The Experts below are selected from a list of 20337 Experts worldwide ranked by ideXlab platform
Gail A. Bishop - One of the best experts on this subject based on the ideXlab platform.
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Roles of the kinase TAK1 in TRAF6-dependent signaling byCD40 and its oncogenic viral mimic
2016Co-Authors: Kelly M. Arcipowski, Gail A. BishopAbstract:The Epstein-Barr virus (EBV)-encoded protein latent membrane protein 1 (LMP1) is essential for EBV-mediated B cell transformation and plays a critical role in the development of post-transplant B cell lymphomas. LMP1 also contributes to the exacerbation of autoimmune diseases such as systemic lupus erythematosus (SLE). LMP1 is a functional mimic of the tumor necrosis factor receptor (TNFR) superfamily member CD40, and relies on TNFR-associated factor (TRAF) adaptor proteins to mediate signaling. However, LMP1 activation signals to the B cell are amplified and sustained compared to CD40 signals. We previously demonstrated that LMP1 and CD40 use TRAF molecules differently. Although associating with CD40 and LMP1 via separate mechanisms, TRAF6 plays a significant role in signal transduction by both. It is unknown whether TRAF6 mediates CD40 versus LMP1 functions via distinct or shared pathways. In this study, we tested the hypothesis that TRAF6 uses the kinase TAK1 to trigger important signaling pathways following both CD40 and LMP1 stimulation. We determined that TAK1 was required for JNK activation and interleukin-6 (IL-6) production mediated by CD40 and LMP1, in both mouse and human B cells. Additionally, TRAF3 negatively regulated TRAF6-dependent, CD40-mediated TAK1 activation by limiting TRAF6 recruitment. This mode of regulation was not observed for LMP1 and may contribute to th
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roles of tumor necrosis factor receptor associated factor 3 traf3 and traf5 in immune cell functions
Immunological Reviews, 2011Co-Authors: Joanne M Hildebrand, Claire M. Buchta, Jayakumar S Poovassery, Laura L Stunz, Gail A. BishopAbstract:A large and diverse group of receptors utilizes the family of cytoplasmic signaling proteins known as tumor necrosis factor receptor (TNFR)-associated factors (TRAFs). In recent years, there has been a resurgence of interest and exploration of the roles played by TRAF3 and TRAF5 in cellular regulation, particularly in cells of the immune system, the cell types of focus in this review. This work has revealed that TRAF3 and TRAF5 can play diverse roles for different receptors even in the same cell type, as well as distinct roles in different cell types. Evidence indicates that TRAF3 and TRAF5 play important roles beyond the TNFR-superfamily (SF) and viral mimics of its members, mediating certain innate immune receptor and cytokine receptor signals, and most recently, signals delivered by the T-cell receptor (TCR) signaling complex. Additionally, much research has demonstrated the importance of TRAF3-mediated cellular regulation via its cytoplasmic interactions with additional signaling proteins. In particular, we discuss below evidence for the participation by TRAF3 in a number of the regulatory post-translational modifications involving ubiquitin that are important in various signaling pathways.
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tumor necrosis factor receptor associated factor 2 traf2 deficient b lymphocytes reveal novel roles for traf2 in cd40 signaling
Journal of Biological Chemistry, 2003Co-Authors: Bruce S Hostager, Sokol Haxhinasto, Gail A. Bishop, Sarah L RowlandAbstract:CD40 function is initiated by tumor necrosis factor (TNF) receptor-associated factor (TRAF) adapter proteins, which play important roles in signaling by numerous receptors. Characterizing roles of individual TRAFs has been hampered by limitations of available experimental models and the poor viability of most TRAF-deficient mice. Here, B cell lines made deficient in TRAF2 using a novel homologous recombination system reveal new roles for TRAF2. We demonstrate that TRAF2 participates in synergy between CD40 and B cell antigen receptor signals, and in CD40-mediated, TNF-dependent IgM production. We also find that TRAF2 participates in the degradation of TRAF3 associated with CD40 signaling, a role that may limit inhibitory actions of TRAF3. Finally, we show that TRAF2 and TRAF6 have overlapping functions in CD40-mediated NF-κB activation and CD80 up-regulation. These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF receptor family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms.
