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TRAF2 and Cellular IAPs: A Critical Link in TNFR Family Signaling

  • Domagoj Vucic
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

When first identified in the mid-1990s, cellular inhibitor of apoptosis (c-IAP1 and c-IAP2) proteins and tumor necrosis factor receptor-associated factor 2 (TRAF2) were described as putative mediators of TNFR2 signaling. The following years witnessed an immense number of studies confirming the seminal role of both cellular IAPs and of TRAF2 in transducing signaling initiated by TNF family ligands. As such, c-IAP1 and c-IAP2 suppress TNF-stimulated cell death by preventing the formation of the TNF receptor 1 (TNFR1) pro-apoptotic signaling complex. In combination with their obligatory binding partner, TRAF2, c-IAP proteins regulate pro-survival nuclear factor-kappaB (NF-κB) signaling pathways. In the TNFα-induced canonical NF-κB pathway, c-IAP1 and 2 are required for receptor interacting protein 1 (RIP1) ubiquitination and NF-κB activation. In the noncanonical NF-κB pathway, c-IAP1 and 2 ubiquitinate NF-κB-inducing kinase (NIK), leading to its proteasomal degradation and abrogation of NF-κB signaling. In addition, through the RING domain mediated ubiquitin ligase activity, c-IAP proteins regulate their own stability and the protein levels of several of their binding partners including TRAF2. Here I discuss the most recent progress in our understanding of the biological roles of c-IAPs and TRAF2, as well as the implications of targeting these molecules for therapeutic interventions.

Keywords

Ring Domain BIR3 Domain Cellular IAPs Amino Acid Patch 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author is thankful to Eugene Varfolomeev, Tatiana Goncharov, Kurt Deshayes, and Jasmin Dynek for helpful discussions and critical reading of the manuscript and to Alison Bruce and Chudi Ndubaku for assistance with figures.

References

  1. 1.
    Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F, Lenz G, Hanamura I, Wright G, Xiao W et al (2007) Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12:115–130CrossRefPubMedGoogle Scholar
  2. 2.
    Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308CrossRefPubMedGoogle Scholar
  3. 3.
    Au PY, Yeh WC (2007) Physiological roles and mechanisms of signaling by TRAF2 and TRAF5. Adv Exp Med Biol 597:32–47CrossRefPubMedGoogle Scholar
  4. 4.
    Basak S, Hoffmann A (2008) Crosstalk via the NF-kappaB signaling system. Cytokine Growth Factor Rev 19:187–197CrossRefPubMedGoogle Scholar
  5. 5.
    Bertrand MJ, Doiron K, Labbé K, Korneluk RG, Barker PA, Saleh M (2009) Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30(6):789–801Google Scholar
  6. 6.
    Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30:689–700CrossRefPubMedGoogle Scholar
  7. 7.
    Blankenship JW, Varfolomeev E, Goncharov T, Fedorova AV, Kirkpatrick DS, Izrael-Tomasevic A, Phu L, Arnott D, Aghajan M, Zobel K et al (2009) Ubiquitin binding modulates IAP antagonist-stimulated proteasomal degradation of c-IAP1 and c-IAP2. Biochem J 417:149–160CrossRefPubMedGoogle Scholar
  8. 8.
    Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635CrossRefPubMedGoogle Scholar
  9. 9.
    Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7:758–765CrossRefPubMedGoogle Scholar
  10. 10.
    Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84:853–862CrossRefPubMedGoogle Scholar
  11. 11.
    Cheung HH, Plenchette S, Kern CJ, Mahoney DJ, Korneluk RG (2008) The RING domain of cIAP1 mediates the degradation of RING-bearing inhibitor of apoptosis proteins by distinct pathways. Mol Biol Cell 19:2729–2740CrossRefPubMedGoogle Scholar
  12. 12.
    Clem RJ, Robson M, Miller LK (1994) Influence of infection route on the infectivity of baculovirus mutants lacking the apoptosis-inhibiting gene p35 and the adjacent gene p94. J Virol 68:6759–6762PubMedGoogle Scholar
  13. 13.
