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SCF-mediated protein degradation and cell cycle control

Oncogene volume 24, pages 2860–2870 (2005)Cite this article

Abstract

The regulatory step in ubiquitin (Ub)-mediated protein degradation involves recognition and selection of the target substrate by an E3 Ub-ligase. E3 Ub-ligases evoke sophisticated mechanisms to regulate their activity temporally and spatially, including multiple post-translational modifications, combinatorial E3 Ub-ligase pathways, and subcellular localization. The phosphodegrons of many substrates incorporate the activities of multiple kinases, and ubiquitination only occurs when all necessary phosphorylation signals have been incorporated. In this manner, the precise timing of degradation can be controlled. Another way that the Ub pathway tightly controls the timing of proteolysis is with multiple E3 Ub-ligases acting upon a single target. Lastly, subcellular localization can either promote or prevent degradation by regulating the accessibility of kinases and E3 Ub-ligases. This review highlights recent findings that exemplify these emerging themes in the regulation of E3 Ub-ligase substrate recognition.

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References

  • Ang XL and Harper JW . (2004). Sci. STKE, 13, pe31.

  • Bahram F, von der Lehr N, Cetinkaya C and Larsson LG . (2000). Blood, 95, 2104–2110.

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

  • Barral Y, Parra M, Bidlingmaier S and Snyder M . (1999). Genes Dev., 13, 176–187.

  • Bashir T, Dorrello NV, Amador V, Guardavaccaro D and Pagano M . (2004). Nature, 428, 190–193.

  • Bhatia K, Huppi K, Spangler G, Siwarski D, Iyer R and Magrath I . (1993). Nat. Genet., 5, 56–61.

  • Boehm M, Yoshimoto T, Crook MF, Nallamshetty S, True A, Nabel GJ and Nabel EG . (2002). EMBO J., 21, 3390–3401.

  • Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M and Draetta GF . (2003). Nature, 426, 87–91.

  • Carrano AC, Eytan E, Hershko A and Pagano M . (1999). Nat. Cell Biol., 1, 193–199.

  • Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M and Pagano M . (1999). Curr. Biol., 9, 1177–1179.

  • Clurman BE, Sheaff RJ, Thress K, Groudine M and Roberts JM . (1996). Genes Dev., 10, 1979–1990.

  • Deshaies RJ . (1999). Annu. Rev. Cell Dev. Biol., 15, 435–467.

  • Deshaies RJ and Ferrell Jr JE . (2001). Cell, 107, 819–822.

  • Fang S, Lorick KL, Jensen JP and Weissman AM . (2003). Semin. Cancer Biol., 13, 5–14.

  • Feldman RM, Correll CC, Kaplan KB and Deshaies RJ . (1997). Cell, 91, 221–230.

  • Fujita N, Sato S, Katayama K and Tsuruo T . (2002). J. Biol. Chem., 277, 28706–28713.

  • Furukawa M, He YJ, Borchers C and Xiong Y . (2003). Nat. Cell Biol., 5, 1001–1007.

  • Geyer R, Wee S, Anderson S, Yates J and Wolf DA . (2003). Mol. Cell, 12, 783–790.

  • Golsteyn RM, Mundt KE, Fry AM and Nigg EA . (1995). J. Cell Biol., 129, 1617–1628.

  • Golsteyn RM, Schultz SJ, Bartek J, Ziemiecki A, Ried T and Nigg EA . (1994). J. Cell Sci., 107, 1509–1517.

  • Gregory MA and Hann SR . (2000). Mol. Cell. Biol., 20, 2423–2435.

  • Guardavaccaro D and Pagano M . (2004). Oncogene, 23, 2037–2049.

  • Hansen DV, Loktev AV, Ban KH and Jackson PK . (2004). Mol. Biol. Cell, 15, 5623–5634.

  • Harper JW . (2002). Trends Cell Biol., 12, 104–107.

  • Harper JW, Burton JL and Solomon MJ . (2002). Genes Dev., 16, 2179–2206.