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recruitment of cd40 and tumor necrosis factor receptor associated factors 2 and 3 to membrane microdomains during cd40 signaling
Journal of Biological Chemistry, 2000Co-Authors: Bruce S Hostager, Ian M Catlett, Gail A. BishopAbstract:Signals delivered to antigen-presenting cells through CD40 are critical for the activation of immune responses. Intracellular tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are key elements of the signal transduction pathways of many TNF receptor family members, including CD40. We show for the first time that engagement of CD40 in intact B cells induces the rapid translocation of TRAF2 from the cytoplasm to the plasma membrane. We found that CD40 engagement also results in its recruitment, together with TRAF2 and TRAF3, to membrane microdomains, regions of the plasma membrane enriched in signaling molecules such as the Src family kinases. Using a membrane-permeable chelator of zinc or a mutant TRAF2 molecule, we show that the putative zinc-binding domains of TRAFs contribute to their recruitment to microdomains and to the downstream activation of c-Jun N-terminal kinase. We suggest that the zinc RING and zinc finger domains of TRAFs are required for communication between CD40 and microdomain-associated signaling molecules and may serve a similar role in the signal transduction pathways of other TNF receptor family members.
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characterization of the roles of tnf receptor associated factor 6 in cd40 mediated b lymphocyte effector functions
Journal of Immunology, 2000Co-Authors: Sangita V Jalukar, Bruce S Hostager, Gail A. BishopAbstract:Signaling through CD40 in B cells leads to B cell proliferation, Ig and IL-6 secretion, isotype switching, and up-regulation of surface molecules. TNF receptor-associated factor (TRAF) proteins associate with the cytoplasmic tail of CD40 and act as adapter molecules. Of the six TRAFs identified to date, TRAFs 2, 3, 5, and 6 are reported to associate directly with the cytoplasmic tail of CD40, but previous studies have principally examined transient overexpression of TRAF6 in cells that do not normally express CD40. Thus, we examined the role of TRAF6 in CD40-mediated B lymphocyte effector functions using two approaches. We produced and stably expressed in mouse B cell lines a human CD40 molecule with two cytoplasmic domain point mutations (hCD40EEAA); this mutant fails to bind TRAF6, while showing normal association with TRAFs 2 and 3. We also inducibly expressed in B cells a transfected “dominant-negative” TRAF6 molecule which contains only the C-terminal TRAF-binding domain of TRAF6. Using both molecules, we found that TRAF6 association with CD40 is important for CD40-induced IL-6 and Ig secretion, and that TRAF6 mediates its effects on CD40-stimulated Ig secretion principally through its effects on IL-6 production by the B cell. TRAF6 association with CD40 was also found to be important for B7-1 up-regulation, but not for up-regulation of other surface molecules. Interestingly, however, although we could show TRAF6-dependent CD40-mediated activation of NF-κB in 293 kidney epithelial cells, no such effect was seen in B cells, suggesting that TRAF6 has cell-type-specific functions.
Hiroyasu Nakano - One of the best experts on this subject based on the ideXlab platform.
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epstein barr virus latent membrane protein 1 activation of nf κb through irak1 and TRAF6
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Micah A Luftig, Hiroyasu Nakano, E E Prinarakis, Teruhito Yasui, Theodore Tsichritzis, Ellen Cahirmcfarland, Junichiro Inoue, Tak W Mak, Wen Chen Yeh, Shizuo AkiraAbstract:Epstein–Barr virus latent membrane protein 1 (LMP1) activation of NF-κB is critical for Epstein–Barr virus-infected B lymphocyte survival. LMP1 activates the IκB kinase complex and NF-κB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKα, IKKβ, IKKγ, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-κB activation. LMP1-induced RelA nuclear translocation was similar in IKKα knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKβ KO MEFs. NF-κB-dependent promoter responses were also substantially deficient in IKKβ KO MEFs but were hyperactive in IKKα KO MEFs. More surprisingly, NF-κB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKγ KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-κB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKα in IKKβ regulation, identify an unusual IKKβ-dependent and IKKγ-independent NF-κB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-κB activation.
