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Cellular and Molecular Life Sciences

, Volume 76, Issue 4, pp 653–665 | Cite as

TGF-β signaling pathway mediated by deubiquitinating enzymes

  • Soo-Yeon Kim
  • Kwang-Hyun BaekEmail author
Review
  • 272 Downloads

Abstract

Ubiquitination is a reversible cellular process mediated by ubiquitin-conjugating enzymes, whereas deubiquitinating enzymes (DUBs) detach the covalently conjugated ubiquitin from target substrates to counter ubiquitination. DUBs play a crucial role in regulating various signal transduction pathways and biological processes including apoptosis, cell proliferation, DNA damage repair, metastasis, differentiation, etc. Since the transforming growth factor-β (TGF-β) signaling pathway participates in various cellular functions such as inflammation, metastasis and embryogenesis, aberrant regulation of TGF-β signaling induces abnormal cellular functions resulting in numerous diseases. This review focuses on DUBs regulating the TGF-β signaling pathway. We discuss the molecular mechanisms of DUBs involved in TGF-β signaling pathway, and biological and therapeutic implications for various diseases.

Keywords

Deubiquitination Post-translational modification Proteasomal degradation TGF-β Ubiquitination 

Notes

Acknowledgements

We would like to thank members of Baek’s laboratory for their critical comments on the manuscript. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (201600490003).

