIGHT in wild-type mouse embryonic fibroblasts, no activation of either of these two pathways is observed in TRAF2 null fibroblasts. However, LIGHT-induced NF-kappaB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF2-/- cells. Interestingly, in contrast to TNF signaling, the activation of both NF-kappaB and JNK by LIGHT was normal in RIP-/- and TRAF5-/- cells. Taken together, our data demonstrate that TRAF2, an important effector molecule of TNF signaling, plays a critical, nonredundant role in LIGHT-LTbetaR signaling.
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PMID:TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin beta receptor signaling. 1574 11

Tumor necrosis factor receptor (TNFR) family members such as glucocorticoid-induced TNFR (GITR) control T cell activation, differentiation, and effector functions. Importantly, GITR functions as a pivotal regulator of physiologic and pathologic immune responses by abrogating the suppressive effects of T regulatory cells and costimulating T effector cells. However, the molecular mechanisms underlying GITR-triggered signal transduction pathways remain unclear. Interestingly, GITR-induced stimulation of TNFR-associated factor (TRAF) 5-deficient T cells resulted in decreased activation of nuclear factor kappaB as well as the mitogen-activated protein kinases p38 and extracellular signal-regulated protein kinase, whereas activation of c-Jun N-terminal kinase was less affected. Consistent with impaired signaling, costimulatory effects of GITR were diminished in TRAF5-/- T cells. In sum, our studies indicate that TRAF5 plays a crucial role in GITR-induced signaling pathways that augment T cell activation.
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PMID:Tumor necrosis factor receptor (TNFR)-associated factor 5 is a critical intermediate of costimulatory signaling pathways triggered by glucocorticoid-induced TNFR in T cells. 1645 75

C/EBPbeta plays a pivotal role in activation of human immunodeficiency virus type 1 (HIV-1) in monocytes/macrophages. However, mechanisms for functional regulation of C/EBPbeta remain uncharacterized. Previous studies indicated that NF-kappaB activation by tumor necrosis factor (TNF) receptor family, which activates TNF receptor associated factor (TRAF), induces HIV-1 expression. We found that TRAF signals activate HIV-1 LTR with mutations of NF-kappaB sites in promonocytic cell line U937, suggesting existence of an alternative HIV-1 activating pathway. In this study, we have characterized the signal transduction pathway of TRAF other than that leading to NF-kappaB, using U937 cell line, and its subline, U1, which is chronically infected by HIV-1. We show that signals downstream of TRAF2 and TRAF5 activate p38 MAPK, which directly phosphorylates C/EBPbeta, and that activation of p38 MAPK potently activates C/EBPbeta-mediated induction of HIV-1 gene expression. We also show TRAF2 and TRAF5 are expressed in monocytes/macrophages of spleen samples from HIV-1 infected patients. Identification of TRAF-p38 MAPK-CEBPbeta pathway provides a new target for controlling reactivation of latent HIV-1 in monocytes/macrophages.
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PMID:TRAF activation of C/EBPbeta (NF-IL6) via p38 MAPK induces HIV-1 gene expression in monocytes/macrophages. 1740 10

RAF2 and TRAF5 are closely related members of the TRAF family of proteins. They are important signal transducers for a wide range of TNF receptor superfamily members, including TNFR1, TNFR2, CD40 and other lymphocyte costimulatory receptors, RANK/TRANCE-R, EDAR, LTbetaR, LMP-1 and IRE1. TRAF2 andTRAF5 therefore regulate diverse physiological roles, ranging from T and B cell signaling and inflammatory responses to organogenesis and cell survival. The major pathways mediated by TRAF2 and TRAF5 are the classical and alternative pathways of NF-kappaB activation, and MAPK and JNK activation. TRAF2 is heavily regulated by ubiquitin signals, and many of the signaling functions of TRAF2 are mediated through its RING domain and likely its own role as an E3 ubiquitin ligase.
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PMID:Physiological roles and mechanisms of signaling by TRAF2 and TRAF5. 1763 15

