Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

USP8 (Ubiquitin-Specific Protease 8)

  • Masayuki KomadaEmail author
  • Martin Reincke
  • Marily Theodoropoulou
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101955


Historical Background

Deubiquitinating enzymes (DUBs) are proteases which specifically hydrolyze the isopeptide bond between ubiquitin and target proteins in ubiquitin-protein conjugates or between ubiquitin molecules in ubiquitin chains. Ubiquitin-specific protease 8 (USP8), also known as ubiquitin isopeptidase Y (UBPY), was originally identified as a DUB which is upregulated in proliferating cells and promotes the entry of cells into the S-phase of the cell cycle (Naviglio et al. 1998). Subsequent studies, however, have accumulated evidence that this DUB plays a major role in regulating the lysosomal traffic/degradation of plasma membrane proteins upon endocytosis from the cell surface.

Downregulation of Growth Factor Receptors

Sustained signaling from ligand-activated growth factor receptors results in overproliferation of cells and tumorigenesis. To avoid such dangerous incidences, cells internalize...
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  1. Forbes SA, Tang G, Bindal N, Bamford S, Dawson E, Cole C, Kok CY, Jia M, Ewing R, Menzies A, Teague JW, Stratton MR, Futreal PA. COSMIC (the catalogue of somatic mutations in cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res. 2010;38:D652–7.PubMedCrossRefGoogle Scholar
  2. Fukuoka H, Cooper O, Ben-Shlomo A, Mamelak A, Ren SG, Bruyette D, Melmed S. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J Clin Invest. 2011;121:4712–21.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Hayashi K, Inoshita N, Kawaguchi K, Ibrahim Ardisasmita A, Suzuki H, Fukuhara N, Okada M, Nishioka H, Takeuchi Y, Komada M, Takeshita A, Yamada S. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur J Endocrinol. 2016;174:213–26.PubMedCrossRefGoogle Scholar
  4. Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell. 2011;21:77–91.PubMedCrossRefGoogle Scholar
  5. Komada M. Controlling receptor downregulation by ubiquitination and deubiquitination. Curr Drug Discov Technol. 2008;5:78–84.PubMedCrossRefGoogle Scholar
  6. Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10:550–63.PubMedCrossRefGoogle Scholar
  7. Kulathu Y, Komander D. Atypical ubiquitylation – the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol. 2012;13:508–23.PubMedCrossRefGoogle Scholar
  8. Ma ZY, Song ZJ, Chen JH, Wang YF, Li SQ, Zhou LF, Mao Y, Li YM, Hu RG, Zhang ZY, Ye HY, Shen M, Shou XF, Li ZQ, Peng H, Wang QZ, Zhou DZ, Qin XL, Ji J, Zheng J, Chen H, Wang Y, Geng DY, Tang WJ, Fu CW, Shi ZF, Zhang YC, Ye Z, He WQ, Zhang QL, Tang QS, Xie R, Shen JW, Wen ZJ, Zhou J, Wang T, Huang S, Qiu HJ, Qiao ND, Zhang Y, Pan L, Bao WM, Liu YC, Huang CX, Shi YY, Zhao Y. Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res. 2015;25:306–17.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Mizuno E, Iura T, Mukai A, Yoshimori T, Kitamura N, Komada M. Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Mol Biol Cell. 2005;16:5163–74.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Mizuno E, Kitamura N, Komada M. 14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase. Exp Cell Res. 2007;313:3624–34.PubMedCrossRefGoogle Scholar
  11. Mohapatra B, Ahmad G, Nadeau S, Zutshi N, An W, Scheffe S, Dong L, Feng D, Goetz B, Arya P, Bailey TA, Palermo N, Borgstahl GE, Natarajan A, Raja SM, Naramura M, Band V, Band H. Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim Biophys Acta. 2013;1833:122–39.PubMedCrossRefGoogle Scholar
  12. Naviglio S, Mattecucci C, Matoskova B, Nagase T, Nomura N, Di Fiore PP, Draetta GF. UBPY: a growth-regulated human ubiquitin isopeptidase. EMBO J. 1998;17:3241–50.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Niendorf S, Oksche A, Kisser A, Löhler J, Prinz M, Schorle H, Feller S, Lewitzky M, Horak I, Knobeloch KP. Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Mol Cell Biol. 2007;27:5029–39.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Perez-Rivas LG, Theodoropoulou M, Ferraù F, Nusser C, Kawaguchi K, Stratakis CA, Faucz FR, Wildemberg LE, Assié G, Beschorner R, Dimopoulou C, Buchfelder M, Popovic V, Berr CM, Tóth M, Ardisasmita AI, Honegger J, Bertherat J, Gadelha MR, Beuschlein F, Stalla G, Komada M, Korbonits M, Reincke M. The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s disease. J Clin Endocrinol Metab. 2015;100:E997–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36:385–486.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Raiborg C, Stenmark H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature. 2009;458:445–52.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet. 2015;47:31–8.PubMedCrossRefGoogle Scholar
  18. Row PE, Prior IA, McCullough J, Clague MJ, Urbé S. The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. J Biol Chem. 2006;281:12618–24.PubMedCrossRefGoogle Scholar
  19. Song ZJ, Reitman ZJ, Ma ZY, Chen JH, Zhang QL, Shou XF, Huang CX, Wang YF, Li SQ, Mao Y, Zhou LF, Lian BF, Yan H, Shi YY, Zhao Y. The genome-wide mutational landscape of pituitary adenomas. Cell Res. 2016;26:1255–9.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Theodoropoulou M, Arzberger T, Gruebler Y, Jaffrain-Rea ML, Schlegel J, Schaaf L, Petrangeli E, Losa M, Stalla GK, Pagotto U. Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J Endocrinol. 2004;183:385–94.PubMedCrossRefGoogle Scholar
  21. Theodoropoulou M, Reincke M, Fassnacht M, Komada M. Decoding the genetic basis of Cushing’s disease: USP8 in the spotlight. Eur J Endocrinol. 2015;173:M73–83.PubMedCrossRefGoogle Scholar
  22. Valassi E, Santos A, Yaneva M, Tóth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M, Feelders RA, Tsagarakis S, Trainer PJ, Franz H, Zopf K, Zacharieva S, Lamberts SW, Tabarin A, Webb SM, ERCUSYN Study Group. The European registry on Cushing’s syndrome: 2-year experience baseline demographic and clinical characteristics. Eur J Endocrinol. 2011;165:383–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Masayuki Komada
    • 1
    Email author
  • Martin Reincke
    • 2
  • Marily Theodoropoulou
    • 2
  1. 1.Cell Biology Unit, Institute of Innovative ResearchTokyo Institute of TechnologyYokohamaJapan
  2. 2.Medizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität MünchenMunichGermany