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  • Original Paper
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How NF-κB is activated: the role of the IκB kinase (IKK) complex

Abstract

Rel/NF-κB transcription factors are primarily regulated by association with inhibitor IκB proteins. Thus, in most cells NF-κB exists in the cytoplasm in an inactive complex bound to IκB. Most agents that activate NF-κB do so through a common pathway based on phosphorylation-induced, proteasome-mediated degradation of IκB. The key regulatory step in this pathway involves activation of a high molecular weight IκB kinase (IKK) complex, whose catalysis is generally carried out by a heterodimeric kinase consisting of IKKα and IKKβ subunits. This review describes the identification of proteins in the IKK complex, and the regulation and physiological functions of IKK.

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References

  • Aberle H, Bauer A, Stappert J, Kispert A and Kemler R. . 1997 EMBO J. 16: 3797–3804.

  • Alkalay I, Yaron A, Hatzubai A, Jung S, Avraham A, Gerlitz O, Pashut-Lavon I and Ben-Neriah, Y. . 1995 Mol. Cell. Biol. 15: 1294–1301.

  • Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier JL and Dargemont C. . 1997 J. Cell Sci. 110: 369–378.

  • Baeuerle PA and Baltimore D. . 1996 Cell 87: 13–20.

  • Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW and Elledge SJ. . 1996 Cell 86: 263–274.

  • Baldwin Jr AS. . 1996 Annu. Rev. Immunol. 14: 649–681.

  • Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C and Dèorken B. . 1997 J. Clin. Invest. 100: 2961–2969.

  • Barnes PJ and Karin M. . 1997 New Engl. J. Med. 336: 1066–1071.

  • Baud V, Liu Z-G, Bennett B, Suzuki N, Xia Y and Karin M. . 1999 Genes Dev. 13: 1297–1308.

  • Beg AA and Baltimore D. . 1996 Science 274: 782–784.

  • Beg AA, Sha WC, Bronson RT, Ghosh S and Baltimore D. . 1995 Nature 376: 167–169.

  • Belvin MP and Anderson KV. . 1996 Annu. Rev. Dev. Biol. 12: 393–416.

  • Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ and Herrlich P. . 1998 EMBO J. 17: 5170–5181.

  • Beraud C, Henzel WJ and Baeuerle PA. . 1999 Proc. Nat. Acad. Sci. USA 96: 429–434.

  • Brown K, Gerstberger S, Carlson L, Franzoso G and Siebenlist U. . 1995 Science 267: 1485–1491.

  • Chen FE and Ghosh G. . 1999 Oncogene 18: 6845–6852.

  • Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D and Maniatis T. . 1995 Genes Dev. 9: 1586–1597.

  • Cohen L, Henzel WJ and Baeuerle PA. . 1998 Nature 395: 292–296.

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

  • DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E and Karin M. . 1997 Nature 388: 548–554.

  • DiDonato JA, Mercurio F and Karin M. . 1995 Mol. Cell. Biol. 15: 1302–1311.

  • DiDonato JA, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S and Karin M. . 1996 Mol. Cell. Biol. 16: 1295–1304.

  • Doi TS, Marino MW, Takahashi T, Yoshida T, Sakakura T, Old LJ and Obata Y. . 1999 Proc. Natl. Acad. Sci. USA 96: 2994–2999.

  • Feldman RMR, Correll CC, Kaplan KB and Deshaies RJ. . 1997 Cell 91: 221–230.

  • Gerondakis S, Grossmann M, Nakamura Y, Pohl T and Grumont R. . 1999 Oncogene 18: 6888–6895.

  • Gilmore TD. . 1997 J. Clin. Invest. 100: 2935–2936.

  • Hershko A and Ciechanover A. . 1998 Annu. Rev. Biochem. 67: 425–479.

  • Hoffmann JA, Kafatos FC, Janeway CAJ and Ezekowiz RAB. . 1999 Science 284: 1313–1318.

  • Horwitz BH, Scott ML, Cherry SR, Bronson RT and Baltimore D. . 1997 Immunity 6: 765–772.

  • Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R and Karin M. . 1999 Science 284: 316–320.

  • Imbert V, Rupec RA, Livolsi A, Pahl HL, Traenckner EB, Mueller-Dieckmann C, Farahifar D, Rossi B, Auberger P, Baeuerle PA and Peyron JF. . 1996 Cell 86: 787–798.

  • Jiang J and Struhl G. . 1998 Nature 391: 493–496.

  • Johnson LN, Noble MEM and Owen DJ. . 1996 Cell 85: 149–158.

