TRAF‐Mediated TNFR‐Family Signaling

Hyunil Ha1, Daehee Han1, Yongwon Choi1

1 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Publication Name:  Current Protocols in Immunology
Unit Number:  Unit 11.9D
DOI:  10.1002/0471142735.im1109ds87
Online Posting Date:  November, 2009
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

The tumor necrosis factor (TNF) superfamily consists of a wide variety of cell‐bound and secreted proteins that regulate numerous cellular processes. In particular, TNF‐family proteins regulate the proliferation and death of tumor cells, as well as activated immune cells. This overview discusses the mammalian TNF receptor‐associated factors (TRAFs), of which TRAF1, 2, 3, 5, and 6 have been shown to interact directly or indirectly with members of the TNF receptor superfamily. Structural features of TRAF proteins are described along with a discussion of TRAF‐interacting proteins and the signaling pathways activated by the TRAF proteins. Finally, we examine the phenotypes observed in TRAF‐knockout mice. Curr. Protoc. Immunol. 87:11.9D.1‐11.9D.19. © 2009 by John Wiley & Sons, Inc.

Keywords: TNF family; TNFR family; IL‐1R/TLR; TRAF proteins; signal transduction; inflammation

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • TNF and TNFR Superfamilies
  • Activated Receptors
  • TRAF Proteins
  • Structural Features of TRAF Proteins
  • TRAF‐Interacting Proteins
  • Signaling Pathways Activated by TRAF Proteins
  • TRAF Knockout Mice
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Abell, A.N. and Johnson, G.L. 2005. MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J. Biol. Chem. 280:35793‐35796.
   Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., and Akira, S. 1998. Targeted disruption of the MyD88 gene results in loss of IL‐1‐ and IL‐18‐mediated function. Immunity 9:143‐150.
   Aggarwal, B.B. 2003. Signalling pathways of the TNF superfamily: A double‐edged sword. Nat. Rev. Immunol. 3:745‐756.
   Aizawa, S., Nakano, H., Ishida, T., Horie, R., Nagai, M., Ito, K., Yagita, H., Okumura, K., Inoue, J., and Watanabe, T. 1997. Tumor necrosis factor receptor‐associated factor (TRAF) 5 and TRAF2 are involved in CD30‐mediated NFkappaB activation. J. Biol. Chem. 272:2042‐2045.
   Anderson, D.M., Maraskovsky, E., Billingsley, W.L., Dougall, W.C., Tometsko, M.E., Roux, E.R., Teepe, M.C., DuBose, R.F., Cosman, D., and Galibert, L. 1997. A homologue of the TNF receptor and its ligand enhance T‐cell growth and dendritic‐cell function. Nature 390:175‐179.
   Arch, R.H., Gedrich, R.W., and Thompson, C.B. 1998. Tumor necrosis factor receptor‐associated factors (TRAFs)–a family of adapter proteins that regulates life and death. Genes Dev. 12:2821‐2830.
   Ashkenazi, A. and Dixit, V.M. 1998. Death receptors: Signaling and modulation. Science 281:1305‐1308.
   Baens, M., Chaffanet, M., Cassiman, J.J., van den Berghe, H., and Marynen, P. 1993. Construction and evaluation of a hncDNA library of human 12p transcribed sequences derived from a somatic cell hybrid. Genomics 16:214‐218.
   Baker, S.J. and Reddy, E.P. 1998. Modulation of life and death by the TNF receptor superfamily. Oncogene 17:3261‐3270.
   Banner, D.W., D'Arcy, A., Janes, W., Gentz, R., Schoenfeld, H.J., Broger, C., Loetscher, H., and Lesslauer, W. 1993. Crystal structure of the soluble human 55 kd TNF receptor‐human TNF beta complex: Implications for TNF receptor activation. Cell 73:431‐445.
   Baud, V. and Karin, M. 2001. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 11:372‐377.
   Baud, V., Liu, Z.G., Bennett, B., Suzuki, N., Xia, Y., and Karin, M. 1999. Signaling by proinflammatory cytokines: Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino‐terminal effector domain. Genes Dev. 13:1297‐1308.
   Beutler, B. 2004. Inferences, questions and possibilities in Toll‐like receptor signalling. Nature 430:257‐263.
   Boone, D.L., Turer, E.E., Lee, E.G., Ahmad, R.C., Wheeler, M.T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., and Ma, A. 2004. The ubiquitin‐modifying enzyme A20 is required for termination of Toll‐like receptor responses. Nat. Immunol. 5:1052‐1060.
   Bouwmeester, T., Bauch, A., Ruffner, H., Angrand, P.O., Bergamini, G., Croughton, K., Cruciat, C., Eberhard, D., Gagneur, J., Ghidelli, S., Hopf, C., Huhse, B., Mangano, R., Michon, A.M., Schirle, M., Schlegl, J., Schwab, M., Stein, M.A., Bauer, A., Casari, G., Drewes, G., Gavin, A.C., Jackson, D.B., Joberty, G., Neubauer, G., Rick, J., Kuster, B., and Superti‐Furga, G. 2004. A physical and functional map of the human TNF‐alpha/NF‐kappa B signal transduction pathway. Nat. Cell Biol. 6:97‐105.
   Brockhaus, M., Schoenfeld, H.J., Schlaeger, E.J., Hunziker, W., Lesslauer, W., and Loetscher, H. 1990. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc. Natl. Acad. Sci. U.S.A. 87:3127‐3131.
   Brummelkamp, T.R., Nijman, S.M., Dirac, A.M., and Bernards, R. 2003. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF‐kappaB. Nature 424:797‐801.
   Burns, K., Clatworthy, J., Martin, L., Martinon, F., Plumpton, C., Maschera, B., Lewis, A., Ray, K., Tschopp, J., and Volpe, F. 2000. Tollip, a new component of the IL‐1RI pathway, links IRAK to the IL‐1 receptor. Nat. Cell Biol. 2:346‐351.
   Camerini, D., Walz, G., Loenen, W.A., Borst, J., and Seed, B. 1991. The T cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family. J. Immunol. 147:3165‐3169.
   Cao, Z., Henzel, W.J., and Gao, X. 1996a. IRAK: A kinase associated with the interleukin‐1 receptor. Science 271:1128‐1131.
   Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., and Goeddel, D.V. 1996b. TRAF6 is a signal transducer for interleukin‐1. Nature 383:443‐446.
