Abstract
Ubiquitination is an important post-translational modification that has a pivotal role in numerous biological functions, such as cell growth, proliferation, apoptosis, DNA damage response, innate immune response and neuron degeneration. Although ubiquitination is thought to achieve these functions by targeting proteins for proteasome-dependent degradation, recent studies suggest that ubiquitination also has nonproteolytic functions, such as protein trafficking, kinase and phosphatase activation, which are involved in cell survival and cancer development. These progresses have advanced our current understanding of the novel functions of ubiquitination in signal transduction pathways and may provide novel paradigms for the treatment of human cancers.
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References
Adhikari A, Chen ZJ . (2009). Diversity of polyubiquitin chains. Dev Cell 16: 485–486.
Adhikary S, Eilers M . (2005). Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6: 635–645.
Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R et al. (2005). The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123: 409–421.
Amati B, Sanchez-Arevalo Lobo VJ . (2007). MYC degradation: deubiquitinating enzymes enter the dance. Nat Cell Biol 9: 729–731.
Ashida H, Kim M, Schmidt-Supprian M, Ma A, Ogawa M, Sasakawa C . (2010). A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol 12: 66–73, sup pp 61–69.
Askham JM, Platt F, Chambers PA, Snowden H, Taylor CF, Knowles MA . (2010). AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K. Oncogene 29: 150–155.
Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P, Rosen N . (2002). Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 277: 39858–39866.
Bellacosa A, Chan TO, Ahmed NN, Datta K, Malstrom S, Stokoe D et al. (1998). Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17: 313–325.
Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J et al. (2008). cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30: 689–700.
Bhoj VG, Chen ZJ . (2009). Ubiquitylation in innate and adaptive immunity. Nature 458: 430–437.
Brazil DP, Park J, Hemmings BA . (2002). PKB binding proteins: getting in on the Akt. Cell 111: 293–303.
Brooks CL, Li M, Hu M, Shi Y, Gu W. . (2007). The p53—Mdm2—HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 26: 7262–7266.
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.
Cantley LC . (2002). The phosphoinositide 3-kinase pathway. Science 296: 1655–1657.
Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM et al. (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448: 439–444.
Chang CJ, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H . (2008). PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol 28: 3281–3289.
Chen D, Kon N, Li M, Zhang W, Qin J, Gu W . (2005). ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121: 1071–1083.
Chen ZJ . (2005). Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7: 758–765.
Chen ZJ, Sun LJ . (2009). Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33: 275–286.
Colland F, Formstecher E, Jacq X, Reverdy C, Planquette C, Conrath S et al. (2009). Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther 8: 2286–2295.
Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q et al. (2009). Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459: 717–721.
Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD . (2008). Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation. Mol Cell Biol 28: 3538–3547.
Cummins JM, Vogelstein B . (2004). HAUSP is required for p53 destabilization. Cell Cycle 3: 689–692.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
De Schutter J, Guillabert A, Imbault V, Degraef C, Erneux C, Communi D et al. (2009). SHIP2 (SH2 domain-containing inositol phosphatase 2) SH2 domain negatively controls SHIP2 monoubiquitination in response to epidermal growth factor. J Biol Chem 284: 36062–36076.
Di Cristofano A, Pandolfi PP . (2000). The multiple roles of PTEN in tumor suppression. Cell 100: 387–390.
Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ et al. (2008). Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci USA 105: 3622–3627.
Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C et al. (2008). The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27: 1932–1943.
Fallon L, Belanger CM, Corera AT, Kontogiannea M, Regan-Klapisz E, Moreau F et al. (2006). A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat Cell Biol 8: 834–842.
Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N et al. (2008). The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc Natl Acad Sci USA 105: 8585–8590.
Giasson BI, Lee VM . (2003). Are ubiquitination pathways central to Parkinson's disease? Cell 114: 1–8.
Gonzalez E, McGraw TE . (2009). The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8: 2502–2508.
Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G et al. (2008). A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 27: 373–383.