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traf5 functions in both rankl and tnfα induced osteoclastogenesis
Journal of Bone and Mineral Research, 2003Co-Authors: Kiyoshi Kanazawa, Hiroyasu Nakano, Yoshiaki Azuma, Akira KudoAbstract:Although TRAF6 is essential for both RANKL- and TNFalpha-induced osteoclastogenesis, it has remained unclear whether other members of the TRAF family are involved in osteoclastogenesis. We examined TRAF5 function in both RANKL- and TNFalpha-induced osteoclastogenesis by using osteoclast progenitor cells from TRAF5-deficient mice. The results demonstrated that RANKL or TNFalpha did not effectively induce osteoclast differentiation from osteoclast progenitor cells derived from these mice into mature multinucleated osteoclasts, although c-jun N-terminal kinase (JNK) and NF-kappaB activation was apparently observed in osteoclast progenitor cells. In the parathyroid hormone (PTH)-induced hypercalcemia model, calcium concentration peaked at day 3 after administration. However, in TRAF5-deficient mice, this peak was delayed and found at day 5, showing less effective osteoclast differentiation. Thus, we have provided the first evidence showing that TRAF5 is involved in osteoclastogenesis.
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the atypical pkc interacting protein p62 channels nf κb activation by the il 1 TRAF6 pathway
The EMBO Journal, 2000Co-Authors: Laura Sanz, Hiroyasu Nakano, Maria T Diazmeco, Jorge MoscatAbstract:The atypical protein kinase C (aPKC)-interacting protein, p62, has previously been shown to interact with RIP, linking these kinases to NF–κB activation by tumor necrosis factor α (TNFα). The aPKCs have been implicated in the activation of IKKβ in TNFα-stimulated cells and have been shown to be activated in response to interleukin–1 (IL–1). Here we demon– strate that the inhibition of the aPKCs or the down-regulation of p62 severely abrogates NF–κB activation by IL–1 and TRAF6, suggesting that both proteins are critical intermediaries in this pathway. Consistent with this we show that p62 selectively interacts with the TRAF domain of TRAF6 but not that of TRAF5 or TRAF2 in co-transfection experiments. The binding of endogenous p62 to TRAF6 is stimulus dependent, reinforcing the notion that this is a physiologically relevant interaction. Furthermore, we demonstrate that the N–terminal domain of TRAF6, which is required for signaling, interacts with ζPKC in a dimerization-dependent manner. Together, these results indicate that p62 is an important intermediary not only in TNFα but also in IL–1 signaling to NF–κB through the specific adapters RIP and TRAF6.
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ask1 is essential for jnk sapk activation by traf2
Molecular Cell, 1998Co-Authors: Hideki Nishitoh, Mike Rothe, Kohsuke Takeda, Hiroyasu Nakano, Masao Saitoh, Yoshiyuki Mochida, Kohei MiyazonoAbstract: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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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
Journal of Biological Chemistry, 1998Co-Authors: Hisaya Akiba, Shigeyuki Nishinaka, Nikolai Malinin, Masahisa Shindo, Machiko Atsuta, Carl F. Ware, Tetsuji Kobata, Chikao Morimoto, Hiroyasu Nakano, David WallachAbstract:Abstract 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-κB 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-κB 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-κB activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-κB and SAPK/JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-κB-inducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-κB and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-κB and SAPK/JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-κB and SAPK/JNK activation.
Tak W Mak - One of the best experts on this subject based on the ideXlab platform.
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epstein barr virus latent membrane protein 1 activation of nf κb through irak1 and TRAF6
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Micah A Luftig, Hiroyasu Nakano, E E Prinarakis, Teruhito Yasui, Theodore Tsichritzis, Ellen Cahirmcfarland, Junichiro Inoue, Tak W Mak, Wen Chen Yeh, Shizuo AkiraAbstract:Epstein–Barr virus latent membrane protein 1 (LMP1) activation of NF-κB is critical for Epstein–Barr virus-infected B lymphocyte survival. LMP1 activates the IκB kinase complex and NF-κB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKα, IKKβ, IKKγ, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-κB activation. LMP1-induced RelA nuclear translocation was similar in IKKα knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKβ KO MEFs. NF-κB-dependent promoter responses were also substantially deficient in IKKβ KO MEFs but were hyperactive in IKKα KO MEFs. More surprisingly, NF-κB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKγ KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-κB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKα in IKKβ regulation, identify an unusual IKKβ-dependent and IKKγ-independent NF-κB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-κB activation.