   Chan, F.K., Chun, H.J., Zheng, L., Siegel, R.M., Bui, K.L., and Lenardo, M.J. 2000. A domain in TNF receptors that mediates ligand‐independent receptor assembly and signaling. Science 288:2351‐2354.
   Chen, Z.J. 2005. Ubiquitin signalling in the NF‐kappaB pathway. Nat. Cell Biol. 7:758‐765.
   Cheng, G. and Baltimore, D. 1996. TANK, a co‐inducer with TRAF2 of TNF‐ and CD 40L‐mediated NF‐kappaB activation. Genes Dev. 10:963‐973.
   Cheng, G., Cleary, A.M., Ye, Z.S., Hong, D.I., Lederman, S., and Baltimore, D. 1995. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 267:1494‐1498.
   Chinnaiyan, A.M., O'Rourke, K., Yu, G.L., Lyons, R.H., Garg, M., Duan, D.R., Xing, L., Gentz, R., Ni, J., and Dixit, V.M. 1996. Signal transduction by DR3, a death domain‐containing receptor related to TNFR‐1 and CD95. Science 274:990‐992.
   Choi, Y.H., Kim, K.B., Kim, H.H., Hong, G.S., Kwon, Y.K., Chung, C.W., Park, Y.M., Shen, Z.J., Kim, B.J., Lee, S.Y., and Jung, Y.K. 2001. FLASH coordinates NF‐kappa B activity via TRAF2. J. Biol. Chem. 276:25073‐25077.
   Chung, J.Y., Park, Y.C., Ye, H., and Wu, H. 2002. All TRAFs are not created equal: Common and distinct molecular mechanisms of TRAF‐mediated signal transduction. J. Cell. Sci. 115:679‐688.
   Croston, G.E., Cao, Z., and Goeddel, D.V. 1995. NF‐kappa B activation by interleukin‐1 (IL‐1) requires an IL‐1 receptor‐associated protein kinase activity. J. Biol. Chem. 270:16514‐16517.
   Dadgostar, H. and Cheng, G. 2000. Membrane localization of TRAF 3 enables JNK activation. J. Biol. Chem. 275:2539‐2544.
   Dadgostar, H., Doyle, S.E., Shahangian, A., Garcia, D.E., and Cheng, G. 2003. T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1). FEBS Lett. 553:403‐407.
   Darnay, B.G., Haridas, V., Ni, J., Moore, P.A., and Aggarwal, B.B. 1998. 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. J. Biol. Chem. 273:20551‐20555.
   Darnay, B.G., Ni, J., Moore, P.A., and Aggarwal, B.B. 1999. 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. J. Biol. Chem. 274:7724‐7731.
   Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., and Chen, Z.J. 2000. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin‐conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351‐361.
   Deng, Y., Ren, X., Yang, L., Lin, Y., and Wu, X. 2003. A JNK‐dependent pathway is required for TNFalpha‐induced apoptosis. Cell 115:61‐70.
   Dougall, W.C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M.E., Maliszewski, C.R., Armstrong, A., Shen, V., Bain, S., Cosman, D., Anderson, D., Morrissey, P.J., Peschon, J.J., and Schuh, J. 1999. RANK is essential for osteoclast and lymph node development. Genes Dev. 13:2412‐2424.
   Dunn, I.F., Sannikova, T.Y., Geha, R.S., and Tsitsikov, E.N. 2000. Identification and characterization of two CD40‐inducible enhancers in the mouse TRAF1 gene locus. Mol. Immunol. 37:961‐973.
   Durkop, H., Latza, U., Hummel, M., Eitelbach, F., Seed, B., and Stein, H. 1992. Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease. Cell 68:421‐427.
   Eby, M.T., Jasmin, A., Kumar, A., Sharma, K., and Chaudhary, P.M. 2000. TAJ, a novel member of the tumor necrosis factor receptor family, activates the c‐Jun N‐terminal kinase pathway and mediates caspase‐independent cell death. J. Biol. Chem. 275:15336‐15342.
   Esparza, E.M. and Arch, R.H. 2004. TRAF4 functions as an intermediate of GITR‐induced NF‐kappaB activation. Cell. Mol. Life Sci. 61:3087‐3092.
   Fata, J.E., Kong, Y.Y., Li, J., Sasaki, T., Irie‐Sasaki, J., Moorehead, R.A., Elliott, R., Scully, S., Voura, E.B., Lacey, D.L., Boyle, W.J., Khokha, R., and Penninger, J.M. 2000. The osteoclast differentiation factor osteoprotegerin‐ligand is essential for mammary gland development. Cell 103:41‐50.
   Feng, X., Gaeta, M.L., Madge, L.A., Yang, J.H., Bradley, J.R., and Pober, J.S. 2001. Caveolin‐1 associates with TRAF2 to form a complex that is recruited to tumor necrosis factor receptors. J. Biol. Chem. 276:8341‐8349.
   Fleckenstein, D.S., Dirks, W.G., Drexler, H.G., and Quentmeier, H. 2003. Tumor necrosis factor receptor‐associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk. Res. 27:687‐694.
   Fotin‐Mleczek, M., Henkler, F., Hausser, A., Glauner, H., Samel, D., Graness, A., Scheurich, P., Mauri, D., and Wajant, H. 2004. Tumor necrosis factor receptor‐associated factor (TRAF) 1 regulates CD40‐induced TRAF2‐mediated NF‐kappaB activation. J. Biol. Chem. 279:677‐685.
   Fuchs, P., Strehl, S., Dworzak, M., Himmler, A., and Ambros, P.F. 1992. Structure of the human TNF receptor 1 (p60) gene (TNFR1) and localization to chromosome 12p13. Genomics 13:219‐224.
   Gamper, C., van Eyndhoven, W.G., Schweiger, E., Mossbacher, M., Koo, B., and Lederman, S. 2000. TRAF‐3 interacts with p62 nucleoporin, a component of the nuclear pore central plug that binds classical NLS‐containing import complexes. Mol. Immunol. 37:73‐84.
   Gatot, J.S., Gioia, R., Chau, T.L., Patrascu, F., Warnier, M., Close, P., Chapelle, J.P., Muraille, E., Brown, K., Siebenlist, U., Piette, J., Dejardin, E., and Chariot, A. 2007. Lipopolysaccharide‐mediated interferon regulatory factor activation involves TBK1‐IKKepsilon‐dependent Lys(63)‐linked polyubiquitination and phosphorylation of TANK/I‐TRAF. J. Biol. Chem. 282:31131‐31146.