    Conte D, Holcik M, Lefebvre CA, Lacasse E, Picketts DJ, Wright KE, Korneluk RG (2006) Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 26:699–708CrossRefPubMedGoogle Scholar
  14. 14.
    Conze DB, Albert L, Ferrick DA, Goeddel DV, Yeh WC, Mak T, Ashwell JD (2005) Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol Cell Biol 25:3348–3356CrossRefPubMedGoogle Scholar
  15. 15.
    Crook NE, Clem RJ, Miller LK (1993) An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol 67:2168–2174PubMedGoogle Scholar
  16. 16.
    Csomos RA, Brady GF, Duckett CS (2009) Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2. J Biol Chem 284:20531–20539CrossRefPubMedGoogle Scholar
  17. 17.
    Daniel D, Wilson NS (2008) Tumor necrosis factor: renaissance as a cancer therapeutic? Curr Cancer Drug Targets 8:124–131CrossRefPubMedGoogle Scholar
  18. 18.
    Dejardin E (2006) The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 72:1161–1179CrossRefPubMedGoogle Scholar
  19. 19.
    Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42CrossRefPubMedGoogle Scholar
  20. 20.
    Duckett CS, Nava VE, Gedrich RW, Clem RJ, Van Dongen JL, Gilfillan MC, Shiels H, Hardwick JM, Thompson CB (1996) A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J 15:2685–2694PubMedGoogle Scholar
  21. 21.
    Eckelman BP, Salvesen GS, Scott FL (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7:988–994CrossRefPubMedGoogle Scholar
  22. 22.
    Ermolaeva MA, Michallet MC, Papadopoulou N, Utermohlen O, Kranidioti K, Kollias G, Tschopp J, Pasparakis M (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9:1037–1046CrossRefPubMedGoogle Scholar
  23. 23.
    Flygare JA, Vucic D (2009) Development of novel drugs targeting inhibitors of apoptosis. Future Oncol 5:141–144CrossRefPubMedGoogle Scholar
  24. 24.
    Gaither A, Porter D, Yao Y, Borawski J, Yang G, Donovan J, Sage D, Slisz J, Tran M, Straub C et al (2007) A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Cancer Res 67:11493–11498CrossRefPubMedGoogle Scholar
  25. 25.
    Grech AP, Amesbury M, Chan T, Gardam S, Basten A, Brink R (2004) TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells. Immunity 21:629–642CrossRefPubMedGoogle Scholar
  26. 26.
    Gyrd-Hansen M, Darding M, Miasari M, Santoro MM, Zender L, Xue W, Tenev T, da Fonseca PC, Zvelebil M, Bujnicki JM et al (2008) IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis. Nat Cell Biol 10:1309–1317CrossRefPubMedGoogle Scholar
  27. 27.
    Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T et al (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36:831–844CrossRefPubMedGoogle Scholar
  28. 28.
    Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, 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 102:2874–2879CrossRefPubMedGoogle Scholar
  29. 29.
    Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362CrossRefPubMedGoogle Scholar
  30. 30.
    He JQ, Oganesyan G, Saha SK, Zarnegar B, Cheng G (2007) TRAF3 and its biological function. Adv Exp Med Biol 597:48–59CrossRefPubMedGoogle Scholar
  31. 31.
    He JQ, Zarnegar B, Oganesyan G, Saha SK, Yamazaki S, Doyle SE, Dempsey PW, Cheng G (2006) Rescue of TRAF3-null mice by p100 NF-kappaB deficiency. J Exp Med 203:2413–2418CrossRefPubMedGoogle Scholar
  32. 32.
    Herman MD, Moche M, Flodin S, Welin M, Tresaugues L, Johansson I, Nilsson M, Nordlund P, Nyman T (2009) Structures of BIR domains from human NAIP and cIAP2. Acta Crystallogr Sect F Struct Biol Cryst Commun 65:1091–1096CrossRefPubMedGoogle Scholar
  33. 33.