Author contributions

SYK: manuscript writing; KHB: manuscript writing, final approval of manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Wilkinson KD (2000) Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Semin Cell Dev Biol 11(3):141–148Google Scholar
  2. 2.
    Swatek KN, Komander D (2016) Ubiquitin modifications. Cell Res 26(4):399–422Google Scholar
  3. 3.
    McDowell GS, Philpott A (2013) Non-canonical ubiquitylation: mechanisms and consequences. Int J Biochem Cell Biol 45(8):1833–1842Google Scholar
  4. 4.
    Grumati P, Dikic I (2018) Ubiquitin signaling and autophagy. J Biol Chem 293(15):5404–5413Google Scholar
  5. 5.
    Lauwers E, Jacob C, Andre B (2009) K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway. J Cell Biol 185(3):493–502Google Scholar
  6. 6.
    Mevissen TET, Komander D (2017) Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 86:159–192Google Scholar
  7. 7.
    Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397Google Scholar
  8. 8.
    Lim KH, Song MH, Baek KH (2016) Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint. Cell Mol Life Sci 73(7):1439–1455Google Scholar
  9. 9.
    He M et al (2017) Emerging role of DUBs in tumor metastasis and apoptosis: therapeutic implication. Pharmacol Ther 177:96–107Google Scholar
  10. 10.
    Burrows JF, Scott CJ, Johnston JA (2010) The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster. BMC Genom 11:250Google Scholar
  11. 11.
    Kim SY et al (2018) PME-1 is regulated by USP36 in ERK and Akt signaling pathways. FEBS Lett 592(9):1575–1588Google Scholar
  12. 12.
    Kee Y, Huang TT (2016) Role of deubiquitinating enzymes in DNA repair. Mol Cell Biol 36(4):524–544Google Scholar
  13. 13.
    Nijman SM et al (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5):773–786Google Scholar
  14. 14.
    Luise C et al (2011) An atlas of altered expression of deubiquitinating enzymes in human cancer. PLoS One 6(1):e15891Google Scholar
  15. 15.
    Hu M et al (2002) Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111(7):1041–1054Google Scholar
  16. 16.
    Johnston SC et al (1999) Structural basis for the specificity of ubiquitin C-terminal hydrolases. EMBO J 18(14):3877–3887Google Scholar
  17. 17.
    Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10(8):550–563Google Scholar
  18. 18.
    Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695(1–3):189–207Google Scholar
  19. 19.
    Mao Y et al (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci USA 102(36):12700–12705Google Scholar
  20. 20.
    Nicastro G et al (2005) The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci USA 102(30):10493–10498Google Scholar
  21. 21.
    Iyer LM, Koonin EV, Aravind L (2004) Novel predicted peptidases with a potential role in the ubiquitin signaling pathway. Cell Cycle 3(11):1440–1450Google Scholar
  22. 22.
    Imamura T, Oshima Y, Hikita A (2013) Regulation of TGF-beta family signalling by ubiquitination and deubiquitination. J Biochem 154(6):481–489Google Scholar
  23. 23.
    Zhang J et al (2014) The regulation of TGF-beta/SMAD signaling by protein deubiquitination. Protein Cell 5(7):503–517Google Scholar
  24. 24.
    Fraile JM et al (2012) Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31(19):2373–2388Google Scholar
  25. 25.
    Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584Google Scholar
  26. 26.
    Weiss A, Attisano L (2013) The TGFbeta superfamily signaling pathway. Wiley Interdiscip Rev Dev Biol 2(1):47–63Google Scholar
  27. 27.
    Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8(12):970–982Google Scholar
  28. 28.
    Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19(1):128–139Google Scholar
  29. 29.
    Conery AR et al (2004) Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6(4):366–372Google Scholar
  30. 30.
    Remy I, Montmarquette A, Michnick SW (2004) PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6(4):358–365Google Scholar
  31. 31.
    Yamashita M et al (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 31(6):918–924Google Scholar
  32. 32.
    Ozdamar B et al (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307(5715):1603–1609Google Scholar
  33. 33.
    Xu P, Liu J, Derynck R (2012) Post-translational regulation of TGF-beta receptor and Smad signaling. FEBS Lett 586(14):1871–1884Google Scholar
  34. 34.
    Wang RN et al (2014) Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 1(1):87–105Google Scholar