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TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1
The EMBO Journal, 2001Co-Authors: Ute Schultheiss, Tak W Mak, Wolfgang Hammerschmidt, Stephanie Puschner, Hartmut Engelmann, Elisabeth Kremmer, Arnd KieserAbstract:The oncogenic latent membrane protein 1 (LMP1) of the Epstein–Barr virus recruits tumor necrosis factor‐receptor (TNFR)‐associated factors (TRAFs), the TNFR‐associated death domain protein (TRADD) and JAK3 to induce intracellular signaling pathways. LMP1 serves as the prototype of a TRADD‐binding receptor that transforms cells but does not induce apoptosis. Here we show that TRAF6 critically mediates LMP1 signaling to p38 mitogen‐activated protein kinase (MAPK) via a MAPK kinase 6‐dependent pathway. In addition, NF‐κB but not c‐Jun N‐terminal kinase 1 (JNK1) induction by LMP1 involves TRAF6. The PxQxT motif of the LMP1 C‐terminal activator region 1 (CTAR1) and tyrosine 384 of CTAR2 together are essential for full p38 MAPK activation and for TRAF6 recruitment to the LMP1 signaling complex. Dominant‐negative TRADD blocks p38 MAPK activation by LMP1. The data suggest that entry of TRAF6 into the LMP1 complex is mediated by TRADD and TRAF2. In TRAF6‐knockout fibroblasts, significant induction of p38 MAPK by LMP1 is dependent on the ectopic expression of TRAF6. We describe a novel role of TRAF6 as an essential signaling mediator of a transforming oncogene, downstream of TRADD and TRAF2.
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critical roles of traf2 and traf5 in tumor necrosis factor induced nf κb activation and protection from cell death
Journal of Biological Chemistry, 2001Co-Authors: Kurisu Tada, Tak W Mak, Tatsuma Okazaki, Sachiko Sakon, Tomonari Kobarai, Kyoko Kurosawa, Shoji Yamaoka, Hiroshi Hashimoto, Hideo YagitaAbstract:Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) were identified as signal transducers for the TNF receptor superfamily. However, the exact roles of TRAF2 and TRAF5 in TNF-induced NF-κB activation still remain controversial. To address this issue, we generated TRAF2 and TRAF5 double knockout (DKO) mice. TNF- but not interleukin-1-induced nuclear translocation of NF-κB was severely impaired in murine embryonic fibroblasts (MEFs) derived from DKO mice. Moreover, DKO MEFs were more susceptible to TNF-induced cytotoxicity than TRAF2 knockout MEFs. Collectively, these results indicate that both TRAF2 and TRAF5 are involved in TNF-induced NF-κB activation and protection from cell death.
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binding sites of cytoplasmic effectors traf1 2 and 3 on cd30 and other members of the tnf receptor superfamily
Biochemical and Biophysical Research Communications, 1997Co-Authors: Louismartin Boucher, Tak W Mak, Luc E M Marengere, Sushil ThukralAbstract:CD30 is present on the surfaces of malignant cells from patients with Hodgkin's lymphoma, anaplastic large cell lymphoma, and other lymphomas. The yeast two hybrid genetic screen method was used to identify molecular effectors which mediate CD30 signalling events. Clones corresponding to genes coding for TRAF1, TRAF2, and TRAF3 molecules, postulated to be involved in signalling via the TNF and CD40 receptors, were isolated. In this report, we show that the CD30 intracellular tail contains two motifs that bind TRAFs. The more amino terminal motif, 558PHYPEQET565, binds TRAF2 and 3, while the more carboxyl terminal motif, 576MLSVEEEG583, binds TRAF1 and 2. We show that these amino acid motifs are conserved in TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in CD30 can selectively bind the TRAFs in a predictable manner.
