Skip to main content

Advertisement

SpringerLink
Log in

TGF-β signaling pathway mediated by deubiquitinating enzymes

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wilkinson KD (2000) Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Semin Cell Dev Biol 11(3):141–148

    Article  CAS  PubMed  Google Scholar 

  2. Swatek KN, Komander D (2016) Ubiquitin modifications. Cell Res 26(4):399–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McDowell GS, Philpott A (2013) Non-canonical ubiquitylation: mechanisms and consequences. Int J Biochem Cell Biol 45(8):1833–1842

    Article  CAS  PubMed  Google Scholar 

  4. Grumati P, Dikic I (2018) Ubiquitin signaling and autophagy. J Biol Chem 293(15):5404–5413

    Article  CAS  PubMed  Google Scholar 

  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):493–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mevissen TET, Komander D (2017) Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 86:159–192

    Article  CAS  PubMed  Google Scholar 

  7. Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397

    Article  CAS  PubMed  Google Scholar 

  8. Lim KH, Song MH, Baek KH (2016) Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint. Cell Mol Life Sci 73(7):1439–1455

    Article  CAS  PubMed  Google Scholar 

  9. He M et al (2017) Emerging role of DUBs in tumor metastasis and apoptosis: therapeutic implication. Pharmacol Ther 177:96–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 11:250

    Article  CAS  Google Scholar 

  11. Kim SY et al (2018) PME-1 is regulated by USP36 in ERK and Akt signaling pathways. FEBS Lett 592(9):1575–1588

    Article  CAS  PubMed  Google Scholar 

  12. Kee Y, Huang TT (2016) Role of deubiquitinating enzymes in DNA repair. Mol Cell Biol 36(4):524–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nijman SM et al (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5):773–786

    Article  CAS  PubMed  Google Scholar 

  14. Luise C et al (2011) An atlas of altered expression of deubiquitinating enzymes in human cancer. PLoS One 6(1):e15891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1041–1054

    Article  CAS  PubMed  Google Scholar 

  16. Johnston SC et al (1999) Structural basis for the specificity of ubiquitin C-terminal hydrolases. EMBO J 18(14):3877–3887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10(8):550–563

    Article  CAS  PubMed  Google Scholar 

  18. Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695(1–3):189–207

    Article  CAS  PubMed  Google Scholar 

  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):12700–12705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):10493–10498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Iyer LM, Koonin EV, Aravind L (2004) Novel predicted peptidases with a potential role in the ubiquitin signaling pathway. Cell Cycle 3(11):1440–1450

    Article  CAS  PubMed  Google Scholar 

  22. Imamura T, Oshima Y, Hikita A (2013) Regulation of TGF-beta family signalling by ubiquitination and deubiquitination. J Biochem 154(6):481–489

    Article  CAS  PubMed  Google Scholar 

  23. Zhang J et al (2014) The regulation of TGF-beta/SMAD signaling by protein deubiquitination. Protein Cell 5(7):503–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fraile JM et al (2012) Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31(19):2373–2388

    Article  CAS  PubMed  Google Scholar 

  25. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584

    Article  CAS  PubMed  Google Scholar 

  26. Weiss A, Attisano L (2013) The TGFbeta superfamily signaling pathway. Wiley Interdiscip Rev Dev Biol 2(1):47–63

    Article  CAS  PubMed  Google Scholar 

  27. Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8(12):970–982

    Article  CAS  PubMed  Google Scholar 

  28. Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19(1):128–139

    Article  CAS  PubMed  Google Scholar 

  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):366–372

    Article  CAS  PubMed  Google Scholar 

  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):358–365

    Article  CAS  PubMed  Google Scholar 

  31. Yamashita M et al (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 31(6):918–924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ozdamar B et al (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307(5715):1603–1609

    Article  CAS  PubMed  Google Scholar 

  33. Xu P, Liu J, Derynck R (2012) Post-translational regulation of TGF-beta receptor and Smad signaling. FEBS Lett 586(14):1871–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang RN et al (2014) Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 1(1):87–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stevenson LF et al (2007) The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J 26(4):976–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Allende-Vega N et al (2010) MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 29(3):432–441

    Article  CAS  PubMed  Google Scholar 

  37. Shan J, Zhao W, Gu W (2009) Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell 36(3):469–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shi Y et al (2011) Ubiquitin-specific cysteine protease 2a (USP2a) regulates the stability of aurora-A. J Biol Chem 286(45):38960–38968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):25280–25291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mahul-Mellier AL et al (2012) De-ubiquitinating proteases USP2a and USP2c cause apoptosis by stabilising RIP1. Biochim Biophys Acta 1823(8):1353–1365

    Article  CAS  PubMed  Google Scholar 

  41. Li Y et al (2013) USP2a positively regulates TCR-induced NF-kappaB activation by bridging MALT1-TRAF6. Protein Cell 4(1):62–70