  35. 35.
    Stevenson LF et al (2007) The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 26(4):976–986Google Scholar
  36. 36.
    Allende-Vega N et al (2010) MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 29(3):432–441Google Scholar
  37. 37.
    Shan J, Zhao W, Gu W (2009) Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell 36(3):469–476Google Scholar
  38. 38.
    Shi Y et al (2011) Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of aurora-A. J Biol Chem 286(45):38960–38968Google Scholar
  39. 39.
    Tong X et al (2012) USP2a protein deubiquitinates and stabilizes the circadian protein CRY1 in response to inflammatory signals. J Biol Chem 287(30):25280–25291Google Scholar
  40. 40.
    Mahul-Mellier AL et al (2012) De-ubiquitinating proteases USP2a and USP2c cause apoptosis by stabilising RIP1. Biochim Biophys Acta 1823(8):1353–1365Google Scholar
  41. 41.
    Li Y et al (2013) USP2a positively regulates TCR-induced NF-kappaB activation by bridging MALT1-TRAF6. Protein Cell 4(1):62–70Google Scholar
  42. 42.
    He X et al (2013) USP2a negatively regulates IL-1beta- and virus-induced NF-kappaB activation by deubiquitinating TRAF6. J Mol Cell Biol 5(1):39–47Google Scholar
  43. 43.
    Kim J et al (2012) The ubiquitin-specific protease USP2a enhances tumor progression by targeting cyclin A1 in bladder cancer. Cell Cycle 11(6):1123–1130Google Scholar
  44. 44.
    Tao BB et al (2013) Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade. J Clin Neurosci 20(5):717–720Google Scholar
  45. 45.
    Graner E et al (2004) The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5(3):253–261Google Scholar
  46. 46.
    Zhao Y et al (2018) USP2a supports metastasis by tuning TGF-beta signaling. Cell Rep 22(9):2442–2454Google Scholar
  47. 47.
    Clerici M et al (2014) The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange. Nat Commun 5:5399Google Scholar
  48. 48.
    Li Z et al (2016) USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2. Oncogene 35(22):2902–2912Google Scholar
  49. 49.
    Zhang X et al (2011) USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO J 30(11):2177–2189Google Scholar
  50. 50.
    Liu H et al (2015) The deubiquitylating enzyme USP4 cooperates with CtIP in DNA double-strand break end resection. Cell Rep 13(1):93–107Google Scholar
  51. 51.
    Hou X et al (2013) Ubiquitin-specific protease 4 promotes TNF-alpha-induced apoptosis by deubiquitination of RIP1 in head and neck squamous cell carcinoma. FEBS Lett 587(4):311–316Google Scholar
  52. 52.
    Xiao N et al (2012) Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha-induced cancer cell migration. Biochem J 441(3):979–986Google Scholar
  53. 53.
    Zhao B et al (2009) The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway. J Cell Mol Med 13(8B):1886–1895Google Scholar
  54. 54.
    Kwon SK, Kim EH, Baek KH (2017) RNPS1 is modulated by ubiquitin-specific protease 4. FEBS Lett 591(2):369–381Google Scholar
  55. 55.
    Park JK et al (2016) Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3. Nucleic Acids Res 44(11):5424–5437Google Scholar
  56. 56.
    Song EJ et al (2010) The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev 24(13):1434–1447Google Scholar
  57. 57.
    Lin R et al (2017) USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells. FEBS Lett 591(12):1677–1686Google Scholar
  58. 58.
    Zhang L et al (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor. Nat Cell Biol 14(7):717–726Google Scholar
  59. 59.
    Kavsak P et al (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6(6):1365–1375Google Scholar
  60. 60.
    Cao WH et al (2016) USP4 promotes invasion of breast cancer cells via Relaxin/TGF-beta1/Smad2/MMP-9 signal. Eur Rev Med Pharmacol Sci 20(6):1115–1122Google Scholar
  61. 61.
    Xu Y, Yu Q, Liu Y (2018) Serum relaxin-2 as a novel biomarker for prostate cancer. Br J Biomed Sci 75(3):145–148Google Scholar
  62. 62.
    Ma J et al (2013) Role of relaxin-2 in human primary osteosarcoma. Cancer Cell Int 13(1):59Google Scholar
  63. 63.
    Mehner C et al (2014) Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer. Oncotarget 5(9):2736–2749Google Scholar
  64. 64.
    Al-Hakim AK et al (2008) Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Biochem J 411(2):249–260Google Scholar
  65. 65.