   Ghosh, S., May, M.J., and Kopp, E.B. 1998. NF‐kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16:225‐260.
   Gohda, J., Matsumura, T., and Inoue, J. 2004. Cutting edge: TNFR‐associated factor (TRAF) 6 is essential for MyD88‐dependent pathway but not toll/IL‐1 receptor domain‐containing adaptor‐inducing IFN‐beta (TRIF)‐dependent pathway in TLR signaling. J. Immunol. 173:2913‐2917.
   Grech, A., Quinn, R., Srinivasan, D., Badoux, X., and Brink, R. 2000. Complete structural characterisation of the mammalian and Drosophila TRAF genes: Implications for TRAF evolution and the role of RING finger splice variants. Mol. Immunol. 37:721‐734.
   Grell, M., Douni, E., Wajant, H., Lohden, M., Clauss, M., Maxeiner, B., Georgopoulos, S., Lesslauer, W., Kollias, G., Pfizenmaier, K., and Scheurich, P. 1995. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80‐kDa tumor necrosis factor receptor. Cell 83:793‐802.
   Gurney, A.L., Marsters, S.A., Huang, R.M., Pitti, R.M., Mark, D.T., Baldwin, D.T., Gray, A.M., Dowd, A.D., Brush, A.D., Heldens, A.D., Schow, A.D., Goddard, A.D., Wood, W.I., Baker, K.P., Godowski, P.J., and Ashkenazi, A. 1999. Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr. Biol. 9:215‐218.
   Ha, Y.J. and Lee, J.R. 2004. Role of TNF receptor‐associated factor 3 in the CD40 signaling by production of reactive oxygen species through association with p40phox, a cytosolic subunit of nicotinamide adenine dinucleotide phosphate oxidase. J. Immunol. 172:231‐239.
   Habelhah, H., Takahashi, S., Cho, S.G., Kadoya, T., Watanabe, T., and Ronai, Z. 2004. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF‐kappaB. Embo J. 23:322‐332.
   Hacker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L.C., Wang, G.G., Kamps, M.P., Raz, E., Wagner, H., Hacker, G., Mann, M., and Karin, M. 2006. Specificity in Toll‐like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439:204‐207.
   Hammerschmidt, W. and Sugden, B. 1989. Genetic analysis of immortalizing functions of Epstein‐Barr virus in human B lymphocytes. Nature 340:393‐397.
   Hauer, J., Puschner, S., Ramakrishnan, P., Simon, U., Bongers, M., Federle, C., and Engelmann, H. 2005. TNF receptor (TNFR)‐associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5‐mediated activation of the noncanonical NF‐kappaB pathway by TRAF‐binding TNFRs. Proc. Natl. Acad. Sci. U.S.A. 102:2874‐2879.
   Henkler, F., Baumann, B., Fotin‐Mleczek, M., Weingartner, M., Schwenzer, R., Peters, N., Graness, A., Wirth, T., Scheurich, P., Schmid, J.A., and Wajant, H. 2003. Caspase‐mediated cleavage converts the tumor necrosis factor (TNF) receptor‐associated factor (TRAF)‐1 from a selective modulator of TNF receptor signaling to a general inhibitor of NF‐kappaB activation. J. Biol. Chem. 278:29216‐29230.
   Heyninck, K., De Valck, D., Vanden Berghe, W., Van Criekinge, W., Contreras, R., Fiers, W., Haegeman, G., and Beyaert, R. 1999. The zinc finger protein A20 inhibits TNF‐induced NF‐kappaB‐dependent gene expression by interfering with an RIP‐ or TRAF2‐mediated transactivation signal and directly binds to a novel NF‐kappaB‐inhibiting protein ABIN. J. Cell Biol. 145:1471‐1482.
   Hoeflich, K.P., Yeh, W.C., Yao, Z., Mak, T.W., and Woodgett, J.R. 1999. Mediation of TNF receptor‐associated factor effector functions by apoptosis signal‐regulating kinase‐1 (ASK1). Oncogene 18:5814‐5820.
   Hohmann, H.P., Remy, R., Brockhaus, M., and van Loon, A.P. 1989. Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha). J. Biol. Chem. 264:14927‐14934.
   Hsu, H., Huang, J., Shu, H.B., Baichwal, V., and Goeddel, D.V. 1996a. TNF‐dependent recruitment of the protein kinase RIP to the TNF receptor‐1 signaling complex. Immunity 4:387‐396.
   Hsu, H., Shu, H.B., Pan, M.G., and Goeddel, D.V. 1996b. TRADD‐TRAF2 and TRADD‐FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299‐308.
   Hu, H.M., O'Rourke, K., Boguski, M.S., and Dixit, V.M. 1994. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J. Biol. Chem. 269:30069‐30072.
   Hu, W.H., Mo, X.M., Walters, W.M., Brambilla, R., and Bethea, J.R. 2004. TNAP, a novel repressor of NF‐kappaB‐inducing kinase, suppresses NF‐kappaB activation. J. Biol. Chem. 279:35975‐35983.
   Idriss, H.T. and Naismith, J.H. 2000. TNF alpha and the TNF receptor superfamily: Structure‐function relationship(s). Microsc. Res. Tech. 50:184‐195.
   Inoue, J., Ishida, T., Tsukamoto, N., Kobayashi, N., Naito, A., Azuma, S., and Yamamoto, T. 2000. Tumor necrosis factor receptor‐associated factor (TRAF) family: Adapter proteins that mediate cytokine signaling. Exp. Cell Res. 254:14‐24.
   Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J.L., Schroter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L.E., and Tschopp, J. 1997. Inhibition of death receptor signals by cellular FLIP. Nature 388:190‐195.
   Irmler, M., Steiner, V., Ruegg, C., Wajant, H., and Tschopp, J. 2000. Caspase‐induced inactivation of the anti‐apoptotic TRAF1 during Fas ligand‐mediated apoptosis. FEBS Lett. 468:129‐133.
   Ishida, T., Mizushima, S., Azuma, S., Kobayashi, N., Tojo, T., Suzuki, K., Aizawa, S., Watanabe, T., Mosialos, G., Kieff, E., Yamamoto, T., and Inoue, J. 1996a. Identification of TRAF6, a novel tumor necrosis factor receptor‐associated factor protein that mediates signaling from an amino‐terminal domain of the CD40 cytoplasmic region. J. Biol. Chem. 271:28745‐28748.