    Article  CAS  PubMed  Google Scholar 

  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):39–47

    Article  CAS  PubMed  Google Scholar 

  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):1123–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tao BB et al (2013) Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade. J Clin Neurosci 20(5):717–720

    Article  CAS  PubMed  Google Scholar 

  45. Graner E et al (2004) The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5(3):253–261

    Article  CAS  PubMed  Google Scholar 

  46. Zhao Y et al (2018) USP2a supports metastasis by tuning TGF-beta signaling. Cell Rep 22(9):2442–2454

    Article  CAS  PubMed  Google Scholar 

  47. Clerici M et al (2014) The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange. Nat Commun 5:5399

    Article  PubMed  Google Scholar 

  48. Li Z et al (2016) USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2. Oncogene 35(22):2902–2912

    Article  CAS  PubMed  Google Scholar 

  49. Zhang X et al (2011) USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO J 30(11):2177–2189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu H et al (2015) The deubiquitylating enzyme USP4 cooperates with CtIP in DNA double-strand break end resection. Cell Rep 13(1):93–107

    Article  CAS  PubMed  Google Scholar 

  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):311–316

    Article  CAS  PubMed  Google Scholar 

  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):979–986

    Article  CAS  PubMed  Google Scholar 

  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):1886–1895

    Article  PubMed  Google Scholar 

  54. Kwon SK, Kim EH, Baek KH (2017) RNPS1 is modulated by ubiquitin-specific protease 4. FEBS Lett 591(2):369–381

    Article  CAS  PubMed  Google Scholar 

  55. Park JK et al (2016) Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3. Nucleic Acids Res 44(11):5424–5437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Song EJ et al (2010) The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev 24(13):1434–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1677–1686

    Article  CAS  PubMed  Google Scholar 

  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):717–726

    Article  CAS  PubMed  Google Scholar 

  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):1365–1375

    Article  CAS  PubMed  Google Scholar 

  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):1115–1122

    PubMed  Google Scholar 

  61. Xu Y, Yu Q, Liu Y (2018) Serum relaxin-2 as a novel biomarker for prostate cancer. Br J Biomed Sci 75(3):145–148

    Article  CAS  PubMed  Google Scholar 

  62. Ma J et al (2013) Role of relaxin-2 in human primary osteosarcoma. Cancer Cell Int 13(1):59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):2736–2749

    Article  PubMed  PubMed Central  Google Scholar 

  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):249–260

    Article  CAS  PubMed  Google Scholar 

  65. Fischer-Vize JA, Rubin GM, Lehmann R (1992) The fat facets gene is required for Drosophila eye and embryo development. Development 116(4):985–1000

    CAS  PubMed  Google Scholar 

  66. Schwickart M et al (2010) Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463(7277):103–107

    Article  CAS  PubMed  Google Scholar 

  67. Vong QP et al (2005) Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310(5753):1499–1504

    Article  CAS  PubMed  Google Scholar 

  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):851–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):805–818

    Article  CAS  PubMed  Google Scholar 

  70. Huntwork-Rodriguez S et al (2013) JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. J Cell Biol 202(5):747–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Theard D et al (2010) USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly. EMBO J 29(9):1499–1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Taya S et al (1998) The Ras target AF-6 is a substrate of the fam deubiquitinating enzyme. J Cell Biol 142(4):1053–1062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):38738–38747

    Article  CAS  PubMed  Google Scholar 

  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):1591–1599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Marx C et al (2010) ErbB2 trafficking and degradation associated with K48 and K63 polyubiquitination. Cancer Res 70(9):3709–3717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Murtaza M et al (2015) La FAM fatale: USP9X in development and disease. Cell Mol Life Sci 72(11):2075–2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Dupont S et al (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 136(1):123–135

    Article  CAS  PubMed  Google Scholar 

  78. Xie F et al (2014) Regulation of TGF-beta superfamily signaling by SMAD mono-ubiquitination. Cells 3(4):981–993

    Article  PubMed  PubMed Central  Google Scholar 

  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):1383–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kinlaw WB et al (2016) Fatty acids and breast cancer: make them on site or have them delivered. J Cell Physiol 231(10):2128–2141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Boden G (2011) Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 18(2):139–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):2976–2985

    Article  CAS  PubMed  Google Scholar 

  83. Stegeman S et al (2013) Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFbeta-mediated axonogenesis. PLoS One 8(7):e68287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Harper S et al (2014) Structure and catalytic regulatory function of ubiquitin specific protease 11N-terminal and ubiquitin-like domains. Biochemistry 53(18):2966–2978