    Hofmann K, Bucher P, Tschopp J (1997) The CARD domain: a new apoptotic signalling motif. Trends Biochem Sci 22:155–156CrossRefPubMedGoogle Scholar
  34. 34.
    Hu S, Yang X (2003) Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO. J Biol Chem 278:10055–10060CrossRefPubMedGoogle Scholar
  35. 35.
    Hunter AM, LaCasse EC, Korneluk RG (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12:1543–1568CrossRefPubMedGoogle Scholar
  36. 36.
    Imoto I, Tsuda H, Hirasawa A, Miura M, Sakamoto M, Hirohashi S, Inazawa J (2002) Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy. Cancer Res 62:4860–4866PubMedGoogle Scholar
  37. 37.
    Imoto I, Yang ZQ, Pimkhaokham A, Tsuda H, Shimada Y, Imamura M, Ohki M, Inazawa J (2001) Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas. Cancer Res 61:6629–6634PubMedGoogle Scholar
  38. 38.
    Isaacson PG (2005) Update on MALT lymphomas. Best Pract Res Clin Haematol 18:57–68CrossRefPubMedGoogle Scholar
  39. 39.
    Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J et al (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039CrossRefPubMedGoogle Scholar
  40. 40.
    Karin M, Gallagher E (2009) TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol Rev 228:225–240CrossRefPubMedGoogle Scholar
  41. 41.
    Kaufmann SH, Vaux DL (2003) Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene 22:7414–7430CrossRefPubMedGoogle Scholar
  42. 42.
    Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M et al (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12:131–144CrossRefPubMedGoogle Scholar
  43. 43.
    Kulathila R, Vash B, Sage D, Cornell-Kennon S, Wright K, Koehn J, Stams T, Clark K, Price A (2009) The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9. Acta Crystallogr D Biol Crystallogr 65:58–66CrossRefPubMedGoogle Scholar
  44. 44.
    LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG (2008) IAP-targeted therapies for cancer. Oncogene 27:6252–6275CrossRefPubMedGoogle Scholar
  45. 45.
    Liao G, Zhang M, Harhaj EW, Sun SC (2004) Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem 279:26243–26250CrossRefPubMedGoogle Scholar
  46. 46.
    Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG (1996) Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379:349–353CrossRefPubMedGoogle Scholar
  47. 47.
    Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408:1004–1008CrossRefPubMedGoogle Scholar
  48. 48.
    Mace PD, Linke K, Feltham R, Schumacher FR, Smith CA, Vaux DL, Silke J, Day CL (2008) Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment. J Biol Chem 283:31633–31640CrossRefPubMedGoogle Scholar
  49. 49.
    Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, Enwere E, Arora V, Mak TW, Lacasse EC, Waring J, Korneluk RG (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci USA 105:11778–11783CrossRefPubMedGoogle Scholar
  50. 50.
    Malinin NL, Boldin MP, Kovalenko AV, Wallach D (1997) MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 385:540–544CrossRefPubMedGoogle Scholar
  51. 51.
    Miller LK (1999) An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol 9:323–328CrossRefPubMedGoogle Scholar
  52. 52.
    Ndubaku C, Cohen F, Varfolomeev E, Vucic D (2009a) Targeting inhibitor of apoptosis (IAP) proteins for therapeutic intervention. Future Med Chem 1:1509–1525CrossRefGoogle Scholar
  53. 53.
    Ndubaku C, Varfolomeev E, Wang L, Zobel K, Lau K, Elliott LO, Maurer B, Fedorova AV, Dynek JN, Koehler M et al (2009b) Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists. ACS Chem Biol 4:557–566CrossRefPubMedGoogle Scholar
  54. 54.
    Nguyen LT, Duncan GS, Mirtsos C, Ng M, Speiser DE, Shahinian A, Marino MW, Mak TW, Ohashi PS, Yeh WC (1999) TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40-mediated responses. Immunity 11:379–389CrossRefPubMedGoogle Scholar
  55. 55.
