Ubiquitylation in immune disorders and cancer: From molecular mechanisms to therapeutic implications

EMBO Molecular Medicine

Volumn 4, Issue 7, 2012, Pages 545-556

  Fulda, Simone ^a   Rajalingam, Krishnaraj ^a   Dikic, Ivan ^a,b  

^a GOETHE UNIVERSITY   (Germany)

^b GOETHE UNIVERSITY MEDICAL SCHOOL   (Germany)

Author keywords

Apoptosis; Cell death; Inflammation; NF B; Ubiquitin

Indexed keywords

BORTEZOMIB; CARFILZOMIB; CASPASE 8; DELANZOMIB; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; ML 4924; NPI 002; PR 957; RECEPTOR INTERACTING PROTEIN 140; UBIQUITIN; UNCLASSIFIED DRUG;

AUTOIMMUNE DISEASE; DNA REPAIR; DOWNSTREAM PROCESSING; ENDOCYTOSIS; HUMAN; INNATE IMMUNITY; MANTLE CELL LYMPHOMA; MULTIPLE MYELOMA; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; UBIQUITINATION;

ANTINEOPLASTIC AGENTS; HUMANS; IMMUNE SYSTEM DISEASES; NEOPLASMS; PROTEIN PROCESSING, POST-TRANSLATIONAL; SIGNAL TRANSDUCTION; UBIQUITIN; UBIQUITINATION;

EID: 84863454687     PISSN: 17574676     EISSN: 17574684     Source Type: Journal    
DOI: 10.1002/emmm.201100707     Document Type: Review

References (120)

1. Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26: 1324- 1337
2. Anderson J, Gordon A, Pritchard-Jones K, Shipley J (1999) Genes, chromosomes, and rhabdomyosarcoma. Genes, Chromosomes, Cancer 26: 275- 285
3. 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- 130
4. Bandi SR, Brandts C, Rensinghoff M, Grundler R, Tickenbrock L, Kohler G, Duyster J, Berdel WE, Muller-Tidow C, Serve H et al (2009) E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease. Blood 114: 4197- 4208
5. Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE (2011) Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov 10: 29- 46
6. Bergink S, Jentsch S (2009) Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458: 461- 467
7. Bertrand MJ, Doiron K, Labbe 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: 789- 801
8. Bhoj VG, Chen ZJ (2009) Ubiquitylation in innate and adaptive immunity. Nature 458: 430- 437
9. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR et al (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25: 160- 165
10. Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA, Bloch W, Haase I, Pasparakis M (2011) The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35: 572- 582
11. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424: 797- 801
12. Cardozo T, Pagano M (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol 5: 739- 751
13. Casas S, Nagy B, Elonen E, Aventin A, Larramendy ML, Sierra J, Ruutu T, Knuutila S (2003) Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia. Leuk Lymphoma 44: 1935- 1941
14. Chen Q, Xie W, Kuhn DJ, Voorhees PM, Lopez-Girona A, Mendy D, Corral LG, Krenitsky VP, Xu W, Moutouh-de Parseval L et al (2008) Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy. Blood 111: 4690- 4699
15. Chen D, Shan J, Zhu WG, Qin J, Gu W (2010) Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature 464: 624- 627
16. Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP (2011) Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 11: 239- 253
17. Clague MJ, Coulson JM, Urbe S (2012) Cellular functions of the DUBs. J Cell Sci 125: 277- 286
18. Crusio KM, King B, Reavie LB, Aifantis I (2010) The ubiquitous nature of cancer: the role of the SCF(Fbw7) complex in development and transformation. Oncogene 29: 4865- 4873
19. Dejardin E (2006) The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 72: 1161- 1179
20. Deribe YL, Pawson T, Dikic I (2010) Post-translational modifications in signal integration. Nat Struct Mol Biol 17: 666- 672
21. Di J, Zheng Y, Zhang J (2011) Reactivation of p53 by inhibiting Mdm2 E3 ligase: a novel antitumor approach. Curr Cancer Drug Targets 11: 987- 994
22. Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P (1999) The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93: 3601- 3609
23. Dikic I, Wakatsuki S, Walters KJ (2009) Ubiquitin-binding domains-from structures to functions. Nat Rev Mol Cell Biol 10: 659- 671
24. Duan S, Cermak L, Pagan JK, Rossi M, Martinengo C, di Celle PF, Chapuy B, Shipp M, Chiarle R, Pagano M (2012) FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 481: 90- 93
25. Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35: 908- 918
26. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Hacker G, Leverkus M (2011) cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43: 449- 463
27. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM et al (2008) The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep 9: 930- 936
28. Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Disc 11: 109- 124
29. Georgescu MM (2010) PTEN tumor suppressor network in PI3K-Akt pathway control. Genes Cancer 1: 1170- 1177
30. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW et al (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471: 591- 596
31. Grabbe C, Husnjak K, Dikic I (2011) The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol 12: 295- 307
32. Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, Kreil S, Jones A, Score J, Metzgeroth G et al (2009) Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113: 6182- 6192
33. Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF et al (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477: 335- 339
34. Haglund K, Dikic I (2005) Ubiquitylation and cell signaling. EMBO J 24: 3353- 3359
35. Han J, Zhong CQ, Zhang DW (2011) Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nat Immunol 12: 1143- 1149
36. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67: 425- 479
37. Hirsch C, Gauss R, Horn SC, Neuber O, Sommer T (2009) The ubiquitylation machinery of the endoplasmic reticulum. Nature 458: 453- 460
38. Hoeller D, Dikic I (2009) Targeting the ubiquitin system in cancer therapy. Nature 458: 438- 444
39. Hovelmeyer N, Wunderlich FT, Massoumi R, Jakobsen CG, Song J, Worns MA, Merkwirth C, Kovalenko A, Aumailley M, Strand D et al (2007) Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. J Exp Med 204: 2615- 2627
40. Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep 9: 536- 542
41. Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J et al (2011) SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature 471: 637- 641
42. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW et al (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471: 104- 109
43. Iwai K, Tokunaga F (2009) Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep 10: 706- 713
44. Janeway CA, Jr., Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20: 197- 216
45. Jin W, Reiley WR, Lee AJ, Wright A, Wu X, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. J Biol Chem 282: 15884- 15893
46. Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471: 368- 372
47. Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J et al (2009) Frequent inactivation of A20 in B-cell lymphomas. Nature 459: 712- 716
48. 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- 144
49. Kirkin V, McEwan DG, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34: 259- 269
50. Koblish HK, Zhao S, Franks CF, Donatelli RR, Tominovich RM, LaFrance LV, Leonard KA, Gushue JM, Parks DJ, Calvo RR et al (2006) Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5: 160- 169
51. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424: 801- 805
52. Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC et al (2009) KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 36: 131- 140
53. Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Bourne P, Ha UH, Ishinaga H et al (2007) Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity 27: 349- 360
54. Lim JH, Ha UH, Woo CH, Xu H, Li JD (2008) CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia. Cell Microbiol 10: 2247- 2256
55. Lind H, Zienolddiny S, Ekstrom PO, Skaug V, Haugen A (2006) Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int J Cancer 119: 718- 721
56. Lipkowitz S, Weissman AM (2011) RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer 11: 629- 643
57. Mann M, Jensen ON (2003) Proteomic analysis of post-translational modifications. Nat Biotechnol 21: 255- 261
58. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125: 665- 677
59. Masuya D, Huang C, Liu D, Nakashima T, Yokomise H, Ueno M, Nakashima N, Sumitomo S (2006) The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways. J Pathol 208: 724- 732
60. Mathew R, White E (2007) Why sick cells produce tumors: the protective role of autophagy. Autophagy 3: 502- 505
61. Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, Geboes L, Louagie E, Guire CM, Vereecke L et al (2011) A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet 43: 908- 912
62. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N (2011) Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44: 279- 289