    Fischer-Vize JA, Rubin GM, Lehmann R (1992) The fat facets gene is required for Drosophila eye and embryo development. Development 116(4):985–1000Google Scholar
  66. 66.
    Schwickart M et al (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463(7277):103–107Google Scholar
  67. 67.
    Vong QP et al (2005) Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310(5753):1499–1504Google Scholar
  68. 68.
    Engel K et al (2016) USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma. EMBO Mol Med 8(8):851–862Google Scholar
  69. 69.
    Nagai H et al (2009) Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death. Mol Cell 36(5):805–818Google Scholar
  70. 70.
    Huntwork-Rodriguez S et al (2013) JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. J Cell Biol 202(5):747–763Google Scholar
  71. 71.
    Theard D et al (2010) USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly. EMBO J 29(9):1499–1509Google Scholar
  72. 72.
    Taya S et al (1998) The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme. J Cell Biol 142(4):1053–1062Google Scholar
  73. 73.
    Mouchantaf R et al (2006) The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X. J Biol Chem 281(50):38738–38747Google Scholar
  74. 74.
    Murray RZ, Jolly LA, Wood SA (2004) The FAM deubiquitylating enzyme localizes to multiple points of protein trafficking in epithelia, where it associates with E-cadherin and beta-catenin. Mol Biol Cell 15(4):1591–1599Google Scholar
  75. 75.
    Marx C et al (2010) ErbB2 trafficking and degradation associated with K48 and K63 polyubiquitination. Cancer Res 70(9):3709–3717Google Scholar
  76. 76.
    Murtaza M et al (2015) La FAM fatale: USP9X in development and disease. Cell Mol Life Sci 72(11):2075–2089Google Scholar
  77. 77.
    Dupont S et al (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 136(1):123–135Google Scholar
  78. 78.
    Xie F et al (2014) Regulation of TGF-beta superfamily signaling by SMAD mono-ubiquitination. Cells 3(4):981–993Google Scholar
  79. 79.
    Wu Y et al (2017) Aberrant phosphorylation of SMAD4 Thr277-mediated USP9x-SMAD4 interaction by free fatty acids promotes breast cancer metastasis. Cancer Res 77(6):1383–1394Google Scholar
  80. 80.
    Kinlaw WB et al (2016) Fatty acids and breast cancer: make them on site or have them delivered. J Cell Physiol 231(10):2128–2141Google Scholar
  81. 81.
    Boden G (2011) Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 18(2):139–143Google Scholar
  82. 82.
    Xie Y et al (2013) Deubiquitinase FAM/USP9X interacts with the E3 ubiquitin ligase SMURF1 protein and protects it from ligase activity-dependent self-degradation. J Biol Chem 288(5):2976–2985Google Scholar
  83. 83.
    Stegeman S et al (2013) Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFbeta-mediated axonogenesis. PLoS One 8(7):e68287Google Scholar
  84. 84.
    Harper S et al (2014) Structure and catalytic regulatory function of ubiquitin specific protease 11N-terminal and ubiquitin-like domains. Biochemistry 53(18):2966–2978Google Scholar
  85. 85.
    Wu HC et al (2014) USP11 regulates PML stability to control Notch-induced malignancy in brain tumours. Nat Commun 5:3214Google Scholar
  86. 86.
    Lee EW et al (2015) USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics. Cell Death Differ 22(9):1463–1476Google Scholar
  87. 87.
    Zhou Z et al (2017) Regulation of XIAP turnover reveals a role for USP11 in promotion of tumorigenesis. EBioMedicine 15:48–61Google Scholar
  88. 88.
    Kapadia B et al (2018) Fatty acid synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL. Nat Commun 9(1):829Google Scholar
  89. 89.
    Wang D et al (2018) Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene expression and activate lung epithelial cells. J Mol Cell Biol 10(1):60–73Google Scholar
  90. 90.
    Zhang E et al (2016) Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4 protein. Am J Cancer Res 6(12):2901–2909Google Scholar
  91. 91.
    Deng T et al (2018) Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses. Proc Natl Acad Sci USA 115(18):4678–4683Google Scholar
  92. 92.
    Schoenfeld AR et al (2004) BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol 24(17):7444–7455Google Scholar
  93. 93.
    Wiltshire TD et al (2010) Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem 285(19):14565–14571Google Scholar
  94. 94.
    Yu M et al (2016) USP11 is a negative regulator to gammaH2AX ubiquitylation by RNF8/RNF168. J Biol Chem 291(2):959–967Google Scholar