    Park YC, Burkitt V, Villa AR, Tong L, Wu H (1999) Structural basis for self-association and receptor recognition of human TRAF2. Nature 398:533–538CrossRefPubMedGoogle Scholar
  56. 56.
    Pobezinskaya YL, Kim YS, Choksi S, Morgan MJ, Li T, Liu C, Liu Z (2008) The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat Immunol 9:1047–1054CrossRefPubMedGoogle Scholar
  57. 57.
    Rajalingam K, Sharma M, Paland N, Hurwitz R, Thieck O, Oswald M, Machuy N, Rudel T (2006) IAP-IAP complexes required for apoptosis resistance of C. trachomatis-infected cells. PLoS Pathog 2:e114CrossRefPubMedGoogle Scholar
  58. 58.
    Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV (1995) The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243–1252CrossRefPubMedGoogle Scholar
  59. 59.
    Rothe M, Wong SC, Henzel WJ, Goeddel DV (1994) A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78:681–692CrossRefPubMedGoogle Scholar
  60. 60.
    Salvesen GS, Abrams JM (2004) Caspase activation - stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene 23:2774–2784CrossRefPubMedGoogle Scholar
  61. 61.
    Samuel T, Welsh K, Lober T, Togo SH, Zapata JM, Reed JC (2006) Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases. J Biol Chem 281:1080–1090CrossRefPubMedGoogle Scholar
  62. 62.
    Scheidereit C (2006) IκB kinase complexes: gateways to NF-κB activation and transcription. Oncogene 25:6685–6705CrossRefPubMedGoogle Scholar
  63. 63.
    Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M (2001) Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293:1495–1499CrossRefPubMedGoogle Scholar
  64. 64.
    Shu HB, Takeuchi M, Goeddel DV (1996) The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci U S A 93:13973–13978CrossRefPubMedGoogle Scholar
  65. 65.
    Silke J, Kratina T, Chu D, Ekert PG, Day CL, Pakusch M, Huang DC, Vaux DL (2005) Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance. Proc Natl Acad Sci U S A 102:16182–16187CrossRefPubMedGoogle Scholar
  66. 66.
    Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S et al (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132CrossRefPubMedGoogle Scholar
  67. 67.
    Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL (1996) Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci USA 93:4974–4978CrossRefPubMedGoogle Scholar
  68. 68.
    Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng PH, Keats JJ, Wang H, Vignali DA, Bergsagel PL, Karin M (2008) Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol 9:1364–1370CrossRefPubMedGoogle Scholar
  69. 69.
    Varfolomeev E, Alicke B, Elliott JM, Zobel K, West K, Wong H, Scheer JM, Ashkenazi A, Gould SE, Fairbrother WJ, Vucic D (2009) X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists. J Biol Chem 284:34553–34560CrossRefPubMedGoogle Scholar
  70. 70.
    Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, TNFα-dependent apoptosis. Cell 131:669–681CrossRefPubMedGoogle Scholar
  71. 71.
    Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, Fairbrother WJ, Vucic D (2008) c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFα)-induced NF-κB activation. J Biol Chem 283:24295–24299CrossRefPubMedGoogle Scholar
  72. 72.
    Varfolomeev E, Vucic D (2008) (Un)expected roles of c-IAPs in apoptotic and NF-κB signaling pathways. Cell Cycle 7:1511–1521PubMedGoogle Scholar
  73. 73.
    Varfolomeev E, Wayson SM, Dixit VM, Fairbrother WJ, Vucic D (2006) The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-κB activation independently of TRAF1 AND TRAF2. J Biol Chem 281:29022–29029CrossRefPubMedGoogle Scholar
  74. 74.
    Vaux DL, Silke J (2005) IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6:287–297CrossRefPubMedGoogle Scholar
  75. 75.
    Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53CrossRefPubMedGoogle Scholar
  76. 76.
    Verhagen AM, Kratina TK, Hawkins CJ, Silke J, Ekert PG, Vaux DL (2007) Identification of mammalian mitochondrial proteins that interact with IAPs via N-terminal IAP binding motifs. Cell Death Differ 14:348–357CrossRefPubMedGoogle Scholar
  77. 77.