Heemers HV, Tindall DJ . (2009). Unraveling the complexities of androgen receptor signaling in prostate cancer cells. Cancer Cell 15: 245–247.
Heldin CH, Landstrom M, Moustakas A . (2009). Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol 21: 166–176.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB . (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4: 988–1004.
Herold S, Herkert B, Eilers M. . (2009). Facilitating replication under stress: an oncogenic function of MYC? Nat Rev Cancer 9: 441–444.
Hicke L, Schubert HL, Hill CP . (2005). Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6: 610–621.
Hoeller D, Dikic I . (2009). Targeting the ubiquitin system in cancer therapy. Nature 458: 438–444.
Hofmann RM, Pickart CM . (2001). in vitro assembly and recognition of Lys-63 polyubiquitin chains. J Biol Chem 276: 27936–27943.
Hou J, Wang P, Lin L, Liu X, Ma F, An H et al. (2009). MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol 183: 2150–2158.
Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB et al. (2007). RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131: 901–914.
Hurst DR, Edmonds MD, Scott GK, Benz CC, Vaidya KS, Welch DR . (2009). Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res 69: 1279–1283.
Hynes NE, MacDonald G . (2009). ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21: 177–184.
Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF et al. (2000). An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275: 27823–27831.
Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K et al. (2009). Frequent inactivation of A20 in B-cell lymphomas. Nature 459: 712–716.
Klein S, Levitzki A . (2009). Targeting the EGFR and the PKB pathway in cancer. Curr Opin Cell Biol 21: 185–193.
Kon N, Kobayashi Y, Li M, Brooks CL, Ludwig T, Gu W . (2009). Inactivation of HAUSP in vivo modulates p53 function. Oncogene 29: 1270–1279.
Kong M, Bui TV, Ditsworth D, Gruber JJ, Goncharov D, Krymskaya VP et al. (2007). The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 282: 29712–29720.
Korchnak AC, Zhan Y, Aguilar MT, Chadee DN . (2009). Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cell Signal 21: 1620–1625.
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.
Lazar DF, Saltiel AR . (2006). Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Discov 5: 333–342.
Lee RJ, Albanese C, Fu M, D′Amico M, Lin B, Watanabe G et al. (2000). Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 20: 672–683.
Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W . (2003). Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302: 1972–1975.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J et al. (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416: 648–653.
Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH et al. (2010). Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464: 374–379.
Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH et al. (2009). Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol 11: 420–432.
Liu P, Cheng H, Roberts TM, Zhao JJ . (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8: 627–644.
Lynch OT, Gadina M . (2004). Ubiquitination for activation: new directions in the NF-kappaB roadmap. Mol Interv 4: 144–146.
Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C et al. (2007). RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131: 887–900.
Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R et al. (2006). ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 281: 18482–18488.
McConnell JL, Watkins GR, Soss SE, Franz HS, McCorvey LR, Spiller BW . (2010). Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination. Biochemistry 49: 1713–1718.
Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE et al. (2005a). Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell 18: 565–576.
Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG . (2005b). ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. Cell Cycle 4: 1166–1170.
Monami G, Emiliozzi V, Morrione A . (2008). Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J Cell Physiol 216: 426–437.
Novak U, Rinaldi A, Kwee I, Nandula SV, Rancoita PM, Compagno M et al. (2009). The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in margin. Blood 113: 4918–4921.
Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M et al. (2007). RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178: 2380–2386.
Pickart CM . (2001). Mechanisms underlying ubiquitination. Annu Rev Biochem 70: 503–533.
Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R et al. (2007). The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol 9: 765–774.
Raiborg C, Stenmark H . (2009). The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458: 445–452.
Rong SB, Hu Y, Enyedy I, Powis G, Meuillet EJ, Wu X et al. (2001). Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides. J Med Chem 44: 898–908.
Salmena L, Carracedo A, Pandolfi PP . (2008). Tenets of PTEN tumor suppression. Cell 133: 403–414.
Sato S, Fujita N, Tsuruo T . (2000). Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA 97: 10832–10837.
Sehat B, Andersson S, Girnita L, Larsson O . (2008). Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis. Cancer Res 68: 5669–5677.