  • Hatakeyama S, Yada M, Matsumoto M, Ishida N and Nakayama KI . (2001). J. Biol. Chem., 276, 33111–33120.

  • Henriksson M, Bakardjiev A, Klein G and Luscher B . (1993). Oncogene, 8, 3199–3209.

  • Hershko A and Ciechanover A . (1998). Annu. Rev. Biochem., 67, 425–479.

  • Hershko D, Bornstein G, Ben-Izhak O, Carrano A, Pagano M, Krausz MM and Hershko A . (2001). Cancer, 91, 1745–1751.

  • Hsu JY, Reimann JD, Sorensen CS, Lukas J and Jackson PK . (2002). Nat. Cell Biol., 4, 358–366.

  • Hubbard EJ, Wu G, Kitajewski J and Greenwald I . (1997). Genes Dev., 11, 3182–3193.

  • Ingham RJ, Gish G and Pawson T . (2004). Oncogene, 23, 1972–1984.

  • Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K and Nakayama KI . (2002). J. Biol. Chem., 277, 14355–14358.

  • Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M and Harper JW . (2004). Genes Dev., 18, 2573–2580.

  • Jin J and Harper JW . (2003). Cancer Cell, 3, 517–518.

  • Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ and Harper JW . (2003). Genes Dev., 17, 3062–3074.

  • Joazeiro CA and Weissman AM . (2000). Cell, 102, 549–552.

  • Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin Jr WG, Elledge SJ, Conaway RC, Harper JW and Conaway JW . (1999). Science, 284, 657–661.

  • Kawakami T, Chiba T, Suzuki T, Iwai K, Yamanaka K, Minato N, Suzuki H, Shimbara N, Hidaka Y, Osaka F, Omata M and Tanaka K . (2001). EMBO J., 20, 4003–4012.

  • Kim SY, Herbst A, Tworkowski KA, Salghetti SE and Tansey WP . (2003). Mol. Cell, 11, 1177–1188.

  • Koepp DM, Harper JW and Elledge SJ . (1999). Cell, 97, 431–434.

  • Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW and Elledge SJ . (2001). Science, 294, 173–177.

  • Lammer D, Mathias N, Laplaza JM, Jiang W, Liu Y, Callis J, Goebl M and Estelle M . (1998). Genes Dev., 12, 914–926.

  • Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G and Pagano M . (2001). Proc. Natl. Acad. Sci. USA, 98, 2515–2520.

  • Levens DL . (2003). Genes Dev., 17, 1071–1077.

  • Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X and He X . (2002). Cell, 108, 837–847.

  • Lutterbach B and Hann SR . (1994). Mol. Cell. Biol., 14, 5510–5522.

  • Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD and Jackson PK . (2003). Dev. Cell, 4, 813–826.

  • Moberg KH, Bell DW, Wahrer DC, Haber DA and Hariharan IK . (2001). Nature, 413, 311–316.

  • Moberg KH, Mukherjee A, Veraksa A, Artavanis-Tsakonas S and Hariharan IK . (2004). Curr. Biol., 14, 965–974.

  • Moshe Y, Boulaire J, Pagano M and Hershko A . (2004). Proc. Natl. Acad. Sci. USA, 101, 7937–7942.

  • Nakayama K, Nagahama H, Minamishima YA, Miyake S, Ishida N, Hatakeyama S, Kitagawa M, Iemura S, Natsume T and Nakayama KI . (2004). Dev. Cell, 6, 661–672.

  • Nash P, Tang X, Orlicky S, Chen Q, Gertler FB, Mendenhall MD, Sicheri F, Pawson T and Tyers M . (2001). Nature, 414, 514–521.

  • Ohta T, Michel JJ, Schottelius AJ and Xiong Y . (1999). Mol. Cell, 3, 535–541.

  • Orlicky S, Tang X, Willems A, Tyers M and Sicheri F . (2003). Cell, 112, 243–256.