   Ishida, T.K., Tojo, T., Aoki, T., Kobayashi, N., Ohishi, T., Watanabe, T., Yamamoto, T., and Inoue, J. 1996b. TRAF5, a novel tumor necrosis factor receptor‐associated factor family protein, mediates CD40 signaling. Proc. Natl. Acad. Sci. U.S.A. 93:9437‐9442.
   Itoh, N., Yonehara, S., Ishii, A., Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S. 1991. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233‐243.
   Jang, H.D., Chung, Y.M., Baik, J.H., Choi, Y.G., Park, I.S., Jung, Y.K., and Lee, S.Y. 2001. Caspase‐cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF‐induced cell death. Biochem. Biophys. Res. Commun. 281:499‐505.
   Jin, W., Chang, M., Paul, E.M., Babu, G., Lee, A.J., Reiley, W., Wright, A., Zhang, M., You, J., and Sun, S.C. 2008. Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J. Clin. Invest. 118:1858‐1866.
   Johnson, D., Lanahan, A., Buck, C.R., Sehgal, A., Morgan, C., Mercer, E., Bothwell, M., and Chao, M. 1986. Expression and structure of the human NGF receptor. Cell 47:545‐554.
   Kadono, Y., Okada, F., Perchonock, C., Jang, H.D., Lee, S.Y., Kim, N., and Choi, Y. 2005. Strength of TRAF6 signaling determines osteoclastogenesis. EMBO Rep. 6:171‐176.
   Kanayama, A., Seth, R.B., Sun, L., Ea, C.K., Hong, M., Shaito, A., Chiu, Y.H., Deng, L., and Chen, Z.J. 2004. TAB2 and TAB3 activate the NF‐kappaB pathway through binding to polyubiquitin chains. Mol. Cell 15:535‐548.
   Karin, M., Liu, Z., and Zandi, E. 1997. AP‐1 function and regulation. Curr. Opin. Cell Biol. 9:240‐246.
   Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., Takeuchi, O., and Akira, S. 2004. Interferon‐alpha induction through Toll‐like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat. Immunol. 5:1061‐1068.
   Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K.M., Eby, M., Pietras, E., Cheng, G., Bazan, J.F., Zhang, Z., Arnott, D., and Dixit, V.M. 2007. DUBA: A deubiquitinase that regulates type I interferon production. Science 318:1628‐1632.
   King, C.G., Kobayashi, T., Cejas, P.J., Kim, T., Yoon, K., Kim, G.K., Chiffoleau, E., Hickman, S.P., Walsh, P.T., Turka, L.A., and Choi, Y. 2006. TRAF6 is a T cell‐intrinsic negative regulator required for the maintenance of immune homeostasis. Nat. Med. 12:1088‐1092.
   Kobayashi, N., Kadono, Y., Naito, A., Matsumoto, K., Yamamoto, T., Tanaka, S., and Inoue, J. 2001. Segregation of TRAF6‐mediated signaling pathways clarifies its role in osteoclastogenesis. Embo J. 20:1271‐1280.
   Kobayashi, T., Walsh, P.T., Walsh, M.C., Speirs, K.M., Chiffoleau, E., King, C.G., Hancock, W.W., Caamano, J.H., Hunter, C.A., Scott, P., Turka, L.A., and Choi, Y. 2003. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19:353‐363.
   Kong, Y.Y., Yoshida, H., Sarosi, I., Tan, H.L., Timms, E., Capparelli, C., Morony, S., Oliveira‐dos‐Santos, A.J., Van, G., Itie, A., Khoo, W., Wakeham, A., Dunstan, C.R., Lacey, D.L., Mak, T.W., Boyle, W.J., and Penninger, J.M. 1999. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph‐node organogenesis. Nature 397:315‐323.
   Kopp, E., Medzhitov, R., Carothers, J., Xiao, C., Douglas, I., Janeway, C.A. and Ghosh, S. 1999. ECSIT is an evolutionarily conserved intermediate in the Toll/IL‐1 signal transduction pathway. Genes Dev. 13:2059‐2071.
   Kovalenko, A., Chable‐Bessia, C., Cantarella, G., Israel, A., Wallach, D., and Courtois, G. 2003. The tumor suppressor CYLD negatively regulates NF‐kappaB signaling by deubiquitination. Nature 424:801‐805.
   Krajewska, M., Krajewski, S., Zapata, J.M., Van Arsdale, T., Gascoyne, R.D., Berern, K., McFadden, D., Shabaik, A., Hugh, J., Reynolds, A., Clevenger, C.V., and Reed, J.C. 1998. TRAF‐4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues. Am. J. Pathol. 152:1549‐1561.
   Laabi, Y., Gras, M.P., Brouet, J.C., Berger, R., Larsen, C.J., and Tsapis, A. 1994. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Res. 22:1147‐1154.
   Lamothe, B., Webster, W.K., Gopinathan, A., Besse, A., Campos, A.D., and Darnay, B.G. 2007. TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. Biochem. Biophys. Res. Commun. 359:1044‐1049.
   Latza, U., Durkop, H., Schnittger, S., Ringeling, J., Eitelbach, F., Hummel, M., Fonatsch, C., and Stein, H. 1994. The human OX40 homolog: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. Eur. J. Immunol. 24:677‐683.
   Lee, S.Y., Lee, S.Y., and Choi, Y. 1997a. TRAF‐interacting protein (TRIP): A novel component of the tumor necrosis factor receptor (TNFR)‐ and CD30‐TRAF signaling complexes that inhibits TRAF2‐mediated NF‐kappaB activation. J. Exp. Med. 185:1275‐1285.
   Lee, S.Y., Reichlin, A., Santana, A., Sokol, K.A., Nussenzweig, M.C., and Choi, Y. 1997b. TRAF2 is essential for JNK but not NF‐kappaB activation and regulates lymphocyte proliferation and survival. Immunity 7:703‐713.
   Leo, E., Welsh, K., Matsuzawa, S., Zapata, J.M., Kitada, S., Mitchell, R.S., Ely, K.R., and Reed, J.C. 1999. Differential requirements for tumor necrosis factor receptor‐associated factor family proteins in CD40‐mediated induction of NF‐kappaB and Jun N‐terminal kinase activation. J. Biol. Chem. 274:22414‐22422.