Shambharkar PB, Blonska M, Pappu BP, Li H, You Y, Sakurai H et al. (2007). Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways. EMBO J 26: 1794–1805.
Shan J, Zhao W, Gu W . (2009). Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell 36: 469–476.
Shi Y . (2009). Serine/threonine phosphatases: mechanism through structure. Cell 139: 468–484.
Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N . (2003). Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 63: 2139–2144.
Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J et al. (2008). The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455: 813–817.
Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N et al. (2008). The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 10: 1199–1207.
Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM et al. (2008). Modelling Myc inhibition as a cancer therapy. Nature 455: 679–683.
Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A et al. (2010). Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 16: 49–58.
Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK . (2007). The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 26: 976–986.
Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura AJ, Hirata N et al. (2009). The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt. Dev Cell 17: 800–810.
Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ . (2004). The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 14: 289–301.
Sun SC . (2008). Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8: 501–511.
Sun SC . (2009). CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ 17: 25–34.
Tang J, Qu LK, Zhang J, Wang W, Michaelson JS, Degenhardt YY et al. (2006). Critical role for Daxx in regulating Mdm2. Nat Cell Biol 8: 855–862.
Toker A . (2009). TTC3 ubiquitination terminates Akt-ivation. Dev Cell 17: 752–754.
Tremblay ML, Giguere V . (2008). Phosphatases at the heart of FoxO metabolic control. Cell Metab 7: 101–103.
Trockenbacher A, Suckow V, Foerster J, Winter J, Krauss S, Ropers HH et al. (2001). MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 29: 287–294.
Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP . (2006). Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523–527.
Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H et al. (2007). Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141–156.
Van Themsche C, Leblanc V, Parent S, Asselin E . (2009). X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization. J Biol Chem 284: 20462–20466.
Varghese B, Barriere H, Carbone CJ, Banerjee A, Swaminathan G, Plotnikov A et al. (2008). Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway. Mol Cell Biol 28: 5275–5287.
Varnai P, Bondeva T, Tamas P, Toth B, Buday L, Hunyady L et al. (2005). Selective cellular effects of overexpressed pleckstrin-homology domains that recognize PtdIns(3,4,5)P3 suggest their interaction with protein binding partners. J Cell Sci 118: 4879–4888.
Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z et al. (2007). NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129–139.
Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP . (2009). Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15: 416–428.
Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN et al. (2008). Negative regulation of AKT activation by BRCA1. Cancer Res 68: 10040–10044.
Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F et al. (2009). Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell 15: 270–282.
Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang YE . (2008). TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 31: 918–924.
Yamazaki K, Gohda J, Kanayama A, Miyamoto Y, Sakurai H, Yamamoto M et al. (2009). Two mechanistically and temporally distinct NF-kappaB activation pathways in IL-1 signaling. Sci Signal 2: ra66.
Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B et al. (2009). The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325: 1134–1138.
Yang WL, Wu CY, Wu J, Lin HK . (2010). Regulation of Akt signaling activation by ubiquitination. Cell Cycle 9: 486–497.
Yu Q, Geng Y, Sicinski P . (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature 411: 1017–1021.
Yuan J, Luo K, Zhang L, Cheville JC, Lou Z . (2010). USP10 regulates p53 localization stability by deubiquitinating p53. Cell 140: 384–396.
Zhong Q, Gao W, Du F, Wang X . (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121: 1085–1095.
Acknowledgements
We thank the members of the Lin's laboratory for their comments and suggestions. We extend our special thanks to Yuan Gao for her critical reading and for editing the paper. We apologize to many investigators whose important works were not cited here due to space limitations. This work is supported by the MD Anderson Research Trust Scholar Fund, a RO1 grant from NCI, and New Investigator Award from the Department of Defense to HK Lin.
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Yang, WL., Zhang, X. & Lin, HK. Emerging role of Lys-63 ubiquitination in protein kinase and phosphatase activation and cancer development. Oncogene 29, 4493–4503 (2010). https://doi.org/10.1038/onc.2010.190
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