Craig B Thompson - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor receptor associated factors trafs a family of adapter proteins that regulates life and death
Genes & Development, 1998Co-Authors: Robert H Arch, Richard W Gedrich, Craig B ThompsonAbstract:The signaling pathways that regulate cell survival are beginning to be defined. Receptors such as Fas and tumor necrosis factor receptor type I (TNFRI) have been shown to be capable of initiating programmed cell death. These death receptors initiate signal transduction pathways that culminate in caspase activation and apoptosis. A number of the intracellular molecules in these signaling pathways have been identified and characterized. In contrast to death receptors, other cell surface receptors appear to be capable of initiating signaling pathways that promote cell survival. The components of survival signal transduction are less well characterized. Recently a family of cytoplasmic proteins has been identified that appears to be capable of both negatively regulating apoptotic pathway(s) as well as inducing the expression of genes that promote cell survival. Members of this family of signal transduction molecules were first described because of their ability to bind to TNFRII and, therefore, were given the name TNF receptor-associated factors (TRAFs). Subsequent studies have demonstrated that TRAFs serve as adapter proteins for a wide variety of cell surface receptors and play important roles in regulating not only apoptosis but also stress responses. In this review we hope to provide an overview of current knowledge concerning the expression and function of this important family of proteins. Identification of the TRAF family Members of the recently described family of TRAF proteins are cytoplasmic adapter proteins that can interact directly with the intracellular domains of cell surface receptors. Among the receptors that have been shown to recruit TRAF proteins are members of the TNFR superfamily, the Epstein‐Barr virus protein LMP1, and the interleukin-1 receptor (IL-1R). To date, six distinct TRAF molecules have been identified in mammalian species (Fig. 1). TRAF1 and TRAF2 were cloned by biochemical
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4 1bb and ox40 are members of a tumor necrosis factor tnf nerve growth factor receptor subfamily that bind tnf receptor associated factors and activate nuclear factor κb
Molecular and Cellular Biology, 1998Co-Authors: Robert H Arch, Craig B ThompsonAbstract:Members of the tumor necrosis factor (TNF)-nerve growth factor (NGF) receptor family have been shown to be important costimulatory molecules for cellular activation. 4-1BB and Ox40 are two recently described members of this protein family which are expressed primarily on activated T cells. To gain insight into the signaling pathways employed by these factors, yeast two-hybrid library screens were performed with the cytoplasmic domains of 4-1BB and Ox40 as baits. TNF receptor-associated factor 2 (TRAF2) was identified as an interacting protein in both screens. The ability of both 4-1BB and Ox40 to interact with TRAF2 was confirmed in mammalian cells by coimmunoprecipitation studies. When the binding of the receptors to other TRAF proteins was investigated, 4-1BB and Ox40 displayed distinct binding patterns. While 4-1BB bound TRAF2 and TRAF1, Ox40 interacted with TRAF3 and TRAF2. Using deletion and alanine scanning analysis, we defined the elements in the cytoplasmic domains of both receptors that mediate these interactions. The 4-1BB receptor was found to have two independent stretches of acidic residues that can mediate association of the TRAF molecules. In contrast, a single TRAF binding domain was identified in the cytoplasmic tail of Ox40. The cytoplasmic domains of both receptors were shown to activate nuclear factor κB in a TRAF-dependent manner. Taken together, our results indicate that 4-1BB and Ox40 bind TRAF proteins to initiate a signaling cascade leading to activation of nuclear factor κB.
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induction of nuclear factor kappab by the cd30 receptor is mediated by traf1 and traf2
Molecular and Cellular Biology, 1997Co-Authors: Colin S Duckett, Molly C Gilfillan, Richard W Gedrich, Craig B ThompsonAbstract:CD30 is a lymphoid cell-specific surface receptor which was originally identified as an antigen expressed on Hodgkin's lymphoma cells. Activation of CD30 induces the nuclear factor kappaB (NF-kappaB) transcription factor. In this study, we define the domains in CD30 which are required for NF-kappaB activation. Two separate elements of the cytoplasmic domain which were capable of inducing NF-kappaB independently of one another were identified. The first domain (domain 1) mapped to a approximately 120-amino-acid sequence in the membrane-proximal region of the CD30 cytoplasmic tail, between residues 410 and 531. A second, more carboxy-terminal region (domain 2) was identified between residues 553 and 595. Domain 2 contains two 5- to 10-amino-acid elements which can mediate the binding of CD30 to members of the tumor necrosis factor receptor-associated factor (TRAF) family of signal transducing proteins. Coexpression of CD30 with TRAF1 or TRAF2 but not TRAF3 augmented NF-kappaB activation through domain 2 but not domain 1. NF-kappaB induction through domain 2 was inhibited by coexpression of either full-length TRAF3 or dominant negative forms of TRAF1 or TRAF2. In contrast, NF-kappaB induction by domain 1 was not affected by alterations in TRAF protein levels. Together, these data support a model in which CD30 can induce NF-kappaB by both TRAF-dependent and -independent mechanisms. TRAF-dependent induction of NF-kappaB appears to be regulated by the relative levels of individual TRAF proteins in the cell.