  95. 95.
    Shah P et al (2017) Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage. Oncotarget 8(57):96522–96535Google Scholar
  96. 96.
    Yamaguchi T et al (2007) The deubiquitinating enzyme USP11 controls an IkappaB kinase alpha (IKKalpha)-p53 signaling pathway in response to tumor necrosis factor alpha (TNFalpha). J Biol Chem 282(47):33943–33948Google Scholar
  97. 97.
    Sun W et al (2010) USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal 22(3):386–394Google Scholar
  98. 98.
    Lim KH et al (2016) Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth. Oncotarget 7(12):14441–14457Google Scholar
  99. 99.
    Ideguchi H et al (2002) Structural and functional characterization of the USP11 deubiquitinating enzyme, which interacts with the RanGTP-associated protein RanBPM. Biochem J 367(Pt 1):87–95Google Scholar
  100. 100.
    Lin CH, Chang HS, Yu WC (2008) USP11 stabilizes HPV-16E7 and further modulates the E7 biological activity. J Biol Chem 283(23):15681–15688Google Scholar
  101. 101.
    Ke JY et al (2014) USP11 regulates p53 stability by deubiquitinating p53. J Zhejiang Univ Sci B 15(12):1032–1038Google Scholar
  102. 102.
    Al-Salihi MA et al (2012) USP11 augments TGFbeta signalling by deubiquitylating ALK5. Open Biol 2(6):120063Google Scholar
  103. 103.
    Jacko AM et al (2016) De-ubiquitinating enzyme, USP11, promotes transforming growth factor beta-1 signaling through stabilization of transforming growth factor beta receptor II. Cell Death Dis 7(11):e2474Google Scholar
  104. 104.
    Li J, Wang G, Sun X (2014) Transforming growth factor beta regulates beta-catenin expression in lung fibroblast through NF-kappaB dependent pathway. Int J Mol Med 34(5):1219–1224Google Scholar
  105. 105.
    Garcia DA et al (2018) USP11 enhances TGFbeta-induced epithelial-mesenchymal plasticity and human breast cancer metastasis. Mol Cancer Res 16(7):1172–1184Google Scholar
  106. 106.
    Ward SJ et al (2018) The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel. J Biol Chem [Epub ahead of print]Google Scholar
  107. 107.
    Schweitzer K et al (2007) CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J 26(6):1532–1541Google Scholar
  108. 108.
    Kawahara K et al (2000) Down-regulation of beta-catenin by the colorectal tumor suppressor APC requires association with Axin and beta-catenin. J Biol Chem 275(12):8369–8374Google Scholar
  109. 109.
    Huang X et al (2009) The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. J Mol Biol 391(4):691–702Google Scholar
  110. 110.
    Zou Q et al (2014) USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 15(6):562–570Google Scholar
  111. 111.
    Vos RM et al (2009) The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J Virol 83(17):8885–8892Google Scholar
  112. 112.
    Inui M et al (2011) USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol 13(11):1368–1375Google Scholar
  113. 113.
    Eichhorn PJ et al (2012) USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med 18(3):429–435Google Scholar
  114. 114.
    Iyengar PV et al (2015) USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. Sci Rep 5:14733Google Scholar
  115. 115.
    Liu WT et al (2017) TGF-beta upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability. Oncogene 36(19):2715–2723Google Scholar
  116. 116.
    Lam YA et al (1997) Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385(6618):737–740Google Scholar
  117. 117.
    Peth A et al (2013) Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs. J Biol Chem 288(11):7781–7790Google Scholar
  118. 118.
    Chen Y et al (2012) Expression and clinical significance of UCH37 in human esophageal squamous cell carcinoma. Dig Dis Sci 57(9):2310–2317Google Scholar
  119. 119.
    Wang L et al (2014) High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer. Tumour Biol 35(11):11427–11433Google Scholar
  120. 120.
    Zhou Z et al (2018) The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating smoothened. J Mol Cell Biol 10(3):243–257Google Scholar
  121. 121.
    Mahanic CS et al (2015) Regulation of E2 promoter binding factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37. J Biol Chem 290(44):26508–26522Google Scholar
  122. 122.
    Randles L et al (2016) The proteasome ubiquitin receptor hRpn13 and its interacting deubiquitinating enzyme Uch37 are required for proper cell cycle progression. J Biol Chem 291(16):8773–8783Google Scholar