  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M . (1995). Science, 269, 682–685.

  • Peters JM . (2002). Mol. Cell, 9, 931–943.

  • Pintard L, Willis JH, Willems A, Johnson JL, Srayko M, Kurz T, Glaser S, Mains PE, Tyers M, Bowerman B and Peter M . (2003). Nature, 425, 311–316.

  • Prinz S, Hwang ES, Visintin R and Amon A . (1998). Curr. Biol., 8, 750–760.

  • Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR and Roberts JM . (1997). Nat. Med., 3, 222–225.

  • Pulverer BJ, Fisher C, Vousden K, Littlewood T, Evan G and Woodgett JR . (1994). Oncogene, 9, 59–70.

  • Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B and Lengauer C . (2004). Nature, 428, 77–81.

  • Reed SI . (2002). Cell Cycle, 1, 389–390.

  • Reed SI . (2003). Nat. Rev. Mol. Cell. Biol., 4, 855–864.

  • Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM and Jackson PK . (2001). Cell, 105, 645–655.

  • Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M and Meloche S . (2001). EMBO J., 20, 6672–6682.

  • Sakchaisri K, Asano S, Yu LR, Shulewitz MJ, Park CJ, Park JE, Cho YW, Veenstra TD, Thorner J and Lee KS . (2004). Proc. Natl. Acad. Sci. USA, 101, 4124–4129.

  • Sears R, Nuckolls F, Haura E, Taya Y, Tamai K and Nevins JR . (2000). Genes Dev., 14, 2501–2514.

  • Seol JH, Feldman RM, Zachariae W, Shevchenko A, Correll CC, Lyapina S, Chi Y, Galova M, Claypool J, Sandmeyer S, Nasmyth K, Deshaies RJ, Shevchenko A and Deshaies RJ . (1999). Genes Dev., 13, 1614–1626.

  • Shirayama M, Zachariae W, Ciosk R and Nasmyth K . (1998). EMBO J., 17, 1336–1349.

  • Shirayama M, Toth A, Galova M and Nasmyth K . (1999). Nature, 402, 203–207.

  • Shulewitz MJ, Inouye CJ and Thorner J . (1999). Mol. Cell. Biol., 19, 7123–7137.

  • Sia RA, Bardes ES and Lew DJ . (1998). EMBO J., 17, 6678–6688.

  • Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M and Pagano M . (2002). J. Clin. Invest., 110, 633–641.

  • Singer JD, Gurian-West M, Clurman B and Roberts JM . (1999). Genes Dev., 13, 2375–2387.

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

  • Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ and Harper JW . (1999). Science, 284, 662–665.

  • Spencer CA and Groudine M . (1991). Adv. Cancer Res., 56, 1–48.

  • Spruck CH, Won KA and Reed SI . (1999). Nature, 401, 297–300.

  • Spruck CH, Strohmaier H, Sangfelt O, Muller HM, Hubalek M, Muller-Holzner E, Marth C, Widschwendter M and Reed SI . (2002). Cancer Res., 62, 4535–4539.

  • Sreenivasan A and Kellogg D . (1999). Mol. Cell. Biol., 19, 7983–7994.

  • Stegmeier F, Visintin R and Amon A . (2002). Cell, 108, 207–220.

  • Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O and Reed SI . (2001). Nature, 413, 316–322.

  • Tetzlaff MT, Yu W, Li M, Zhang P, Finegold M, Mahon K, Harper JW, Schwartz RJ and Elledge SJ . (2004). Proc. Natl. Acad. Sci. USA, 101, 3338–3345.

  • Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T and Nakayama KI . (2004). J. Biol. Chem., 279, 9417–9423.

  • Tyers M and Jorgensen P . (2000). Curr. Opin. Genet. Dev., 10, 54–64.

  • Visintin R, Hwang ES and Amon A . (1999). Nature, 398, 818–823.