  • Karin M and Delhase M. . 1998 Proc. Natl. Acad. Sci. USA 95: 9067–9069.

  • Krappmann D, Emmerich F, Kordes U, Scharschmidt E, Dörken B and Scheidereit C. . 1999 Oncogene 18: 943–953.

  • Li N and Karin M. . 1998 Proc. Natl. Acad. Sci. USA 95: 13012–13017.

  • Li Q, Van Antwerp D, Mercurio F, Lee K-F and Verma IM. . 1999a Science 284: 321–325.

  • Li Y, Kang J, Friedman J, Tarassishin L, Ye J, Kovalenko A, Wallach D and Horwitz MS. . 1999b Proc. Natl. Acad. Sci. USA 96: 1042–1047.

  • Li Z-W, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R and Karin M. . 1999c J Exp. Med. 189: 1839–1845.

  • Ling L, Cao Z and Goeddel DV. . 1998 Proc. Natl. Acad. Sci. USA 95: 2791–2797.

  • Liu Z-G, Hu H, Goeddel DV and Karin M. . 1996 Cell 87: 565–576.

  • Malinin NL, Boldin MP, Kovalenko AV and Wallach D. . 1997 Nature 385: 540–544.

  • Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K and Benarous R. . 1998 Mol. Cell 1: 565–574.

  • Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M and Manning AM. . 1999 Mol. Cell. Biol. 19: 1526–1538.

  • Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A and Rao A. . 1997 Science 278: 860–866.

  • Otero G, Fellows J, Li Y, de Bizemont T, Dirac AM, Gustafsson CM, Erdjument-Bromage H, Tempst P and Svejstrup JQ. . 1999 Mol. Cell 3: 109–118.

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

  • Patton EE, Willems AR. and Tyers M. . 1998 Trends Genet. 14: 236–243.

  • Rayet B and Gélinas C. . 1999 Oncogene 18: 6938–6947.

  • Reach M, Galindo RL, Towb P, Allen JL, Karin M and Wasserman SA. . 1996 Dev. Biol. 180: 353–364.

  • Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z and Rothe M. . 1997 Cell 90: 373–383.

  • Rothwarf DM, Zandi E, Natoli G and Karin M. . 1998 Nature 395: 297–300.

  • Sachdev S, Hoffmann A and Hannink M. . 1998 Mol. Cell. Biol. 18: 2524–2534.

  • Scherer DC, Brockman J, Chen Z, Maniatis T and Ballard D. . 1995 Proc. Natl. Acad. Sci. USA 92: 11259–11263.

  • Seitz CS, Lin Q, Deng H and Khavari PA. . 1998 Proc. Natl. Acad. Sci. USA 95: 2307–2312.

  • Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T and Honjo T. . 1999 Naure. Genet. 22: 74–77.

  • Skowyra D, Craig KL, Tyers M, Elledge SJ and Harper JW. . 1997 Cell 91: 209–219.

  • Sun S-C and Ballard DW. . 1999 Oncogene 18: 6948–6958.

  • Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N and Akira S. . 1999 Science 284: 313–316.

  • Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL and Goeddel DV. . 1999 Immunity 10: 421–429.

  • Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M and Sun S-C. . 1998 J. Biol. Chem. 273: 21132–21136.

  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR and Verma IM. . 1996 Science 274: 787–789.

  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D and Miyamoto S. . 1995 Genes Dev. 9: 2723–2735.

  • Wang C-Y, Mayo MW and Baldwin Jr AS. . 1996 Science 274: 784–787.

  • Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ and Harper JW. . 1999 Genes Dev. 13: 270–283.

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

  • Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ and Israël A. . 1998 Cell 93: 1231–1240.

  • Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S, Beyth S, Mercurio F, Manning AM, Ciechanover A. and Ben-Neriah Y. . 1997 EMBO J. 16: 6486–6494.

  • Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F and Ben-Neriah Y. . 1998 Nature 396: 590–594.

  • Zandi E, Chen Y and Karin M. . 1998 Science 281: 1360–1363.

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

  • Zheng C-F and Guan K-L. . 1994 EMBO J. 13: 1123–1131.

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Acknowledgements

I thank B Thompson for excellent manuscript assistance and M Delhase, Y Hu and D Rothwarf for discussions and artwork. Work in the author's laboratory is supported by the National Institutes of Health (NIEHS and NIAID) and the Department of Energy. M Karin is the Frank and Else Schilling-American Cancer Society Research Professor.

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Karin, M. How NF-κB is activated: the role of the IκB kinase (IKK) complex. Oncogene 18, 6867–6874 (1999). https://doi.org/10.1038/sj.onc.1203219

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