    Vince JE, Chau D, Callus B, Wong WW, Hawkins CJ, Schneider P, McKinlay M, Benetatos CA, Condon SM, Chunduru SK et al (2008) TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha. J Cell Biol 182:171–184CrossRefPubMedGoogle Scholar
  78. 78.
    Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmuckle AC, Davidson AJ, Callus BA, Wong WW, Gentle IE et al (2009) TRAF2 must bind to cIAPs for TNF to efficiently activate NF-{kappa}B and to prevent TNF-induced apoptosis. J Biol ChemGoogle Scholar
  79. 79.
    Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M et al (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693CrossRefPubMedGoogle Scholar
  80. 80.
    Vucic D (2008) Targeting IAP (inhibitor of apoptosis) proteins for therapeutic intervention in tumors. Curr Cancer Drug Targets 8:110–117CrossRefPubMedGoogle Scholar
  81. 81.
    Vucic D, Fairbrother WJ (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13:5995–6000CrossRefPubMedGoogle Scholar
  82. 82.
    Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ (2005) Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J 385:11–20CrossRefPubMedGoogle Scholar
  83. 83.
    Wallach D, Boldin M, Varfolomeev E, Beyaert R, Vandenabeele P, Fiers W (1997) Cell death induction by receptors of the TNF family: towards a molecular understanding. FEBS Lett 410:96–106CrossRefPubMedGoogle Scholar
  84. 84.
    Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331–367CrossRefPubMedGoogle Scholar
  85. 85.
    Wang L, Du F, Wang X (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133:693–703CrossRefPubMedGoogle Scholar
  86. 86.
    Wertz IE, Dixit VM (2008) Ubiquitin-mediated regulation of TNFR1 signaling. Cytokine Growth Factor Rev 19:313–324CrossRefPubMedGoogle Scholar
  87. 87.
    Wong WW, Gentle IE, Nachbur U, Anderton H, Vaux DL, Silke J (2009) RIPK1 is not essential for TNFR1-induced activation of NF-kappaB. Cell Death DifferGoogle Scholar
  88. 88.
    Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012CrossRefPubMedGoogle Scholar
  89. 89.
    Xiao G, Fong A, Sun SC (2004) Induction of p100 processing by NF-κB-inducing kinase involves docking IκB kinase alpha (IKKα) to p100 and IKKα-mediated phosphorylation. J Biol Chem 279:30099–30105CrossRefPubMedGoogle Scholar
  90. 90.
    Xie P, Stunz LL, Larison KD, Yang B, Bishop GA (2007) Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organs. Immunity 27:253–267CrossRefPubMedGoogle Scholar
  91. 91.
    Xu L, Zhu J, Hu X, Zhu H, Kim HT, LaBaer J, Goldberg A, Yuan J (2007) c-IAP1 cooperates with Myc by acting as a ubiquitin ligase for Mad1. Mol Cell 28:914–922CrossRefPubMedGoogle Scholar
  92. 92.
    Xu M, Skaug B, Zeng W, Chen ZJ (2009) A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. Mol Cell 36:302–314CrossRefPubMedGoogle Scholar
  93. 93.
    Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, Saitoh T, Yamamoto N, Sakurai H, Ishii KJ et al (2006) Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 7:962–970CrossRefPubMedGoogle Scholar
  94. 94.
    Yang QH, Du C (2004) Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. J Biol Chem 279:16963–16970CrossRefPubMedGoogle Scholar
  95. 95.
    Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, Iscove N et al (1997) Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715–725CrossRefPubMedGoogle Scholar
  96. 96.
    Yin Q, Lamothe B, Darnay BG, Wu H (2009) Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 48:10558–10567CrossRefPubMedGoogle Scholar
  97. 97.
    Zarnegar BJ, Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, Shiba T, Yang X, Yeh WC, Mak TW et al (2008) Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol 9:1371–1378CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Protein EngineeringGenentech, Inc.South San FranciscoUSA
  2. 2.Department of Protein EngineeringGenentech, Inc.South San FranciscoUSA

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