    Article  CAS  PubMed  Google Scholar 

  85. Wu HC et al (2014) USP11 regulates PML stability to control Notch-induced malignancy in brain tumours. Nat Commun 5:3214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lee EW et al (2015) USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics. Cell Death Differ 22(9):1463–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhou Z et al (2017) Regulation of XIAP turnover reveals a role for USP11 in promotion of tumorigenesis. EBioMedicine 15:48–61

    Article  PubMed  Google Scholar 

  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):829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):60–73

    Article  CAS  PubMed  Google Scholar 

  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):2901–2909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):4678–4683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):7444–7455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):14565–14571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yu M et al (2016) USP11 is a negative regulator to gammaH2AX ubiquitylation by RNF8/RNF168. J Biol Chem 291(2):959–967

    Article  CAS  PubMed  Google Scholar 

  95. Shah P et al (2017) Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage. Oncotarget 8(57):96522–96535

    Article  PubMed  PubMed Central  Google Scholar 

  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):33943–33948

    Article  CAS  PubMed  Google Scholar 

  97. Sun W et al (2010) USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal 22(3):386–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):14441–14457

    Article  PubMed  PubMed Central  Google Scholar 

  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):87–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lin CH, Chang HS, Yu WC (2008) USP11 stabilizes HPV-16E7 and further modulates the E7 biological activity. J Biol Chem 283(23):15681–15688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ke JY et al (2014) USP11 regulates p53 stability by deubiquitinating p53. J Zhejiang Univ Sci B 15(12):1032–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Al-Salihi MA et al (2012) USP11 augments TGFbeta signalling by deubiquitylating ALK5. Open Biol 2(6):120063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):e2474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1219–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Garcia DA et al (2018) USP11 enhances TGFbeta-induced epithelial-mesenchymal plasticity and human breast cancer metastasis. Mol Cancer Res 16(7):1172–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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]

  107. Schweitzer K et al (2007) CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J 26(6):1532–1541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):8369–8374

    Article  CAS  PubMed  Google Scholar 

  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):691–702

    Article  CAS  PubMed  Google Scholar 

  110. Zou Q et al (2014) USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 15(6):562–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vos RM et al (2009) The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J Virol 83(17):8885–8892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Inui M et al (2011) USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol 13(11):1368–1375

    Article  CAS  PubMed  Google Scholar 

  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):429–435

    Article  CAS  PubMed  Google Scholar 

  114. Iyengar PV et al (2015) USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. Sci Rep 5:14733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):2715–2723

    Article  CAS  PubMed  Google Scholar 

  116. Lam YA et al (1997) Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385(6618):737–740

    Article  CAS  PubMed  Google Scholar 

  117. Peth A et al (2013) Ubiquitinated proteins activate the proteasomal ATPases by binding to Usp14 or Uch37 homologs. J Biol Chem 288(11):7781–7790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen Y et al (2012) Expression and clinical significance of UCH37 in human esophageal squamous cell carcinoma. Dig Dis Sci 57(9):2310–2317

    Article  CAS  PubMed  Google Scholar 

  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):11427–11433

    Article  CAS  PubMed  Google Scholar 

  120. Zhou Z et al (2018) The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating smoothened. J Mol Cell Biol 10(3):243–257

    Article  CAS  PubMed  Google Scholar 

  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):26508–26522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):8773–8783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wicks SJ et al (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene 24(54):8080–8084

    Article  CAS  PubMed  Google Scholar 

  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):604–612

    Article  CAS  PubMed  Google Scholar 

  125. Edelmann MJ et al (2009) Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J 418(2):379–390

    Article  CAS  PubMed  Google Scholar 

  126. Zhou Y et al (2014) OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer. Mol Cancer 13:258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Iglesias-Gato D et al (2015) OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. Mol Cancer 14:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 14:88

    Article  PubMed  PubMed Central  Google Scholar 

  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):36681–36697

    PubMed  PubMed Central  Google Scholar 

  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):545–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Weng W et al (2016) OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma. Am J Transl Res 8(5):2234–2244

    CAS  PubMed  PubMed Central  Google Scholar 

  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):680–688

    Article  CAS  Google Scholar 

  133. Zhou H et al (2018) OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability. Oncogene 37(25):3356–3368

    Article  CAS  PubMed  Google Scholar 

  134. Karunarathna U et al (2016) OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance. Oncogene 35(11):1433–1444

    Article  CAS  PubMed  Google Scholar 

  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):4291–4297

    Article  CAS  PubMed  Google Scholar 

  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):4883–4892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):5097–5108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Goncharov T et al (2013) OTUB1 modulates c-IAP1 stability to regulate signalling pathways. EMBO J 32(8):1103–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):245–249

    Article  CAS  Google Scholar 

  140. Chen Y et al (2017) Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget 8(7):11053–11062

    PubMed  Google Scholar 

  141. Herhaus L et al (2013) OTUB1 enhances TGFbeta signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat Commun 4:2519