63. Menin C, Scaini MC, De Salvo GL, Biscuola M, Quaggio M, Esposito G, Belluco C, Montagna M, Agata S, D'Andrea E et al (2006) Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst 98: 285- 288
64. Miliani de Marval PL, Zhang Y (2011) The RP-Mdm2-p53 pathway and tumorigenesis. Oncotarget 2: 234- 238
65. Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A et al (1992) Profound block in thymocyte development in mice lacking p56lck. Nature 357: 161- 164
66. Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315: 201- 205
67. Naumann I, Kappler R, von Schweinitz D, Debatin KM, Fulda S (2011) Bortezomib primes neuroblastoma cells for TRAIL-induced apoptosis by linking the death receptor to the mitochondrial pathway. Clin Cancer Res 17: 3204- 3218
68. Oberoi TK, Dogan T, Hocking JC, Scholz RP, Mooz J, Anderson CL, Karreman C, Meyer Zu Heringdorf D, Schmidt G, Ruonala M et al (2012) IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation. EMBO J 31: 14- 28
69. Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alboran IM, Nakayama K, Nakayama KI (2007) Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med 204: 2875- 2888
70. Otto T, Horn S, Brockmann M, Eilers U, Schuttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H et al (2009) Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15: 67- 78
71. Pasparakis M (2009) Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9: 778- 788
72. Pereg Y, Liu BY, O'Rourke KM, Sagolla M, Dey A, Komuves L, French DM, Dixit VM (2010) Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. Nat Cell Biol 12: 400- 406
73. Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8: 49- 62
74. Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D et al (2009) Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell 136: 1098- 1109
75. Reiley W, Zhang M, Wu X, Granger E, Sun SC (2005) Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol 25: 3886- 3895
76. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7: 411- 417
77. Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M et al (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204: 1475- 1485
78. Ruschak AM, Slassi M, Kay LE, Schimmer AD (2011) Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst 103: 1007- 1017
79. Sargin B, Choudhary C, Crosetto N, Schmidt MH, Grundler R, Rensinghoff M, Thiessen C, Tickenbrock L, Schwable J, Brandts C et al (2007) Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110: 1004- 1012
80. Sayers TJ, Murphy WJ (2006) Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for cancer therapy. Cancer Immunol Immunother 55: 76- 84
81. Schmidt MH, Dikic I (2005) The Cbl interactome and its functions. Nat Rev Mol Cell Biol 6: 907- 918
82. Schulman BA, Harper JW (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 10: 319- 331
83. Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, Maecker H, O'Rourke K, Bazan F, Eastham-Anderson J et al (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463: 103- 107
84. Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7: 473- 483
85. Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP (2007) Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun 8: 416- 421
86. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP (2008) The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455: 813- 817
87. Straub CS (2011) Targeting IAPs as an approach to anti-cancer therapy. Curr Top Med Chem 11: 291- 316
88. Strobel P, Zettl A, Ren Z, Starostik P, Riedmiller H, Storkel S, Muller-Hermelink HK, Marx A (2002) Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm. Am J Surg Pathol 26: 119- 124
89. Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8: 501- 511
90. Sun SC (2010) CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ 17: 25- 34
91. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140: 805- 820
92. Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, Macfarlane M, Cain K et al (2011) The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol cell 43: 432- 448
93. Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K (2011) SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature 471: 633- 636
94. Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H et al (2007) Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141- 156
95. Unterkircher T, Cristofanon S, Vellanki SH, Nonnenmacher L, Karpel-Massler G, Wirtz CR, Debatin KM, Fulda S (2011) Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. Clin Cancer Res 17: 4019- 4030
96. 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- 1370
97. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11: 700- 714
98. Varshavsky A (2005) Regulated protein degradation. Trends Biochem Sci 30: 283- 286
99. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844- 848
100. Vereecke L, Beyaert R, van Loo G (2009) The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 30: 383- 391
101. Verma R, Peters NR, D'Onofrio M, Tochtrop GP, Sakamoto KM, Varadan R, Zhang M, Coffino P, Fushman D, Deshaies RJ et al (2004) Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306: 117- 120
102. Vivanco I, Rohle D, Versele M, Iwanami A, Kuga D, Oldrini B, Tanaka K, Dang J, Kubek S, Palaskas N et al (2010) The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc Natl Acad Sci USA 107: 6459- 6464
103. Vucic D, Dixit VM, Wertz IE (2011) Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol 12: 439- 452
104. Walczak H, Iwai K, Dikic I (2012) Generation and physiological roles of linear ubiquitin chains. BMC Biol 10: 23
105. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C et al (2007) NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129- 139
106. Wang L, Du F, Wang X (2008) TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133: 693- 703
107. Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G, Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477: 330- 334
108. Wertz IE, Dixit VM (2010) Signaling to NF-kappaB: regulation by ubiquitination. Cold Spring Harb Perspect Biol 2: a003350
109. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL et al (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430: 694- 699
110. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J et al (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471: 110- 114
111. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333: 228- 233
112. Yang Y, Ludwig RL, Jensen JP, Pierre SA, Medaglia MV, Davydov IV, Safiran YJ, Oberoi P, Kenten JH, Phillips AC et al (2005) Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7: 547- 559
113. Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, Pierre SA, Jensen JP, Davydov IV, Oberoi P et al (2007) Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res 67: 9472- 9481
114. Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG et al (2009) The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325: 1134- 1138
115. Yim EK, Peng G, Dai H, Hu R, Li K, Lu Y, Mills GB, Meric-Bernstam F, Hennessy BT, Craven RJ et al (2009) Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell 15: 304- 314
116. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z (2010) USP10 regulates p53 localization and stability by deubiquitinating p53. Cell 140: 384- 396
117. 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- 1378
118. Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J, Fan ST, Luk JM, Wigler M, Hannon GJ et al (2006) Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253- 1267
119. Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM, Jain A (2006) Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest 116: 3042- 3049
120. Zhang M, Wu X, Lee AJ, Jin W, Chang M, Wright A, Imaizumi T, Sun SC (2008) Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem 283: 18621- 18626