  123. 123.
    Wicks SJ et al (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene 24(54):8080–8084Google Scholar
  124. 124.
    Cutts AJ et al (2011) Early phase TGFbeta receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses. Int J Biochem Cell Biol 43(4):604–612Google Scholar
  125. 125.
    Edelmann MJ et al (2009) Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J 418(2):379–390Google Scholar
  126. 126.
    Zhou Y et al (2014) OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer. Mol Cancer 13:258Google Scholar
  127. 127.
    Iglesias-Gato D et al (2015) OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. Mol Cancer 14:8Google Scholar
  128. 128.
    Iglesias-Gato D et al (2015) Erratum: OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. Mol Cancer 14:88Google Scholar
  129. 129.
    Wang Y et al (2016) OTUB1-catalyzed deubiquitination of FOXM1 facilitates tumor progression and predicts a poor prognosis in ovarian cancer. Oncotarget 7(24):36681–36697Google Scholar
  130. 130.
    Wang YQ et al (2016) Upregulation of the non-coding RNA OTUB1-isoform 2 contributes to gastric cancer cell proliferation and invasion and predicts poor gastric cancer prognosis. Int J Biol Sci 12(5):545–557Google Scholar
  131. 131.
    Weng W et al (2016) OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma. Am J Transl Res 8(5):2234–2244Google Scholar
  132. 132.
    Ni Q et al (2017) Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion. Acta Biochim Biophys Sin (Shanghai) 49(8):680–688Google Scholar
  133. 133.
    Zhou H et al (2018) OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability. Oncogene 37(25):3356–3368Google Scholar
  134. 134.
    Karunarathna U et al (2016) OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance. Oncogene 35(11):1433–1444Google Scholar
  135. 135.
    Li S et al (2010) Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J Biol Chem 285(7):4291–4297Google Scholar
  136. 136.
    Zhao L et al (2018) OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR. J Biol Chem 293(13):4883–4892Google Scholar
  137. 137.
    Li Y et al (2014) Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. J Biol Chem 289(8):5097–5108Google Scholar
  138. 138.
    Goncharov T et al (2013) OTUB1 modulates c-IAP1 stability to regulate signalling pathways. EMBO J 32(8):1103–1114Google Scholar
  139. 139.
    Blackford AN, Stewart GS (2011) When cleavage is not attractive: non-catalytic inhibition of ubiquitin chains at DNA double-strand breaks by OTUB1. DNA Repair (Amst) 10(2):245–249Google Scholar
  140. 140.
    Chen Y et al (2017) Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget 8(7):11053–11062Google Scholar
  141. 141.
    Herhaus L et al (2013) OTUB1 enhances TGFbeta signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat Commun 4:2519Google Scholar
  142. 142.
    Sato Y et al (2008) Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455(7211):358–362Google Scholar
  143. 143.
    Davies CW et al (2011) Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability. J Mol Biol 413(2):416–429Google Scholar
  144. 144.
    Ibarrola N et al (2004) Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor beta signaling. BMC Cell Biol 5:2Google Scholar
  145. 145.
    Fan YH et al (2011) USP4 targets TAK1 to downregulate TNFalpha-induced NF-kappaB activation. Cell Death Differ 18(10):1547–1560Google Scholar
  146. 146.
    Wang PJ et al (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27(4):422–426Google Scholar
  147. 147.
    Ribarski I et al (2009) USP26 gene variations in fertile and infertile men. Hum Reprod 24(2):477–484Google Scholar
  148. 148.
    Ma Q et al (2016) A novel missense mutation in USP26 gene is associated with nonobstructive azoospermia. Reprod Sci 23(10):1434–1441Google Scholar
  149. 149.
    Dirac AM, Bernards R (2010) The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Mol Cancer Res 8(6):844–854Google Scholar
  150. 150.
    Zhang W et al (2015) Evidence from enzymatic and meta-analyses does not support a direct association between USP26 gene variants and male infertility. Andrology 3(2):271–279Google Scholar
  151. 151.
    Typas D et al (2015) The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic Acids Res 43(14):6919–6933Google Scholar
  152. 152.
    Ning B et al (2017) USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components. Nat Commun 8(1):349Google Scholar
