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Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

Abstract

The diverse cellular and biological functions of the nuclear factor kappa B (NF-κB) pathway, together with the catastrophic consequences of its aberrant regulation, demand specific and highly regulated control of its activity. As described in this review, regulation of the NF-κB pathway is brought about through multiple post-translational modifications that control the activity of the core components of NF-κB signaling: the IκB kinase (IKK) complex, the IκB proteins and the NF-κB subunits themselves. These regulatory modifications, which include phosphorylation, ubiquitination, acetylation, sumoylation and nitrosylation, can vary, depending on the nature of the NF-κB-inducing stimulus. Moreover, they frequently have distinct, sometimes antagonistic, functional consequences and the same modification can have different effects depending on the context. Given the important role of NF-κB in human health and disease, understanding these pathways will not only provide valuable insights into mechanism and function, but could also lead to new drug targets and the development of diagnostic and prognostic biomarkers for many pathological conditions.

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References

  • Abbott DW, Wilkins A, Asara JM, Cantley LC . (2004). Curr Biol 14: 2217–2227.

  • Abu-Amer Y, Ross FP, McHugh KP, Livolsi A, Peyron JF, Teitelbaum SL . (1998). J Biol Chem 273: 29417–29423.

  • Amir RE, Haecker H, Karin M, Ciechanover A . (2004). Oncogene 23: 2540–2547.

  • Anrather J, Racchumi G, Iadecola C . (2005). J Biol Chem 280: 244–252.

  • Babu GR, Jin W, Norman L, Waterfield M, Chang M, Wu X et al. (2006). Biochim Biophys Acta 1763: 174–181.

  • Beinke S, Deka J, Lang V, Belich MP, Walker PA, Howell S et al. (2003). Mol Cell Biol 23: 4739–4752.

  • Bohuslav J, Chen LF, Kwon H, Mu Y, Greene WC . (2004). J Biol Chem 279: 26115–26125.

  • Bonizzi G, Karin M . (2004). Trends Immunol 25: 280–288.

  • Bui NT, Livolsi A, Peyron JF, Prehn JH . (2001). J Cell Biol 152: 753–764.

  • Burns KA, Martinon F . (2004). Curr Biol 14: R1040–R1042.

  • Buss H, Dorrie A, Schmitz ML, Frank R, Livingstone M, Resch K et al. (2004a). J Biol Chem 279: 49571–49574.

  • Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M . (2004b). J Biol Chem 279: 55633–55643.

  • Campbell KJ, Witty JM, Rocha S, Perkins ND . (2006). Cancer Res 66: 929–935.

  • Carter RS, Pennington KN, Arrate P, Oltz EM, Ballard DW . (2005). J Biol Chem 280: 43272–43279.

  • Carter RS, Pennington KN, Ungurait BJ, Ballard DW . (2003). J Biol Chem 278: 19642–19648.

  • Chen ZJ . (2005). Nat Cell Biol 7: 758–765.

  • Chen E, Hrdlickova R, Nehyba J, Longo DL, Bose Jr HR, Li C-CH . (1998). J Biol Chem 273: 35201–35207.

  • Chen LF, Greene WC . (2004). Nat Rev Mol Cell Biol 5: 392–401.

  • Chen LF, Mu YJ, Greene WC . (2002). EMBO J 21: 6539–6548.

  • Chen LF, Williams SA, Mu Y, Nakano H, Duerr JM, Buckbinder L et al. (2005). Mol Cell Biol 25: 7966–7975.

  • Chen ZJ, Bhoj V, Seth RB . (2006). Cell Death Differ 13: 687–692.

  • Chu ZL, McKinsey TA, Liu L, Qi X, Ballard DW . (1996). Mol Cell Biol 16: 5974–5984.

  • Cohen S, Achbert-Weiner H, Ciechanover A . (2004). Mol Cell Biol 24: 475–486.

  • Delhase M, Hayakawa M, Chen Y, Karin M . (1999). Science 284: 309–313.

  • Demarchi F, Bertoli C, Sandy P, Schneider C . (2003). J Biol Chem 278: 39583–39590.

  • Deng WG, Tang ST, Tseng HP, Wu KK . (2006). Blood 108: 518–524.

  • Deng WG, Zhu Y, Wu KK . (2003). J Biol Chem 278: 4770–4777.

  • Desterro JMP, Rodriguez MS, Hay RT . (1998). Mol Cell 2: 233–239.

  • Druker BJ, Neumann M, Okuda K, Franza Jr BR, Griffin JD . (1994). J Biol Chem 269: 5387–5390.