TNF-receptor-associated factors (TRAFs) are intracellular proteins that bind to the cytoplasmic portion of TNF receptors and mediate downstream signaling. The six known TRAF proteins play overlapping yet distinct roles in controlling immune responses as well as cellular processes such as activation of NF-kappaB and JNK signaling pathways. For example, CD40 binds to TRAF2, TRAF3 and TRAF6 to control B cell differentiation, proliferation and growth. In contrast, binding of lymphotoxin-beta receptor (LTbetaR) to TRAF2 and TRAF5 propagates signals leading to activation of NF-kappaB, while binding to TRAF3 induces negative regulation of this pathway and leads to apoptosis in tumor cells. Binding recognition is mediated by specific contacts of a consensus recognition sequence in the partner with residues in a hydrophobic crevice on the TRAF molecule. Since each of these protein-protein interactions occurs within this same binding crevice, it appears that TRAF-mediated cellular mechanisms may be regulated, in part, by the level of expression or recruitment of the adaptor proteins or receptors that are competing for the crevice. The specific contacts of CD40, LTbetaR and BAFF-R have been defined in crystal structures of the complex with TRAF3. In addition, the downstream regulator TANK and the viral oncogenic protein LMP1 from the Epstein Barr virus also bind to the same TRAF crevice and these contacts have also been described crystallographically. Comparison of these five crystal structures has revealed that the recognition motifs in each of these proteins are accommodated in one TRAF3 binding crevice and that the binding interface is structurally and functionally adaptive. In this chapter, the molecular details of the interactions will be described and correlated with the functional implications for multiple TRAF3 roles in cellular regulation.
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PMID:Protein-protein interactions in TRAF3. 1763 21

The activation of NF-kappaB by neutrophil lactoferrin (Lf) is regulated via the IkappaB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IkappaB. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser(536), but not the Ser(276) residue, and stimulated the translocation of p65 into the nucleus. Lf was also shown to enhance the association between p65 and CREB-binding protein/p300 in vivo. To elucidate the mechanism by which Lf triggers these signaling pathways, we attempted to delineate the roles of the upstream components of the IKK complex, using their dominant-negative mutants and IKKalpha(-/-) and IKKbeta(-/-) mouse embryonic cells. We demonstrated that both IKKalpha and IKKbeta as well as NF-kappaB-inducing kinase are indispensable for Lf-induced p65 phosphorylation. However, MAPK kinase kinase 1 is not essentially required for this activation. We also observed that Lf-induced p65 phosphorylation was either partially or completely abrogated as the result of treatment with the mutant forms of TNFR-associated factor (TRAF) 2, TRAF5, or TRAF6. Moreover, we demonstrated that Lf directly interacted with TRAF5. Expression of the dominant-negative mutant of TRAF5 or its small interfering RNA almost completely abrogated the Lf-induced p65 phosphorylation. These results suggest that signaling pathways, including TRAFs/NF-kappaB-inducing kinase/IKKs, may be involved in the regulation of Lf-induced p65 activation, thereby resulting in the activation of members of the NF-kappaB family.
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PMID:A distinct role of neutrophil lactoferrin in RelA/p65 phosphorylation on Ser536 by recruiting TNF receptor-associated factors to IkappaB kinase signaling complex. 1794 40

Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) and TRAF5 are adapter proteins involved in TNFalpha-induced activation of the c-Jun N-terminal kinase and nuclear factor kappaB (NF-kappaB) pathways. Currently, TNFalpha-induced NF-kappaB activation is believed to be impaired in TRAF2 and TRAF5 double knockout (T2/5 DKO) cells. Here, we report instead that T2/5 DKO cells exhibit high basal IkappaB kinase (IKK) activity and elevated expression of NF-kappaB-dependent genes in unstimulated conditions. Although TNFalpha-induced receptor-interacting protein 1 ubiquitination is indeed impaired in T2/5 DKO cells, TNFalpha stimulation further increases IKK activity in these cells, resulting in significantly elevated expression of NF-kappaB target genes to a level higher than that in wild-type cells. Inhibition of NIK in T2/5 DKO cells attenuates basal IKK activity and restores robust TNFalpha-induced IKK activation to a level comparable with that seen in wild-type cells. This suggests that TNFalpha can activate IKK in the absence of TRAF2 and TRAF5 expression and receptor-interacting protein 1 ubiquitination. In addition, both the basal and TNFalpha-induced expression of anti-apoptotic proteins are normal in T2/5 DKO cells, yet these DKO cells remain sensitive to TNFalpha-induced cell death, due to the impaired recruitment of anti-apoptotic proteins to the TNFR1 complex in the absence of TRAF2. Thus, our data demonstrate that TRAF2 negatively regulates basal IKK activity in resting cells and inhibits TNFalpha-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-kappaB pathway.
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PMID:TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can activate IKK in TRAF2 and TRAF5 double knockout cells. 1940 3