   Leo, E., Deveraux, Q.L., Buchholtz, C., Welsh, K., Matsuzawa, S., Stennicke, H.R., Salvesen, G.S. and Reed, J.C. 2001. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor‐alpha‐induced apoptosis. J. Biol. Chem. 276:8087‐8093.
   Leonardi, A., Ellinger‐Ziegelbauer, H., Franzoso, G., Brown, K., and Siebenlist, U. 2000. Physical and functional interaction of filamin (actin‐binding protein‐280) and tumor necrosis factor receptor‐associated factor 2. J. Biol. Chem. 275:271‐278.
   Liao, G., Zhang, M., Harhaj, E.W., and Sun, S.C. 2004. Regulation of the NF‐kappaB‐inducing kinase by tumor necrosis factor receptor‐associated factor 3‐induced degradation. J. Biol. Chem. 279:26243‐26250.
   Lieberson, R., Mowen, K.A., McBride, K.D., Leautaud, V., Zhang, X., Suh, W.K., Wu, L., and Glimcher, L.H. 2001. Tumor necrosis factor receptor‐associated factor (TRAF)2 represses the T helper cell type 2 response through interaction with NFAT‐interacting protein (NIP45). J. Exp. Med. 194:89‐98.
   Lin, Y., Ryan, J., Lewis, J., Wani, M.A., Lingrel, J.B., and Liu, Z.G. 2003. TRAF2 exerts its antiapoptotic effect by regulating the expression of Kruppel‐like factor LKLF. Mol. Cell. Biol. 23:5849‐5856.
   Ling, L. and Goeddel, D.V. 2000a. MIP‐T3, a novel protein linking tumor necrosis factor receptor‐associated factor 3 to the microtubule network. J. Biol. Chem. 275:23852‐23860.
   Ling, L. and Goeddel, D.V. 2000b. T6BP, a TRAF6‐interacting protein involved in IL‐1 signaling. Proc. Natl. Acad. Sci. U.S.A. 97:9567‐9572.
   Locksley, R.M., Killeen, N., and Lenardo, M.J. 2001. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 104:487‐501.
   Lomaga, M.A., Yeh, W.C., Sarosi, I., Duncan, G.S., Furlonger, C., Ho, A., Morony, S., Capparelli, C., Van, G., Kaufman, S., van der Heiden, A., Itie, A., Wakeham, A., Khoo, W., Sasaki, T., Cao, Z., Penninger, J.M., Paige, C.J., Lacey, D.L., Dunstan, C.R., Boyle, W.J., Goeddel, D.V., and Mak, T.W. 1999. TRAF6 deficiency results in osteopetrosis and defective interleukin‐1, CD40, and LPS signaling. Genes Dev. 13:1015‐1024.
   MacLachlan, T.K., Sang, N., De Luca, A., Puri, P.L., Levrero, M., and Giordano, A. 1998. Binding of CDK9 to TRAF2. J. Cell. Biochem. 71:467‐478.
   Mahoney, D.J., Cheung, H.H., Mrad, R.L., Plenchette, S., Simard, C., Enwere, E., Arora, V., Mak, T.W., Lacasse, E.C., Waring, J., and Korneluk, R.G. 2008. Both cIAP1 and cIAP2 regulate TNFalpha‐mediated NF‐kappaB activation. Proc. Natl. Acad. Sci. U.S.A. 105:11778‐11783.
   Malinin, N.L., Boldin, M.P., Kovalenko, A.V., and Wallach, D. 1997. MAP3K‐related kinase involved in NF‐kappaB induction by TNF, CD95 and IL‐1. Nature 385:540‐544.
   Marsters, S.A., Sheridan, J.P., Pitti, R.M., Huang, A., Skubatch, M., Baldwin, D., Yuan, J., Gurney, A., Goddard, A.D., Godowski, P., and Ashkenazi, A. 1997. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr. Biol. 7:1003‐1006.
   Mauro, C., Pacifico, F., Lavorgna, A., Mellone, S., Iannetti, A., Acquaviva, R., Formisano, S., Vito, P., and Leonardi, A. 2006. ABIN‐1 binds to NEMO/IKKgamma and co‐operates with A20 in inhibiting NF‐kappaB. J. Biol. Chem. 281:18482‐18488.
   McCarthy, J.V., Ni, J., and Dixit, V.M. 1998. RIP2 is a novel NF‐kappaB‐activating and cell death‐inducing kinase. J. Biol. Chem. 273:16968‐16975.
   Meylan, E., Martinon, F., Thome, M., Gschwendt, M., and Tschopp, J. 2002. RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF‐kappa B and is processed during apoptosis. EMBO Rep. 3:1201‐1208.
   Micheau, O. and Tschopp, J. 2003. Induction of TNF receptor I‐mediated apoptosis via two sequential signaling complexes. Cell 114:181‐190.
   Monreal, A.W., Ferguson, B.M., Headon, D.J., Street, S.L., Overbeek, P.A., and Zonana, J. 1999. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat. Genet. 22:366‐369.
   Montgomery, R.I., Warner, M.S., Lum, B.J., and Spear, P.G. 1996. Herpes simplex virus‐1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87:427‐436.
   Moore, C.R. and Bishop, G.A. 2005. Differential regulation of CD40‐mediated TNF receptor‐associated factor degradation in B lymphocytes. J. Immunol. 175:3780‐3789.
   Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C., and Kieff, E. 1995. The Epstein‐Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80:389‐399.
   Muzio, M., Ni, J., Feng, P., and Dixit, V.M. 1997. IRAK (Pelle) family member IRAK‐2 and MyD88 as proximal mediators of IL‐1 signaling. Science 278:1612‐1615.
   Naito, A., Azuma, S., Tanaka, S., Miyazaki, T., Takaki, S., Takatsu, K., Nakao, K., Nakamura, K., Katsuki, M., Yamamoto, T., and Inoue, J. 1999. Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice. Genes Cells 4:353‐362.
   Naito, A., Yoshida, H., Nishioka, E., Satoh, M., Azuma, S., Yamamoto, T., Nishikawa, S., and Inoue, J. 2002. TRAF6‐deficient mice display hypohidrotic ectodermal dysplasia. Proc. Natl. Acad. Sci. U.S.A. 99:8766‐8771.