  • Duran A, Diaz-Meco MT, Moscat J . (2003). EMBO J 22: 3910–3918.

  • Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ . (2006). Mol Cell 22: 245–257.

  • Fan C, Li Q, Ross D, Engelhardt JF . (2003). J Biol Chem 278: 2072–2080.

  • Fischer C, Page S, Weber M, Eisele T, Neumeier D, Brand K . (1999). J Biol Chem 274: 24625–24632.

  • Fognani C, Rondi R, Romano A, Blasi F . (2000). Oncogene 19: 2224–2232.

  • Furia B, Deng L, Wu K, Baylor S, Kehn K, Li H et al. (2002). J Biol Chem 277: 4973–4980.

  • Gapuzan ME, Pitoc GA, Gilmore TD . (2003). Biochem Biophys Res Commun 307: 92–99.

  • Garcia-Pineres AJ, Lindenmeyer MT, Merfort I . (2004). Life Sci 75: 841–856.

  • Gilmore TD . (2006). Oncogene 25: 6680–6684.

  • Glineur C, Davioud-Charvet E, Vandenbunder B . (2000). Biochem J 352 (Part 2): 583–591.

  • Guan H, Hou S, Ricciardi RP . (2005). J Biol Chem 280: 9957–9962.

  • Gustin JA, Korgaonkar CK, Pincheira R, Li Q, Donner DB . (2006). J Biol Chem 281: 16473–16481.

  • Gustin JA, Ozes ON, Akca H, Pincheira R, Mayo LD, Li Q et al. (2004). J Biol Chem 279: 1615–1620.

  • Haller D, Russo MP, Sartor RB, Jobin C . (2002). J Biol Chem 277: 38168–38178.

  • Harris J, Oliere S, Sharma S, Sun Q, Lin R, Hiscott J et al. (2006). J Immunol 177: 2527–2535.

  • Hayden MS, Ghosh S . (2004). Genes Dev 18: 2195–2224.

  • Hoberg JE, Yeung F, Mayo MW . (2004). Mol Cell 16: 245–255.

  • Hou S, Guan H, Ricciardi RP . (2003). J Biol Chem 278: 45994–45998.

  • Hu J, Colburn NH . (2005). Mol Cancer Res 3: 100–109.

  • Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG et al. (2004). Nat Immunol 5: 98–103.

  • Huang TT, Wuerzbrger-Davis SM, Wu ZH, Miyamoto S . (2003a). Cell 115: 565–576.

  • Huang WC, Chen JJ, Chen CC . (2003b). J Biol Chem 278: 9944–9952.

  • Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C et al. (1996). Cell 86: 787–798.

  • Jiang X, Takahashi N, Matsui N, Tetsuka T, Okamoto T . (2003). J Biol Chem 278: 919–926.

  • Kang JL, Lee HS, Pack IS, Hur KC, Castranova V . (2003). Mol Cell Biochem 248: 17–24.

  • Kato T, Delhase M, Hoffmann A, Karin M . (2003). Mol Cell 12: 829–839.

  • Kiernan R, Bres V, Ng RWM, Coudart MP, El Messaoudi S, Sardet C et al. (2003). J Biol Chem 278: 2758–2766.

  • Koong AC, Chen EY, Giaccia AJ . (1994). Cancer Res 54: 1425–1430.

  • Krappmann D, Scheidereit C . (2005). EMBO Rep 6: 321–326.

  • Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM . (2001). Chem Biol 8: 759–766.

  • Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A et al. (2003). Mol Cell Biol 23: 402–413.

  • Lawrence T, Bebien M, Liu GY, Nizet V, Karin M . (2005). Nature 434: 1138–1143.

  • Lee KY, D'Acquisto F, Hayden MS, Shim JH, Ghosh S . (2005). Science 308: 114–118.

  • Liang C, Zhang M, Sun SC . (2006a). Cell Signal 18: 1309–1317.

  • Liang MC, Bardhan S, Pace EA, Rosman D, Beutler JA, Porco Jr JA et al. (2006b). Biochem Pharmacol 71: 634–645.

  • Liang MC, Bardhan S, Porco Jr JA, Gilmore TD . (2006c). Cancer Lett, in press.

  • Lin L, DeMartino GN, Greene WC . (1998). Cell 92: 819–828.

  • Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J . (1996). Mol Cell Biol 16: 1401–1409.

  • Ling L, Cao ZD, Goeddel DV . (1998). Proc Natl Acad Sci USA 95: 3792–3797.