  • von der Lehr N, Johansson S, Wu S, Bahram F, Castell A, Cetinkaya C, Hydbring P, Weidung I, Nakayama K, Nakayama KI, Soderberg O, Kerppola TK and Larsson LG . (2003). Mol. Cell, 11, 1189–1200.

  • Wang W, Ungermannova D, Jin J, Harper JW and Liu X . (2004). Oncogene, 23, 1064–1075.

  • Wasch R and Cross FR . (2002). Nature, 418, 556–562.

  • Watanabe N, Arai H, Nishihara Y, Taniguchi M, Watanabe N, Hunter T and Osada H . (2004). Proc. Natl. Acad. Sci. USA, 101, 4419–4424.

  • Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW and Kaelin Jr WG . (2004). Nature, 428, 194–198.

  • Welcker M, Orian A, Jin J, Grim JA, Harper JW, Eisenman RN and Clurman BE . (2004a). Proc. Natl. Acad. Sci. USA, 101, 9085–9090.

  • Welcker M, Singer J, Loeb KR, Grim J, Bloecher A, Gurien-West M, Clurman B and Roberts JM . (2003). Mol. Cell, 12, 381–392.

  • Welcker M, Orian A, Grim JA, Eisenmann RN and Clurman BE . (2004b). Curr. Biol., 14, 1852–1857.

  • Winston JT, Chu C and Harper JW . (1999a). Genes Dev., 13, 2751–2757.

  • Winston JT, Koepp DM, Zhu C, Elledge SJ and Harper JW . (1999b). Curr. Biol., 9, 1180–1182.

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

  • Wirbelauer C, Sutterluty H, Blondel M, Gstaiger M, Peter M, Reymond F and Krek W . (2000). EMBO J., 19, 5362–5375.

  • Won KA and Reed SI . (1996). EMBO J., 15, 4182–4193.

  • Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW and Pavletich NP . (2003). Mol. Cell, 11, 1445–1456.

  • Xu L, Wei Y, Reboul J, Vaglio P, Shin TH, Vidal M, Elledge SJ and Harper JW . (2003). Nature, 425, 316–321.

  • Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, Ishida N, Okumura F, Nakayama K and Nakayama KI . (2004). EMBO J., 23, 2116–2125.

  • Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC and Harper JW . (2002). Clin. Cancer Res., 8, 3419–3426.

  • Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, Means AR and Sears R . (2004). Nat. Cell Biol., 6, 308–318.

  • Ye X, Nalepa G, Welcker M, Kessler BM, Spooner E, Qin J, Elledge SJ, Clurman BE and Harper JW . (2004). J. Biol. Chem., 279, 50110–50119.

  • Ye X, Wei Y, Nalepa G and Harper JW . (2003). Mol. Cell. Biol., 23, 8586–8600.

  • Yokoi S, Yasui K, Mori M, Iizasa T, Fujisawa T and Inazawa J . (2004). Am. J. Pathol., 165, 175–180.

  • Yokoi S, Yasui K, Saito-Ohara F, Koshikawa K, Iizasa T, Fujisawa T, Terasaki T, Horii A, Takahashi T, Hirohashi S and Inazawa J . (2002). Am. J. Pathol., 161, 207–216.

  • Yoshida Y, Chiba T, Tokunaga F, Kawasaki H, Iwai K, Suzuki T, Ito Y, Matsuoka K, Yoshida M, Tanaka K and Tai T . (2002). Nature, 418, 438–442.

  • Zheng N, Wang P, Jeffrey PD and Pavletich NP . (2000). Cell, 102, 533–539.

  • Zhou P and Howley PM . (1998). Mol. Cell, 2, 571–580.

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Acknowledgements

The work in this laboratory is supported by NIH Grants GM54137 and AG11085.

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  1. Program in Biological and Biomedical Sciences, Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA

    Xiaolu L Ang & J Wade Harper

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Ang, X., Wade Harper, J. SCF-mediated protein degradation and cell cycle control. Oncogene 24, 2860–2870 (2005). https://doi.org/10.1038/sj.onc.1208614

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