   Nakano, H., Oshima, H., Chung, W., Williams‐Abbott, L., Ware, C.F., Yagita, H., and Okumura, K. 1996. TRAF5, an activator of NF‐kappaB and putative signal transducer for the lymphotoxin‐beta receptor. J. Biol. Chem. 271:14661‐14664.
   Nakano, H., Sakon, S., Koseki, H., Takemori, T., Tada, K., Matsumoto, M., Munechika, E., Sakai, T., Shirasawa, T., Akiba, H., Kobata, T., Santee, S.M., Ware, C.F., Rennert, P.D., Taniguchi, M., Yagita, H., and Okumura, K. 1999. Targeted disruption of Traf5 gene causes defects in CD40‐ and CD27‐mediated lymphocyte activation. Proc. Natl. Acad. Sci. U.S.A. 96:9803‐9808.
   Nguyen, L.T., Duncan, G.S., Mirtsos, C., Ng, M., Speiser, D.E., Shahinian, A., Marino, M.W., Mak, T.W., Ohashi, P.S., and Yeh, W.C. 1999. TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40‐mediated responses. Immunity 11:379‐389.
   Ninomiya‐Tsuji, J., Kishimoto, K., Hiyama, A., Inoue, J., Cao, Z., and Matsumoto, K. 1999. The kinase TAK1 can activate the NIK‐I kappaB as well as the MAP kinase cascade in the IL‐1 signalling pathway. Nature 398:252‐256.
   Nishitoh, H., Saitoh, M., Mochida, Y., Takeda, K., Nakano, H., Rothe, M., Miyazono, K., and Ichijo, H. 1998. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell 2:389‐395.
   O'Neill, L.A. 2006. How Toll‐like receptors signal: What we know and what we don't know. Curr. Opin. Immunol. 18:3‐9.
   Oganesyan, G., Saha, S.K., Guo, B., He, J.Q., Shahangian, A., Zarnegar, B., Perry, A., and Cheng, G. 2006. Critical role of TRAF3 in the Toll‐like receptor‐dependent and ‐independent antiviral response. Nature 439:208‐211.
   Pan, G., Ni, J., Wei, Y.F., Yu, G., Gentz, R., and Dixit, V.M. 1997a. An antagonist decoy receptor and a death domain‐containing receptor for TRAIL. Science 277:815‐818.
   Pan, G., O'Rourke, K., Chinnaiyan, A.M., Gentz, R., Ebner, R., Ni, J., and Dixit, V.M. 1997b. The receptor for the cytotoxic ligand TRAIL. Science 276:111‐113.
   Pan, G., Bauer, J.H., Haridas, V., Wang, S., Liu, D., Yu, G., Vincenz, C., Aggarwal, B.B., Ni, J., and Dixit, V.M. 1998. Identification and functional characterization of DR6, a novel death domain‐containing TNF receptor. FEBS Lett. 431:351‐356.
   Park, Y.C., Burkitt, V., Villa, A.R., Tong, L., and Wu, H. 1999. Structural basis for self‐association and receptor recognition of human TRAF2. Nature 398:533‐538.
   Park, Y.C., Ye, H., Hsia, C., Segal, D., Rich, R.L., Liou, H.C., Myszka, D.G., and Wu, H. 2000. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD‐TRAF2 interaction. Cell 101:777‐787.
   Pomerantz, J.L. and Baltimore, D. 1999. NF‐kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK‐related kinase. Embo J. 18:6694‐6704.
   Pullen, S.S., Miller, H.G., Everdeen, D.S., Dang, T.T., Crute, J.J., and Kehry, M.R. 1998. CD40‐tumor necrosis factor receptor‐associated factor (TRAF) interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero‐oligomerization. Biochemistry 37:11836‐11845.
   Pype, S., Declercq, W., Ibrahimi, A., Michiels, C., Van Rietschoten, J.G., Dewulf, N., de Boer, M., Vandenabeele, P., Huylebroeck, D., and Remacle, J.E. 2000. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor‐75 and TNF receptor‐associated factors (TRAFs), and that inhibits nuclear factor‐kappa B activation. J. Biol. Chem. 275:18586‐18593.
   Qian, Y., Zhao, Z., Jiang, Z., and Li, X. 2002. Role of NF kappa B activator Act1 in CD40‐mediated signaling in epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 99:9386‐9391.
   Rao, K.M. 2001. MAP kinase activation in macrophages. J. Leukoc. Biol. 69:3‐10.
   Regnier, C.H., Tomasetto, C., Moog‐Lutz, C., Chenard, M.P., Wendling, C., Basset, P., and Rio, M.C. 1995. Presence of a new conserved domain in CART1, a novel member of the tumor necrosis factor receptor‐associated protein family, which is expressed in breast carcinoma. J. Biol. Chem. 270:25715‐25721.
   Regnier, C.H., Masson, R., Kedinger, V., Textoris, J., Stoll, I., Chenard, M.P., Dierich, A., Tomasetto, C., and Rio, M.C. 2002. Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4‐deficient mice. Proc. Natl. Acad. Sci. U.S.A. 99:5585‐5590.
   Rothe, M., Wong, S.C., Henzel, W.J., and Goeddel, D.V. 1994. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78:681‐692.
   Rothe, M., Pan, M.G., Henzel, W.J., Ayres, T.M., and Goeddel, D.V. 1995. The TNFR2‐TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243‐1252.
   Rothe, M., Xiong, J., Shu, H.B., Williamson, K., Goddard, A., and Goeddel, D.V. 1996. I‐TRAF is a novel TRAF‐interacting protein that regulates TRAF‐mediated signal transduction. Proc. Natl. Acad. Sci. U.S.A. 93:8241‐8246.
   Sabbagh, L., Srokowski, C.C., Pulle, G., Snell, L.M., Sedgmen, B.J., Liu, Y., Tsitsikov, E.N., and Watts, T.H. 2006. A critical role for TNF receptor‐associated factor 1 and Bim down‐regulation in CD8 memory T cell survival. Proc. Natl. Acad. Sci. U.S.A. 103:18703‐18708.
   Sanz, L., Diaz‐Meco, M.T., Nakano, H., and Moscat, J. 2000. The atypical PKC‐interacting protein p62 channels NF‐kappaB activation by the IL‐1‐TRAF6 pathway. Embo J. 19:1576‐1586.
   Schwarz, H., Tuckwell, J., and Lotz, M. 1993. A receptor induced by lymphocyte activation (ILA): A new member of the human nerve‐growth‐factor/tumor‐necrosis‐factor receptor family. Gene 134:295‐298.