  • Liu J, Beller D . (2002). J Immunol 169: 581–586.

  • Mahabeleshwar GH, Kundu GC . (2003). J Biol Chem 278: 52598–52612.

  • Maier HJ, Marienfeld R, Wirth T, Baumann B . (2003). J Biol Chem 278: 39242–39250.

  • Marienfeld R, Berberich-Siebelt F, Berberich I, Denk A, Serfling E, Neumann M . (2001). Oncogene 20: 8142–8147.

  • Martin AG, Fresno M . (2000). J Biol Chem 275: 24383–24391.

  • Martin AG, San-Antonio B, Fresno M . (2001). J Biol Chem 276: 15840–15849.

  • Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fässler R . (2006). Cell 125: 665–677.

  • Matthews JR, Botting CH, Panico M, Morris HR, Hay RT . (1996). Nucleic Acids Res 24: 2236–2242.

  • Mattioli I, Geng H, Sebald A, Hodel M, Bucher C, Kracht M et al. (2006). J Biol Chem 281: 6175–6183.

  • Mattioli I, Sebald A, Bucher C, Charles RP, Nakano H, Doi T et al. (2004). J Immunol 172: 6336–6344.

  • McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV . (1996). Mol Cell Biol 16: 899–906.

  • McKinsey TA, Chu ZL, Ballard DW . (1997). J Biol Chem 272: 22377–22380.

  • Mercurio F, Zhu HY, Murray BW, Shevchenko A, Bennett BL, Li JW et al. (1997). Science 278: 860–866.

  • Mosialos G, Hamer P, Capobianco AJ, Laursen RA, Gilmore TD . (1991). Mol Cell Biol 11: 5867–5877.

  • Mukhopadhyay A, Manna SK, Aggarwal BB . (2000). J Biol Chem 275: 8549–8555.

  • Na HK, Surh YJ . (2006). Mol Carcinog 45: 368–380.

  • Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE et al. (2004). Science 306: 704–708.

  • Neumann M, Tsapos K, Scheppler JA, Ross J, Franza Jr BR . (1992). Oncogene 7: 2095–3104.

  • Orian A, Gonen H, Bercovich B, Fajerman I, Eytan E, Israel A et al. (2000). EMBO J 19: 2580–25891.

  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB . (1999). Nature 401: 82–85.

  • Pahl HL . (1999). Oncogene 18: 6853–6866.

  • Park MH, Song HS, Kim KH, Son DJ, Lee SH, Yoon do Y et al. (2005a). Biochemistry 44: 8326–8336.

  • Park SW, Huq MD, Hu X, Wei LN . (2005b). Mol Cell Proteomics 4: 300–309.

  • Pellegatta F, Bertelli AA, Staels B, Duhem C, Fulgenzi A, Ferrero ME . (2003). Am J Clin Nutr 77: 1220–1228.

  • Perkins ND, Gilmore TD . (2006). Cell Death Differ 13: 759–772.

  • Prajapati S, Gaynor RB . (2002). J Biol Chem 277: 24331–24339.

  • Quivy V, Van Lint C . (2004). Biochem Pharmacol 68: 1221–1229.

  • Reynaert NL, Ckless K, Korn SH, Vos N, Guala AS, Wouters EF et al. (2004). Proc Natl Acad Sci USA 101: 8945–8950.

  • Rocha S, Garrett MD, Campbell KJ, Schumm K, Perkins ND . (2005). EMBO J 24: 1157–1169.

  • Rodriguez MS, Dargemont C, Hay RT . (2001). J Biol Chem 276: 12654–12659.

  • Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE . (2002). Cancer Res 62: 6770–6778.

  • Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G et al. (2003). Mol Cell 12: 1413–1426.

  • Saccani S, Marazzi I, Beg AA, Natoli G . (2004). J Exp Med 200: 107–113.

  • Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W . (1999). J Biol Chem 274: 30353–30356.

  • Sánchez-Valdepeñas C, Martin AG, Ramakrishnan P, Wallach D, Fresno M . (2006). J Immunol 176: 4666–4674.

  • Sasaki CY, Barberi TJ, Ghosh P, Longo DL . (2005). J Biol Chem 280: 34538–34547.

  • Schomer Miller B, Higashimoto T, Lee YK, Zandi E . (2006). J Biol Chem 281: 15268–15276.

  • Schoonbroodt S, Ferreira V, Best-Belpomme M, Boelaert JR, Legrand-Poels S, Korner M et al. (2000). J Immunol 164: 4292–4300.

