NEDD4 Family of E3 Ubiquitin Ligases in Breast Cancer: Spotlight on SMURFs, WWPs and NEDD4

  • Ghazala Butt
  • Ilhan Yaylim
  • Rukset Attar
  • Aliye Aras
  • Mirna Azalea Romero
  • Muhammad Zahid Qureshi
  • Jelena Purenovic
  • Ammad Ahmad FarooqiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1152)


Massively parallel sequencing, genomic and proteomic technologies have provided near complete resolution of signaling landscape of breast cancer (BCa). NEDD4 family of E3-ubiquitin ligases comprises a large family of proteins particularly, SMURFs (SMURF1, SMURF2), WWPs and NEDD4 which are ideal candidates for targeted therapy. However, it is becoming progressively more understandable that SMURFs and NEDD4 have “split-personalities”. These molecules behave dualistically in breast cancer and future studies must converge on detailed identification of context specific role of these proteins in BCa. Finally, we provide scattered clues of regulation of SMURF2 by oncogenic miRNAs, specifically considering longstanding questions related to regulation of SMURF1 and WWPs by miRNAs in BCa. SMURFS, WWPs and NEDD4 are versatile regulators and represent a fast-growing field in cancer research and better understanding of the underlying mechanisms will be helpful in transition of our knowledge from a segmented view to a more conceptual continuum.