    Article  CAS  PubMed  Google Scholar 

  142. Sato Y et al (2008) Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455(7211):358–362

    Article  CAS  PubMed  Google Scholar 

  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):416–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ibarrola N et al (2004) Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor beta signaling. BMC Cell Biol 5:2

    Article  PubMed  PubMed Central  Google Scholar 

  145. Fan YH et al (2011) USP4 targets TAK1 to downregulate TNFalpha-induced NF-kappaB activation. Cell Death Differ 18(10):1547–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang PJ et al (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27(4):422–426

    Article  CAS  PubMed  Google Scholar 

  147. Ribarski I et al (2009) USP26 gene variations in fertile and infertile men. Hum Reprod 24(2):477–484

    Article  CAS  PubMed  Google Scholar 

  148. Ma Q et al (2016) A novel missense mutation in USP26 gene is associated with nonobstructive azoospermia. Reprod Sci 23(10):1434–1441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dirac AM, Bernards R (2010) The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Mol Cancer Res 8(6):844–854

    Article  CAS  PubMed  Google Scholar 

  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):271–279

    Article  CAS  PubMed  Google Scholar 

  151. Typas D et al (2015) The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. Nucleic Acids Res 43(14):6919–6933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ning B et al (2017) USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components. Nat Commun 8(1):349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):106–111

    Article  CAS  PubMed  Google Scholar 

  154. Kit Leng Lui S et al (2017) USP26 regulates TGF-beta signaling by deubiquitinating and stabilizing SMAD7. EMBO Rep 18(5):797–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):451–464

    Article  CAS  PubMed  Google Scholar 

  156. Brummelkamp TR et al (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424(6950):797–801

    Article  CAS  PubMed  Google Scholar 

  157. Kovalenko A et al (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424(6950):801–805

    Article  CAS  PubMed  Google Scholar 

  158. Trompouki E et al (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424(6950):793–796

    Article  CAS  PubMed  Google Scholar 

  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):41111–41121

    Article  CAS  PubMed  Google Scholar 

  160. Lim JH et al (2007) Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity 27(2):349–360

    Article  CAS  PubMed  Google Scholar 

  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):1875–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):40520–40530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Komander D, Barford D (2008) Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochem J 409(1):77–85

    Article  CAS  PubMed  Google Scholar 

  164. Shembade N, Harhaj E (2010) A20 inhibition of NFkappaB and inflammation: targeting E2:E3 ubiquitin enzyme complexes. Cell Cycle 9(13):2481–2482

    Article  CAS  PubMed  Google Scholar 

  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):4182–4190

    Article  CAS  PubMed  Google Scholar 

  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):2376–2384

    Article  CAS  PubMed  Google Scholar 

  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):595–601

    Article  CAS  PubMed  Google Scholar 

  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):2227–2236

    Article  CAS  PubMed  Google Scholar 

  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):ra42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):963–979

    Article  CAS  PubMed  Google Scholar 

  171. Jung SM et al (2013) Smad6 inhibits non-canonical TGF-beta1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nat Commun 4:2562

    Article  CAS  PubMed  Google Scholar 

  172. Iyengar PV (2017) Regulation of ubiquitin enzymes in the TGF-beta pathway. Int J Mol Sci 18(4):877

    Article  CAS  PubMed Central  Google Scholar 

  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):24628–24640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):901–911

    Article  CAS  PubMed  Google Scholar 

  175. Ernst A et al (2013) A strategy for modulation of enzymes in the ubiquitin system. Science 339(6119):590–595

    Article  CAS  PubMed  Google Scholar 

  176. Tomala MD et al (2018) Identification of small-molecule inhibitors of USP2a. Eur J Med Chem 150:261–267

    Article  CAS  PubMed  Google Scholar 

  177. Ndubaku C, Tsui V (2015) Inhibiting the deubiquitinating enzymes (DUBs). J Med Chem 58(4):1581–1595

    Article  CAS  PubMed  Google Scholar 

  178. Kang JS et al (2008) The type I TGF-beta receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10(6):654–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):27853–27863

    Article  CAS  PubMed  Google Scholar 

  180. Inoue Y, Imamura T (2008) Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci 99(11):2107–2112

    Article  CAS  PubMed  Google Scholar 

  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):974–979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):36818–36822

    Article  CAS  PubMed  Google Scholar 

Download references

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 information

Authors and Affiliations

  1. Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam, Gyeonggi, 13488, Republic of Korea

    Soo-Yeon Kim & Kwang-Hyun Baek

Authors
  1. Soo-Yeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kwang-Hyun Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Kwang-Hyun Baek.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, SY., Baek, KH. TGF-β signaling pathway mediated by deubiquitinating enzymes. Cell. Mol. Life Sci. 76, 653–665 (2019). https://doi.org/10.1007/s00018-018-2949-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2949-y

Keywords

Search

Navigation