TNFR-associated factors (TRAFs) participate in diverse biological processes, such as adaptive and innate immunity, stress response, and bone metabolism. We report that all TRAFs except TRAF3 are expressed at mRNA and protein levels in B cell-derived Hodgkin's lymphoma cell lines (L428 and KM-H2). Both the classical (p50-RelA) and the alternative NF-kappaB activity (p52-RelB) are sustained in L428 and KM-H2 cells. A successful depletion of TRAF1 protein expression by means of RNA interference abrogates the anti-apoptosis activity in L428 cells. The TRAF1-deficiency reduces the classical NF-kappaB activity but not the alternative activity. The expression of the NF-kappaB targeting genes, such as ICAM-1, c-Flip, and Cyclin D1, is suppressed in the TRAF1-depleted cells. On the other hand, CD30 signaling upregulates the TRAF1 expression while reducing the expression of TRAF2 and TRAF5. Importantly, the CD30-induced alternative NF-kappaB activation is inhibited by the depletion of the TRAF1 expression. We also demonstrate that the phosphorylation of the extracellular signal-regulated kinase (ERK) upon CD30 stimulation in Hodgkin's lymphoma cells is independent of TRAF1 expression. Our data shed new light on the function of TRAF1 in B cell-derived lymphoma cells. We conclude that TRAF1 is an important molecule mediating both the CD30 signaling-dependent and independent NF-kappaB activation, which prevents the lymphoma cells from spontaneous and induced apoptosis.
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PMID:TRAF1 is involved in the classical NF-kappaB activation and CD30-induced alternative activity in Hodgkin's lymphoma cells. 1954 May 95

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-alpha (TNF-alpha) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-alpha stimulation. The mechanism by which TNF-alpha activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-alpha treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-alpha treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-alpha-induced activation of MLK3 and its downstream target, JNK.
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PMID:TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation. 1991 65

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1) play critical roles in activating c-Jun N-terminal kinase (JNK) and inhibitor of kappaB kinase (IKK), as well as in inhibiting apoptosis induced by TNFalpha. The TRAF2 RING domain-mediated polyubiquitination of RIP1 is believed to be essential for TNFalpha-induced IKK activation, and the RING-domain-deleted TRAF2 (TRAF2-DeltaR) has been widely used as a dominant negative in transient overexpression systems to block TNFalpha-induced JNK and IKK activation. Here, we report that stable expression of TRAF2-DeltaR at a physiological level in TRAF2 and TRAF5 double knockout (TRAF2/5 DKO) cells almost completely restores normal TNFalpha-induced IKK activation, but not RIP1 polyubiquitination. In addition, stable expression of TRAF2-DeltaR in TRAF2/5 DKO cells efficiently inhibited the TNFalpha-induced later phase of prolonged JNK activation, yet failed to inhibit TNFalpha-induced cell death. Although the basal and inducible expression of anti-apoptotic proteins in TRAF2-DeltaR-expressing TRAF2/5 DKO cells was normal, the cells remained sensitive to TNFalpha-induced cell death because anti-apoptotic proteins were not recruited to the TNFR1 complex efficiently. Moreover, stable expression of TRAF2-DeltaR in TRAF2/5 DKO cells failed to suppress constitutive p100 processing in these cells. These data suggest that (i) the TRAF2 RING domain plays a critical role in inhibiting cell death induced by TNFalpha and is essential for suppressing the noncanonical nuclear factor kappaB pathway in unstimulated cells; (ii) RIP1 polyubiquitination is not essential for TNFalpha-induced IKK activation; and (iii) prolonged JNK activation has no obligate role in TNFalpha-induced cell death.
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PMID:The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. 2006 26


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