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cd30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor associated factor family of signal transducing proteins
Journal of Biological Chemistry, 1996Co-Authors: Richard W Gedrich, Craig B Thompson, Molly C Gilfillan, Colin S Duckett, Jennifer Van DongenAbstract:CD30 is a member of the tumor necrosis factor (TNF) receptor family of proteins. CD30 can regulate proliferation of lymphocytes and may also play an important role in human immunodeficiency virus replication. However, little is known about CD30 signal transduction. We performed a yeast two-hybrid library screen with the cytoplasmic domain of CD30 and isolated multiple independent cDNAs encoding human tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF2, and CRAF1 (TRAF3). The ability of TRAF1, TRAF2, and CRAF1 to associate with CD30 was confirmed using an in vitro coprecipitation assay, further demonstrating that the interaction was specific and direct. The TRAF-binding domain of CD30 was mapped to the COOH-terminal 36 amino acid residues, which contained two independent binding sites. CRAF1 bound only a single site, which contained the sequence PEQET, whereas TRAF1 and TRAF2 were capable of binding to either the PEQET site or an additional downstream domain. These data indicate that the TRAF protein binding pattern of CD30 differs from other TNF receptor family members and suggest that signaling specificity through TNF receptor family proteins may be achieved through differences in their abilities to bind TRAF proteins.
Junichiro Inoue - One of the best experts on this subject based on the ideXlab platform.
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characteristics and biological functions of TRAF6
Advances in Experimental Medicine and Biology, 2007Co-Authors: Junichiro Inoue, Jin Gohda, Taishin AkiyamaAbstract:TRAF6 is divergent from other members of the TRAF family. Therefore, TRAF6 was expected to play physiological roles distinct from those of other TRAFs. In this chapter, we focused on the physiological functions specific to TRAF6 but not other TRAFs in immune system, formation of skin appendices, and nervous system development by describing abnormal phenotypes observed in TRAF6-deficient mice. The role of TRAF6 in osteoclastogenesis and the molecular mechanisms of TRAF6-mediated signal transduction are described in other chapters.
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epstein barr virus latent membrane protein 1 activation of nf κb through irak1 and TRAF6
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Micah A Luftig, Hiroyasu Nakano, E E Prinarakis, Teruhito Yasui, Theodore Tsichritzis, Ellen Cahirmcfarland, Junichiro Inoue, Tak W Mak, Wen Chen Yeh, Shizuo AkiraAbstract:Epstein–Barr virus latent membrane protein 1 (LMP1) activation of NF-κB is critical for Epstein–Barr virus-infected B lymphocyte survival. LMP1 activates the IκB kinase complex and NF-κB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKα, IKKβ, IKKγ, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-κB activation. LMP1-induced RelA nuclear translocation was similar in IKKα knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKβ KO MEFs. NF-κB-dependent promoter responses were also substantially deficient in IKKβ KO MEFs but were hyperactive in IKKα KO MEFs. More surprisingly, NF-κB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKγ KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-κB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKα in IKKβ regulation, identify an unusual IKKβ-dependent and IKKγ-independent NF-κB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-κB activation.
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tumor necrosis factor receptor associated factor traf 5 and traf2 are involved in cd30 mediated nfkappab activation
Journal of Biological Chemistry, 1997Co-Authors: Shigemi Aizawa, Hiroyasu Nakano, Junichiro Inoue, Hideo Yagita, Ko Okumura, Takaomi Ishida, Ryouichi Horie, Masae Nagai, Kinji Ito, Toshiki WatanabeAbstract:Signals emanated from CD30 can activate the nuclear factor kappaB (NFkappaB). The two conserved subdomains, D1 and D2, in the C-terminal cytoplasmic region of CD30 were tested for interaction with two tumor necrosis factor receptor-associated factor (TRAF) proteins with NFkappaB activating capacity, TRAF2 and TRAF5. TRAF5 is the newest member of the TRAF family that binds to lymphotoxin beta receptor and CD40. TRAF5, as well as TRAF2, interacted with the D2 subdomain of CD30 in vitro and in vivo. Deletion analysis by the yeast two-hybrid system revealed that the C-terminal 22 and 30 amino acid residues are dispensable for interaction of TRAF5 and TRAF2 with CD30, respectively. Substitution of alanine for threonine at 463 abolished the interaction with TRAF2. Overexpression of the TRAF domain of TRAF2 or TRAF5 showed a dominant negative effect on CD30-mediated NFkappaB activation. Simultaneous expression of these TRAF domains further suppressed the NFkappaB activation, suggesting an interplay of these TRAF proteins. Expression of TRAF2 and TRAF5 mRNA was demonstrated in T- and B-cell lines that express CD30. Taken together, our results indicate that TRAF2 and TRAF5 directly interact with CD30 and are involved in NFkappaB activation by CD30 signaling.