   Schwenzer, R., Siemienski, K., Liptay, S., Schubert, G., Peters, N., Scheurich, P., Schmid, R.M., and Wajant, H. 1999. The human tumor necrosis factor (TNF) receptor‐associated factor 1 gene (TRAF1) is up‐regulated by cytokines of the TNF ligand family and modulates TNF‐induced activation of NF‐kappaB and c‐Jun N‐terminal kinase. J. Biol. Chem. 274:19368‐19374.
   Sheridan, J.P., Marsters, S.A., Pitti, R.M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C.L., Baker, K., Wood, W.I., Goddard, A.D., Godowski, P., and Ashkenazi, A. 1997. Control of TRAIL‐induced apoptosis by a family of signaling and decoy receptors. Science 277:818‐821.
   Shi, C.S. and Kehrl, J.H. 2003. Tumor necrosis factor (TNF)‐induced germinal center kinase‐related (GCKR) and stress‐activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13‐Uev1A/TNF receptor‐associated factor 2 (TRAF2). J. Biol. Chem. 278:15429‐15434.
   Shiels, H., Li, X., Schumacker, P.T., Maltepe, E., Padrid, P.A., Sperling, A., Thompson, C.B., and Lindsten, T. 2000. TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs. Am. J. Pathol. 157:679‐688.
   Silverman, N. and Maniatis, T. 2001. NF‐kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15:2321‐2342.
   Simonet, W.S., Lacey, D.L., Dunstan, C.R., Kelley, M., Chang, M.S., Luthy, R., Nguyen, H.Q., Wooden, S., Bennett, L., Boone, T., Shimamoto, G., DeRose, M., Elliott, R., Colombero, A., Tan, H.L., Trail, G., Sullivan, J., Davy, E., Bucay, N., Renshaw‐Gegg, L., Hughes, T.M., Hill, D., Pattison, W., Campbell, P., Sander, S., Van, G., Tarpley, J., Derby, P., Lee, R., and Boyle, W.J. 1997. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 89:309‐319.
   Smith, C.A., Davis, T., Anderson, D., Solam, L., Beckmann, M.P., Jerzy, R., Dower, S.K., Cosman, D., and Goodwin, R.G. 1990. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248:1019‐1023.
   Smith, C.A., Farrah, T., and Goodwin, R.G. 1994. The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death. Cell 76:959‐962.
   So, T., Salek‐Ardakani, S., Nakano, H., Ware, C.F., and Croft, M. 2004. TNF receptor‐associated factor 5 limits the induction of Th2 immune responses. J. Immunol. 172:4292‐4297.
   Song, H.Y., Rothe, M., and Goeddel, D.V. 1996. The tumor necrosis factor‐inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF‐kappaB activation. Proc. Natl. Acad. Sci. U.S.A. 93:6721‐6725.
   Song, H.Y., Regnier, C.H., Kirschning, C.J., Goeddel, D.V., and Rothe, M. 1997. Tumor necrosis factor (TNF)‐mediated kinase cascades: Bifurcation of nuclear factor‐kappaB and c‐jun N‐terminal kinase (JNK/SAPK) pathways at TNF receptor‐associated factor 2. Proc. Natl. Acad. Sci. U.S.A. 94:9792‐9796.
   Stamenkovic, I., Clark, E.A., and Seed, B. 1989. A B‐lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. Embo J. 8:1403‐1410.
   Sun, L., Deng, L., Ea, C.K., Xia, Z.P., and Chen, Z.J. 2004. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14:289‐301.
   Sun, S.C. 2008. Deubiquitylation and regulation of the immune response. Nat. Rev. Immunol. 8:501‐511.
   Sun, S.C. and Ley, S.C. 2008. New insights into NF‐kappaB regulation and function. Trends Immunol. 29:469‐478.
   Tada, K., Okazaki, T., Sakon, S., Kobarai, T., Kurosawa, K., Yamaoka, S., Hashimoto, H., Mak, T.W., Yagita, H., Okumura, K., Yeh, W.C., and Nakano, H. 2001. Critical roles of TRAF2 and TRAF5 in tumor necrosis factor‐induced NF‐kappa B activation and protection from cell death. J. Biol. Chem. 276:36530‐36534.
   Takaesu, G., Kishida, S., Hiyama, A., Yamaguchi, K., Shibuya, H., Irie, K., Ninomiya‐Tsuji, J., and Matsumoto, K. 2000. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL‐1 signal transduction pathway. Mol. Cell 5:649‐658.
   Takeshita, F., Ishii, K.J., Kobiyama, K., Kojima, Y., Coban, C., Sasaki, S., Ishii, N., Klinman, D.M., Okuda, K., Akira, S., and Suzuki, K. 2005. TRAF4 acts as a silencer in TLR‐mediated signaling through the association with TRAF6 and TRIF. Eur. J. Immunol. 35:2477‐2485.
   Takeuchi, M., Rothe, M., and Goeddel, D.V. 1996. Anatomy of TRAF2. Distinct domains for nuclear factor‐kappaB activation and association with tumor necrosis factor signaling proteins. J. Biol. Chem. 271:19935‐19942.
   Thome, M., Hofmann, K., Burns, K., Martinon, F., Bodmer, J.L., Mattmann, C., and Tschopp, J. 1998. Identification of CARDIAK, a RIP‐like kinase that associates with caspase‐1. Curr. Biol. 8:885‐888.
   Tobiume, K., Matsuzawa, A., Takahashi, T., Nishitoh, H., Morita, K., Takeda, K., Minowa, O., Miyazono, K., Noda, T., and Ichijo, H. 2001. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2:222‐228.
   Tsitsikov, E.N., Laouini, D., Dunn, I.F., Sannikova, T.Y., Davidson, L., Alt, F.W., and Geha, R.S. 2001. TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1‐deficient mice. Immunity 15:647‐657.
   Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H.P., and Ron, D. 2000. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664‐666.
   Varfolomeev, E., Blankenship, J.W., Wayson, S.M., Fedorova, A.V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J.N., Elliott, L.O., Wallweber, H.J., Flygare, J.A., Fairbrother, W.J., Deshayes, K., Dixit, V.M., and Vucic, D. 2007. IAP antagonists induce autoubiquitination of c‐IAPs, NF‐kappaB activation, and TNFalpha‐dependent apoptosis. Cell 131:669‐681.
   von Bulow, G.U. and Bram, R.J. 1997. NF‐AT activation induced by a CAML‐interacting member of the tumor necrosis factor receptor superfamily. Science 278:138‐141.