  153. 153.
    Lahav-Baratz S et al (2017) The testis-specific USP26 is a deubiquitinating enzyme of the ubiquitin ligase Mdm2. Biochem Biophys Res Commun 482(1):106–111Google Scholar
  154. 154.
    Kit Leng Lui S et al (2017) USP26 regulates TGF-beta signaling by deubiquitinating and stabilizing SMAD7. EMBO Rep 18(5):797–808Google Scholar
  155. 155.
    Komander D et al (2008) The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 29(4):451–464Google Scholar
  156. 156.
    Brummelkamp TR et al (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424(6950):797–801Google Scholar
  157. 157.
    Kovalenko A et al (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424(6950):801–805Google Scholar
  158. 158.
    Trompouki E et al (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424(6950):793–796Google Scholar
  159. 159.
    Yoshida H et al (2005) The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem 280(49):41111–41121Google Scholar
  160. 160.
    Lim JH et al (2007) Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity 27(2):349–360Google Scholar
  161. 161.
    Chen W et al (2003) Conversion of peripheral CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886Google Scholar
  162. 162.
    Zhao Y et al (2011) The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor beta (TGF-beta) signaling and the development of regulatory T cells. J Biol Chem 286(47):40520–40530Google Scholar
  163. 163.
    Komander D, Barford D (2008) Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochem J 409(1):77–85Google Scholar
  164. 164.
    Shembade N, Harhaj E (2010) A20 inhibition of NFkappaB and inflammation: targeting E2:E3 ubiquitin enzyme complexes. Cell Cycle 9(13):2481–2482Google Scholar
  165. 165.
    De Valck D et al (1999) The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases. Oncogene 18(29):4182–4190Google Scholar
  166. 166.
    Daniel S et al (2004) A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood 104(8):2376–2384Google Scholar
  167. 167.
    Hovelmeyer N et al (2011) A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur J Immunol 41(3):595–601Google Scholar
  168. 168.
    Chu Y et al (2011) B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117(7):2227–2236Google Scholar
  169. 169.
    Shi CS, Kehrl JH (2010) TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci Signal 3(123):ra42Google Scholar
  170. 170.
    Inomata M et al (2012) Regulation of toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20. Cell Mol Life Sci 69(6):963–979Google Scholar
  171. 171.
    Jung SM et al (2013) Smad6 inhibits non-canonical TGF-beta1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nat Commun 4:2562Google Scholar
  172. 172.
    Iyengar PV (2017) Regulation of ubiquitin enzymes in the TGF-beta pathway. Int J Mol Sci 18(4):877Google Scholar
  173. 173.
    Davis MI et al (2016) Small molecule inhibition of the ubiquitin-specific protease USP2 accelerates cyclin D1 degradation and leads to cell cycle arrest in colorectal cancer and mantle cell lymphoma models. J Biol Chem 291(47):24628–24640Google Scholar
  174. 174.
    Burkhart RA et al (2013) Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. Mol Cancer Res 11(8):901–911Google Scholar
  175. 175.
    Ernst A et al (2013) A strategy for modulation of enzymes in the ubiquitin system. Science 339(6119):590–595Google Scholar
  176. 176.
    Tomala MD et al (2018) Identification of small-molecule inhibitors of USP2a. Eur J Med Chem 150:261–267Google Scholar
  177. 177.
    Ndubaku C, Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58(4):1581–1595Google Scholar
  178. 178.
    Kang JS et al (2008) The type I TGF-beta receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10(6):654–664Google Scholar
  179. 179.
    Lee PS et al (2003) Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling. J Biol Chem 278(30):27853–27863Google Scholar
  180. 180.
    Inoue Y, Imamura T (2008) Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci 99(11):2107–2112Google Scholar
  181. 181.
    Zhang Y et al (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98(3):974–979Google Scholar
  182. 182.
    Lin X, Liang M, Feng XH (2000) Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 275(47):36818–36822Google Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Biomedical ScienceCHA UniversitySeongnamRepublic of Korea

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