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tumor necrosis factor receptor associated factor traf 5 and traf2 are involved in cd30 mediated nfκb activation
Journal of Biological Chemistry, 1997Co-Authors: Shigemi Aizawa, Hiroyasu Nakano, Junichiro Inoue, Hideo Yagita, Ko Okumura, Takaomi Ishida, Ryouichi Horie, Masae Nagai, Kinji Ito, Toshiki WatanabeAbstract:Signals emanated from CD30 can activate the nuclear factor kappaB (NFkappaB). The two conserved subdomains, D1 and D2, in the C-terminal cytoplasmic region of CD30 were tested for interaction with two tumor necrosis factor receptor-associated factor (TRAF) proteins with NFkappaB activating capacity, TRAF2 and TRAF5. TRAF5 is the newest member of the TRAF family that binds to lymphotoxin beta receptor and CD40. TRAF5, as well as TRAF2, interacted with the D2 subdomain of CD30 in vitro and in vivo. Deletion analysis by the yeast two-hybrid system revealed that the C-terminal 22 and 30 amino acid residues are dispensable for interaction of TRAF5 and TRAF2 with CD30, respectively. Substitution of alanine for threonine at 463 abolished the interaction with TRAF2. Overexpression of the TRAF domain of TRAF2 or TRAF5 showed a dominant negative effect on CD30-mediated NFkappaB activation. Simultaneous expression of these TRAF domains further suppressed the NFkappaB activation, suggesting an interplay of these TRAF proteins. Expression of TRAF2 and TRAF5 mRNA was demonstrated in T- and B-cell lines that express CD30. Taken together, our results indicate that TRAF2 and TRAF5 directly interact with CD30 and are involved in NFkappaB activation by CD30 signaling.
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traf5 a novel tumor necrosis factor receptor associated factor family protein mediates cd40 signaling
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Takaomi Ishida, Norihiko Kobayashi, Tadashi Tojo, Toshiki Watanabe, Tsutomu Aoki, Tsukasa Ohishi, Tadashi Yamamoto, Junichiro InoueAbstract:Abstract Signals emanating from CD40 play crucial roles in B-cell function. To identify molecules that transduce CD40 signalings, we have used the yeast two-hybrid system to done cDNAs encoding proteins that bind the cytoplasmic tail of CD40. A cDNA encoding a putative signal transducer protein, designated TRAF5, has been molecularly cloned. TRAF5 has a tumor necrosis factor receptor-associated factor (TRAF) domain in its carboxyl terminus and is most homologous to TRAF3, also known as CRAF1, CD40bp, or LAP-1, a previously identified CD40-associated factor. The amino terminus has a RING finger domain, a cluster of zinc fingers and a coiled-coil domain, which are also present in other members of the TRAF family protein except for TRAF1. In vitro binding assays revealed that TRAF5 associates with the cytoplasmic tail of CD40, but not with the cytoplasmic tail of tumor receptor factor receptor type 2, which associates with TRAF2. Based on analysis of the association between TRAF5 and various CD40 mutants, residues 230-269 of CD40 are required for the association with TRAF5. In contrast to TRAF3, overexpression of TRAF5 activates transcription factor nuclear factor kappa B. Furthermore, amino-terminally truncated forms of TRAF5 suppress the CD40-mediated induction of CD23 expression, as is the case with TRAF3. These results suggest that TRAF5 and TRAF3 could be involved in both common and distinct signaling pathways emanating from CD40.