  • Schwabe RF, Sakurai H . (2005). FASEB J 19: 1758–1760.

  • Schwarz EM, Van Antwerp D, Verma IM . (1996). Mol Cell Biol 16: 3554–3559.

  • Senftleben U, Cao YX, Xiao GT, Greten FR, Krahn G, Bonizzi G et al. (2001). Science 293: 1495–1499.

  • Singh S, Darnay BG, Aggarwal BB . (1996). J Biol Chem 271: 31049–31054.

  • Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR . (2002). J Biol Chem 277: 3863–3869.

  • Starczynowski DT, Reynolds JG, Gilmore TD . (2005). Oncogene 24: 7355–7368.

  • Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH et al. (2000). Proc Natl Acad Sci USA 97: 4844–4849.

  • Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ . (2004). Mol Cell 14: 289–301.

  • Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB . (2003). J Biol Chem 278: 24233–24241.

  • Tanaka H, Fujita N, Tsuruo T . (2005). J Biol Chem 280: 40965–40973.

  • Tang ED, Wang CY, Xiong Y, Guan KL . (2003). J Biol Chem 278: 37297–37305.

  • Thompson JE, Phillips RJ, Erdjumentbromage H, Tempst P, Ghosh S . (1995). Cell 80: 573–582.

  • Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G . (2003). EMBO J 22: 1313–1324.

  • Viatour P, Dejardin E, Warnier M, Lair F, Claudio E, Bureau F et al. (2004). Mol Cell 16: 35–45.

  • Viatour P, Merville MP, Bours V, Chariot A . (2005). Trends Biochem Sci 30: 43–52.

  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ . (2001). Nature 412: 346–351.

  • Wang D, Westerheide SD, Hanson JL, Baldwin Jr AS . (2000). J Biol Chem 275: 32592–32597.

  • Waterfield M, Jin W, Reiley W, Zhang M, Sun S-C . (2004). Mol Cell Biol 24: 6040–6048.

  • Weil R, Laurent-Winter C, Israël A . (1997). J Biol Chem 272: 9942–9949.

  • Whiteside ST, Epinat J-C, Rice NR, Israël A . (1997). EMBO J 16: 1413–1426.

  • Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV . (1997). Science 278: 866–869.

  • Wu C, Ghosh S . (2003). J Biol Chem 278: 31980–31987.

  • Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD . (2006a). Nat Cell Biol 8: 398–406.

  • Wu ZH, Shi Y, Tibbetts RS, Miyamoto S . (2006b). Science 311: 1141–1146.

  • Xiao G, Fong A, Sun S-C . (2004). J Biol Chem 279: 30099–30105.

  • Xiao GT, Harhaj EW, Sun S-C . (2001). Mol Cell 7: 401–409.

  • Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L et al. (2001). Nat Immunol 2: 620–624.

  • Yeh PY, Yeh KH, Chuang SE, Song YC, Cheng AL . (2004). J Biol Chem 279: 26143–26148.

  • Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA et al. (2004). EMBO J 23: 2369–2380.

  • Yu SH, Chiang WC, Shih HM, Wu KJ . (2004). J Mol Med 82: 621–628.

  • Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M . (1997). Cell 91: 243–252.

  • Zhang L, Cui R, Cheng X, Du J . (2005). Cancer Res 65: 457–464.

  • Zhong HH, May MJ, Jimi E, Ghosh S . (2002). Mol Cell 9: 625–636.

  • Zhong HH, Voll RE, Ghosh S . (1998). Mol Cell 1: 661–671.

  • Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M et al. (2004). Nature 427: 167–171.

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Acknowledgements

In putting together in this review paper, I am aware of how much easier this has been as a result of the excellent and comprehensive reviews on related topics written by many of my colleagues. I have tried to cite all of these reviews in this manuscript, together with the primary literature. My apologies to any reports I was unable to cite either due to lack of space or my oversight. Thanks to Drs Cameron Bracken, Kirsteen Campbell and Sonia Rocha for their critical reading of the manuscript. Analysis and numbering of subunit domain structure was aided by online tools provided by the European Bioinformatics Institute (www.ebi.ac.uk) and DNADyNAmo software (www.bluetractorsoftware.co.uk). Research in the author's laboratory is supported by a programme grant from Cancer Research UK (C1443/A5435) together with funding from the Association of International Cancer Research (AICR) and the Wellcome Trust.

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Perkins, N. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 25, 6717–6730 (2006). https://doi.org/10.1038/sj.onc.1209937

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