   Wajant, H., Henkler, F., and Scheurich, P. 2001. The TNF‐receptor‐associated factor family: Scaffold molecules for cytokine receptors, kinases and their regulators. Cell. Signal. 13:389‐400.
   Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., and Boldin, M.P. 1999. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu. Rev. Immunol. 17:331‐367.
   Wang, C., Deng, L., Hong, M., Akkaraju, G.R., Inoue, J., and Chen, Z.J. 2001. TAK1 is a ubiquitin‐dependent kinase of MKK and IKK. Nature 412:346‐351.
   Wang, F., Gregory, C., Sample, C., Rowe, M., Liebowitz, D., Murray, R., Rickinson, A., and Kieff, E. 1990. Epstein‐Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA‐2 and LMP1 cooperatively induce CD23. J. Virol. 64:2309‐2318.
   Weiss, T., Grell, M., Siemienski, K., Muhlenbeck, F., Durkop, H., Pfizenmaier, K., Scheurich, P., and Wajant, H. 1998. TNFR80‐dependent enhancement of TNFR60‐induced cell death is mediated by TNFR‐associated factor 2 and is specific for TNFR60. J. Immunol. 161:3136‐3142.
   Wertz, I.E., O'Rourke, K.M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D.L., Ma, A., Koonin, E.V., and Dixit, V.M. 2004. De‐ubiquitination and ubiquitin ligase domains of A20 downregulate NF‐kappaB signalling. Nature 430:694‐699.
   Wesche, H., Henzel, W.J., Shillinglaw, W., Li, S., and Cao, Z. 1997. MyD88: An adapter that recruits IRAK to the IL‐1 receptor complex. Immunity 7:837‐847.
   Wesche, H., Gao, X., Li, X., Kirschning, C.J., Stark, G.R., and Cao, Z. 1999. IRAK‐M is a novel member of the Pelle/interleukin‐1 receptor‐associated kinase (IRAK) family. J. Biol. Chem. 274:19403‐19410.
   Widmann, C., Gibson, S., Jarpe, M.B., and Johnson, G.L. 1999. Mitogen‐activated protein kinase: Conservation of a three‐kinase module from yeast to human. Physiol. Rev. 79:143‐180.
   Wong, B.R., Josien, R., Lee, S.Y., Vologodskaia, M., Steinman, R.M., and Choi, Y. 1998. The TRAF family of signal transducers mediates NF‐kappaB activation by the TRANCE receptor. J. Biol. Chem. 273:28355‐28359.
   Wong, B.R., Besser, D., Kim, N., Arron, J.R., Vologodskaia, M., Hanafusa, H., and Choi, Y. 1999. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c‐Src. Mol. Cell. 4:1041‐1049.
   Xie, P., Hostager, B.S., Munroe, M.E., Moore, C.R., and Bishop, G.A. 2006. Cooperation between TNF receptor‐associated factors 1 and 2 in CD40 signaling. J. Immunol. 176:5388‐5400.
   Xing, L., Venegas, A.M., Chen, A., Garrett‐Beal, L., Boyce, B.F., Varmus, H.E., and Schwartzberg, P.L. 2001. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 15:241‐253.
   Xu, L.G., Li, L.Y., and Shu, H.B. 2004. TRAF7 potentiates MEKK3‐induced AP1 and CHOP activation and induces apoptosis. J. Biol. Chem. 279:17278‐17282.
   Xu, Y., Cheng, G., and Baltimore, D. 1996. Targeted disruption of TRAF3 leads to postnatal lethality and defective T‐dependent immune responses. Immunity 5:407‐415.
   Yang, J., Lin, Y., Guo, Z., Cheng, J., Huang, J., Deng, L., Liao, W., Chen, Z., Liu, Z., and Su, B. 2001. The essential role of MEKK3 in TNF‐induced NF‐kappaB activation. Nat. Immunol. 2:620‐624.
   Ye, H., Park, Y.C., Kreishman, M., Kieff, E., and Wu, H. 1999a. The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol. Cell. 4:321‐330.
   Ye, X., Mehlen, P., Rabizadeh, S., VanArsdale, T., Zhang, H., Shin, H., Wang, J.J., Leo, E., Zapata, J., Hauser, C.A., Reed, J.C., and Bredesen, D.E. 1999b. TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction. J. Biol. Chem. 274:30202‐30208.
   Ye, H., Arron, J.R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N.K., Segal, D., Dzivenu, O.K., Vologodskaia, M., Yim, M., Du, K., Singh, S., Pike, J.W., Darnay, B.G., Choi, Y., and Wu, H. 2002. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418:443‐447.
   Yeh, W.C., Shahinian, A., Speiser, D., Kraunus, J., Billia, F., Wakeham, A., de la Pompa, J.L., Ferrick, D., Hum, B., Iscove, N., Ohashi, P., Rothe, M., Goeddel, D.V., and Mak, T.W. 1997. Early lethality, functional NF‐kappaB activation, and increased sensitivity to TNF‐induced cell death in TRAF2‐deficient mice. Immunity 7:715‐725.
   Yeiser, E.C., Rutkoski, N.J., Naito, A., Inoue, J., and Carter, B.D. 2004. Neurotrophin signaling through the p75 receptor is deficient in traf6‐/‐ mice. J. Neurosci. 24:10521‐10529.
   Yuasa, T., Ohno, S., Kehrl, J.H., and Kyriakis, J.M. 1998. Tumor necrosis factor signaling to stress‐activated protein kinase (SAPK)/Jun NH2‐terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen‐activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen‐activated protein kinase kinase kinase upstream of MKK6 and p38. J. Biol. Chem. 273:22681‐22692.
   Yujiri, T., Ware, M., Widmann, C., Oyer, R., Russell, D., Chan, E., Zaitsu, Y., Clarke, P., Tyler, K., Oka, Y., Fanger, G.R., Henson, P., and Johnson, G.L. 2000. MEK kinase 1 gene disruption alters cell migration and c‐Jun NH2‐terminal kinase regulation but does not cause a measurable defect in NF‐kappa B activation. Proc. Natl. Acad. Sci. U.S.A. 97:7272‐7277.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library