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)

CD40 activates nuclear factor kappa B (NF kappa B) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal-regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor-associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NF kappa B activation. Here we report that transient expression of TRAF6 stimulated both ERK and NF kappa B activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40 delta 246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40 delta 246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40 delta 246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.
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PMID:Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway. 943 81

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

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

Tumor necrosis factor (TNF)-induced activation of the c-jun N-terminal kinase (JNK, also known as SAPK; stress-activated protein kinase) requires TNF receptor-associated factor 2 (TRAF2). The apoptosis signal-regulating kinase 1 (ASK1) is activated by TNF and stimulates JNK activation. Here we show that ASK1 interacts with members of the TRAF family and is activated by TRAF2, TRAF5, and TRAF6 overexpression. A truncated derivative of TRAF2, which inhibits JNK activation by TNF, blocks TNF-induced ASK1 activation. A catalytically inactive mutant of ASK1 is a dominant-negative inhibitor of TNF- and TRAF2-induced JNK activation. In untransfected mammalian cells, ASK1 rapidly associates with TRAF2 in a TNF-dependent manner. Thus, ASK1 is a mediator of TRAF2-induced JNK activation.
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PMID:ASK1 is essential for JNK/SAPK activation by TRAF2. 977 77

Several tumor necrosis factor receptor-associated factor (TRAF) family proteins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been implicated as potential mediators of CD40 signaling. An extensive in vitro binding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic tail (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 and TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incapable of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-kappaB and stress-activated protein kinase activation, as well as the up-regulation of the intercellular adhesion molecule-1 (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable for all of these functions. Overexpression of a dominantly active IkappaBalpha strongly inhibited CD40-induced NF-kappaB activation, ICAM-1 promoter activity, and cell-surface ICAM-1 up-regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcriptional activation of the ICAM-1 gene.
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PMID:Specificities of CD40 signaling: involvement of TRAF2 in CD40-induced NF-kappaB activation and intercellular adhesion molecule-1 up-regulation. 999 39

Receptor activator of NF-kappaB (RANK) is a recently cloned member of the tumor necrosis factor receptor (TNFR) superfamily, and its function has been implicated in osteoclast differentiation and dendritic cell survival. Many of the TNFR family receptors recruit various members of the TNF receptor-associated factor (TRAF) family for transduction of their signals to NF-kappaB and c-Jun N-terminal kinase. In this study, the involvement of TRAF family members and the activation of the JNK pathway in signal transduction by RANK were investigated. TRAF1, 2, 3, 5, and 6 were found to bind RANK in vitro. Association of RANK with each of these TRAF proteins was also detected in vivo. Expression of RANK in cultured cells also induced the activation of JNK, which was blocked by a dominant-negative form of JNK. Furthermore, by employing various C-terminal deletion mutants of RANK, the regions responsible for TRAF interaction and JNK activation were identified. TRAF5 was determined to bind to the C-terminal 11 amino acids and the other TRAF members to a region N-terminal to the TRAF5 binding site. The domain responsible for JNK activation was localized to the same region where TRAF1, 2, 3, and 6 bound, which suggests that these TRAF molecules might mediate the RANK-induced JNK activation.
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PMID:Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. 1002 51

Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear factor kappaB (NF-kappaB) and the c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) and NF-kappaB-inducing kinase (NIK). We have previously shown that the cytoplasmic domain of receptor activator of NF-kappaB (RANK) interacts with TRAF2, TRAF5, and TRAF6 and that its overexpression activates NF-kappaB and JNK pathways. Through a detailed mutational analysis of the cytoplasmic domain of RANK, we demonstrate that TRAF2 and TRAF5 bind to consensus TRAF binding motifs located in the C terminus at positions 565-568 and 606-611, respectively. In contrast, TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. Furthermore, transfection experiments with RANK and its deletion mutants in human embryonic 293 cells revealed that the TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. Moreover, a kinase mutant of NIK (NIK-KM) inhibited RANK-induced NF-kappaB activation. However, RANK-mediated JNK activation required a distal portion (427-603) of RANK containing the TRAF2-binding domain. Thus, our results indicate that RANK interacts with various TRAFs through distinct motifs and activates NF-kappaB via a novel TRAF6 interaction motif, which then activates NIK, thus leading to NF-kappaB activation, whereas RANK most likely activates JNK through a TRAF2-interacting region in RANK.
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PMID:Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. 1007 62

We have previously shown that CD40 causes strong activation of the c-Jun N-terminal kinase (JNK), the p38 mitogen-activated protein kinases (MAPK) and MAPKAP kinase-2, a downstream target of p38 MAPK. To identify signaling motifs in the CD40 cytoplasmic domain that are responsible for activation of these kinases, we have created a set of 11 chimeric receptors consisting of the extracellular and transmembrane domains of CD8 fused to portions of the murine CD40 cytoplasmic domain. These chimeric receptors were expressed in WEHI-231 B lymphoma cells. We found that amino acids 35-45 of the CD40 cytoplasmic domain constitute an independent signaling motif that is sufficient for activation of the JNK and p38 MAPK pathways, as well as for induction of I kappa B alpha phosphorylation and degradation. Amino acids 35-45 were also sufficient to protect WEHI-231 cells from anti-IgM-induced growth arrest. This is the same region of CD40 required for binding the TNF receptor-associated factor-2 (TRAF2), TRAF3, and TRAF5 adapter proteins. These data support the idea that one or more of these TRAF proteins couple CD40 to the kinase cascades that activate NF-kappa B, JNK, and p38 MAPK.
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PMID:An 11-amino acid sequence in the cytoplasmic domain of CD40 is sufficient for activation of c-Jun N-terminal kinase, activation of MAPKAP kinase-2, phosphorylation of I kappa B alpha, and protection of WEHI-231 cells from anti-IgM-induced growth arrest. 1020 13

TRAF5 [tumor necrosis factor (TNF) receptor-associated factor 5] is implicated in NF-kappaB and c-Jun NH(2)-terminal kinase/stress-activated protein kinase activation by members of the TNF receptor superfamily, including CD27, CD30, CD40, and lymphotoxin-beta receptor. To investigate the functional role of TRAF5 in vivo, we generated TRAF5-deficient mice by gene targeting. Activation of either NF-kappaB or c-Jun NH(2)-terminal kinase/stress-activated protein kinase by tumor necrosis factor, CD27, and CD40 was not abrogated in traf5(-/-) mice. However, traf5(-/-) B cells showed defects in proliferation and up-regulation of various surface molecules, including CD23, CD54, CD80, CD86, and Fas in response to CD40 stimulation. Moreover, in vitro Ig production of traf5(-/-) B cells stimulated with anti-CD40 plus IL-4 was reduced substantially. CD27-mediated costimulatory signal also was impaired in traf5(-/-) T cells. Collectively, these results demonstrate that TRAF5 is involved in CD40- and CD27-mediated signaling.
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PMID:Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. 1044 75

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor kappaB (NF-kappaB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-kappaB activator (TANK), in TRAF2-mediated NF-kappaB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-kappaB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.
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PMID:TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway. 1049 Jun 5


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