SMURF1 NEDD4 Cancer Apoptosis Signaling 


  1. 1.
    Kumar S, Tomooka Y, Noda M (1992) Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem Biophys Res Commun 185(3):1155–1161PubMedGoogle Scholar
  2. 2.
    Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10(6):398–409. Scholar
  3. 3.
    Yang B, Kumar S (2010) Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ 17(1):68–77. Scholar
  4. 4.
    Yu L, Liu X, Cui K, Di Y, Xin L, Sun X, Zhang W, Yang X, Wei M, Yao Z, Yang J (2015) SND1 acts downstream of TGFβ1 and upstream of Smurf1 to promote breast cancer metastasis. Cancer Res 75(7):1275–1286. Scholar
  5. 5.
    Hodge RG, Ridley AJ (2016) Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol 17(8):496–510. Scholar
  6. 6.
    Wong JS, Iorns E, Rheault MN, Ward TM, Rashmi P, Weber U, Lippman ME, Faul C, Mlodzik M, Mundel P (2012) Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin α in RhoA stabilization. EMBO J 31(4):1028–1040. Scholar
  7. 7.
    Xie Y, Avello M, Schirle M, McWhinnie E, Feng Y, Bric-Furlong E, Wilson C, Nathans R, Zhang J, Kirschner MW, Huang SM, Cong F (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. Scholar
  8. 8.
    Li H, Xiao N, Wang Y, Wang R, Chen Y, Pan W, Liu D, Li S, Sun J, Zhang K, Sun Y, Ge X (2017) Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKIγ. Oncogene 36(41):5668–5680. Scholar
  9. 9.
    Li Q, Li Z, Wei S, Wang W, Chen Z, Zhang L, Chen L, Li B, Sun G, Xu J, Li Q, Wang L, Xu Z, Xia Y, Zhang D, Xu H, Xu Z (2017) Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer. J Exp Clin Cancer Res 36(1):59. Scholar
  10. 10.
    Chandhoke AS, Chanda A, Karve K, Deng L, Bonni S (2017) The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness. Oncotarget 8(13):21001–21014. Scholar
  11. 11.
    Lu KT, Wang BY, Chi WY, Chang-Chien J, Yang JJ, Lee HT, Tzeng YM, Chang WW (2016) Ovatodiolide inhibits breast cancer stem/progenitor cells through SMURF2-mediated downregulation of Hsp27. Toxins (Basel) 8(5):E127. Scholar
  12. 12.
    Tsao SM, Hsu HY (2016) Fucose-containing fraction of Ling-Zhi enhances lipid rafts-dependent ubiquitination of TGFβ receptor degradation and attenuates breast cancer tumorigenesis. Sci Rep 6:36563. Scholar
  13. 13.
    David D, Surendran A, Thulaseedharan JV, Nair AS (2018) Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression. BMC Cancer 18(1):284. Scholar
  14. 14.
    Fukunaga E, Inoue Y, Komiya S, Horiguchi K, Goto K, Saitoh M, Miyazawa K, Koinuma D, Hanyu A, Imamura T (2008) Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J Biol Chem 283(51):35660–35667. Scholar
  15. 15.
    Liu X, Gu X, Sun L, Flowers AB, Rademaker AW, Zhou Y, Kiyokawa H (2014) Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: involvement of the RB-microRNA axis. BMC Cancer 14:57. Scholar
  16. 16.
    Li Y, Li W, Ying Z, Tian H, Zhu X, Li J, Li M (2014) Metastatic heterogeneity of breast cancer cells is associated with expression of a heterogeneous TGFβ-activating miR424-503 gene cluster. Cancer Res 74(21):6107–6118. Scholar
  17. 17.
    Wang W, Ren F, Wu Q, Jiang D, Li H, Peng Z, Wang J, Shi H (2014) MicroRNA-497 inhibition of ovarian cancer cell migration and invasion through targeting of SMAD specific E3 ubiquitin protein ligase 1. Biochem Biophys Res Commun 449(4):432–437. Scholar
  18. 18.
    Liu L, Zheng W, Song Y, Du X, Tang Y, Nie J, Han W (2015) miRNA-497 enhances the sensitivity of colorectal cancer cells to neoadjuvant chemotherapeutic drug. Curr Protein Pept Sci 16(4):310–315PubMedGoogle Scholar
  19. 19.
    Ma M, Yang J, Wang B, Zhao Z, Xi JJ (2017) High-throughput identification of miR-596 inducing p53-mediated apoptosis in HeLa and HCT116 cells using cell microarray. SLAS Technol 22(6):636–645. Scholar
  20. 20.
    Subik K, Shu L, Wu C, Liang Q, Hicks D, Boyce B, Schiffhauer L, Chen D, Chen C, Tang P, Xing L (2012) The ubiquitin E3 ligase WWP1 decreases CXCL12-mediated MDA231 breast cancer cell migration and bone metastasis. Bone 50(4):813–823. Scholar
  21. 21.
    Li Y, Zhou Z, Alimandi M, Chen C (2009) WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer. Oncogene 28(33):2948–2958. Scholar
  22. 22.
    Sahu A, Patra PK, Yadav MK, Varma M (2017) Identification and characterization of ErbB4 kinase inhibitors for effective breast cancer therapy. J Recept Signal Transduct Res 37(5):470–480. Scholar
  23. 23.
    Yeung B, Ho KC, Yang X (2013) WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells. PLoS One 8(4):e61027. Scholar
  24. 24.
    Ge F, Chen W, Qin J, Zhou Z, Liu R, Liu L, Tan J, Zou T, Li H, Ren G, Chen C (2015) Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5). Oncotarget 6(25):21369–21378PubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen C, Zhou Z, Liu R, Li Y, Azmi PB, Seth AK (2008) The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11. Oncogene 27(54):6845–6855. Scholar
  26. 26.
    Zhou Z, Liu R, Chen C (2012) The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer. Int J Cancer 130(7):1504–1510. Scholar
  27. 27.
    Chen J, Shi H, Chen Y, Fan S, Liu D (2017) Li C. DNA damage induces expression of WWP1 to target ΔNp63α to degradation. PLoS One 12(4):e0176142. Scholar
  28. 28.
    Lønne GK, Masoumi KC, Lennartsson J, Larsson C (2009) Protein kinase Cdelta supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway. J Biol Chem 284(48):33456–33465. Scholar
  29. 29.
    Verma N, Müller AK, Kothari C, Panayotopoulou E, Kedan A, Selitrennik M, Mills GB, Nguyen LK, Shin S, Karn T, Holtrich U, Lev S (2017) Targeting of PYK2 synergizes with EGFR antagonists in basal-like TNBC and circumvents HER3-associated resistance via the NEDD4-NDRG1 Axis. Cancer Res 77(1):86–99. Scholar
  30. 30.
    Tsai CF, Cheng YK, Lu DY, Wang SL, Chang CN, Chang PC, Yeh WL (2018) Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol 338:182–190. Scholar
  31. 31.
    Jung S, Li C, Jeong D, Lee S, Ohk J, Park M, Han S, Duan J, Kim C, Yang Y, Kim KI, Lim JS, Kang YS, Lee MS (2013) Oncogenic function of p34SEI-1 via NEDD4-1-mediated PTEN ubiquitination/degradation and activation of the PI3K/AKT pathway. Int J Oncol 43(5):1587–1595. Scholar
  32. 32.
    Yim EK, Peng G, Dai H, Hu R, Li K, Lu Y, Mills GB, Meric-Bernstam F, Hennessy BT, Craven RJ, Lin SY (2009) Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell 15(4):304–314. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ghazala Butt
    • 1
  • Ilhan Yaylim
    • 2
  • Rukset Attar
    • 3
  • Aliye Aras
    • 4
  • Mirna Azalea Romero
    • 5
  • Muhammad Zahid Qureshi
    • 6
  • Jelena Purenovic
    • 7
  • Ammad Ahmad Farooqi
    • 8
    Email author
  1. 1.Department of BotanyGCULahorePakistan
  2. 2.Department of Molecular Medicine, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
  3. 3.Department of Obstetrics and GynecologyYeditepe University Hospital IstanbulIstanbulTurkey
  4. 4.Department of Botany, Faculty of ScienceIstanbul UniversityIstanbulTurkey
  5. 5.Facultad de Medicina, Laboratorio de Investigación ClínicaUniversidad Autónoma de GuerreroAcapulcoMexico
  6. 6.Department of ChemistryGCULahorePakistan
  7. 7.Faculty of Technical SciencesCacak University of KragujevacCacakSerbia
  8. 8.Institute of Biomedical and Genetic Engineering (IBGE)IslamabadPakistan

Personalised recommendations