Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NEDD4–2

  • Tanya Lynn Henshall
  • Sharad Kumar
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101704

Synonyms

Historical Background

NEDD4–2 (neural precursor cell expressed, developmentally downregulated 4-like) encoded by the Nedd4L gene, belongs to the NEDD4 family of ubiquitin protein ligases. NEDD4 family members are HECT-type ubiquitin ligases (E3) that act at the final step of the ubiquitin cascade to accept ubiquitin from a ubiquitin-conjugating enzyme (E2) and transfer it to their cognate substrates. Ubiquitination of a protein often targets it for degradation; however it may also affect protein localization, trafficking, and recognition by signaling or regulatory complexes. The other members of the NEDD4 family include NEDD4, ITCH, SMURF1, SMURF2, WWP1, WWP2, NEDL1, and NEDL2 (Rotin and Kumar 2009).

NEDD4–2 (originally submitted in the database as mouse KIAA0439 or human NEDD4Lgene) is most closely related to the founding member, NEDD4, which was originally identified in the early embryonic central nervous system as a developmentally...

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References

  1. Araki N, Umemura M, Miyagi Y, Yabana M, Miki Y, Tamura K, et al. Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension. Hypertension. 2008;51(3):773–7.CrossRefPubMedGoogle Scholar
  2. Arevalo JC, Waite J, Rajagopal R, Beyna M, Chen ZY, Lee FS, et al. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron. 2006;50(4):549–59.CrossRefPubMedGoogle Scholar
  3. Bhalla V, Daidie D, Li H, Pao AC, LaGrange LP, Wang J, et al. Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3. Mol Endocrinol. 2005;19(12):3073–84.CrossRefPubMedGoogle Scholar
  4. Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, et al. Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nat Commun. 2011;2:287.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D. Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain. Biochem J. 2008;415(1):155–63.CrossRefPubMedGoogle Scholar
  6. Cachemaille M, Laedermann CJ, Pertin M, Abriel H, Gosselin RD, Decosterd I. Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain. Neuroscience. 2012;227:370–80.CrossRefPubMedGoogle Scholar
  7. de Groot T, Trimpert C, Wesche D, Wong V, van den Berg D, Stagljar I, et al. NDFIP1: the missing adaptor for aquaporin-2 regulation by NEDD4 and NEDD4L (LB723). FASEB J 2014;28(1):LB723.Google Scholar
  8. Ekberg JA, Boase NA, Rychkov G, Manning J, Poronnik P, Kumar S. Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons. Biochem J. 2014;457(1):27–31.CrossRefPubMedGoogle Scholar
  9. Foot N, Henshall T, Kumar S. Ubiquitination and the regulation of membrane proteins. Physiol Rev. 2017;97(1):253–81.PubMedCrossRefGoogle Scholar
  10. Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang B, et al. Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood. 2008;112(10):4268–75.CrossRefPubMedGoogle Scholar
  11. Fotia AB, Dinudom A, Shearwin KE, Koch JP, Korbmacher C, Cook DI, et al. The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB J. 2003;17(1):70–2.CrossRefPubMedGoogle Scholar
  12. Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, Kumar S. Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J Biol Chem. 2004;279(28):28930–5.CrossRefPubMedGoogle Scholar
  13. Goel P, Manning JA, Kumar S. NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. Gene. 2015;557(1):1–10.CrossRefPubMedGoogle Scholar
  14. Harvey KF, Dinudom A, Cook DI, Kumar S. The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J Biol Chem. 2001;276(11):8597–601.CrossRefPubMedGoogle Scholar
  15. Harvey KF, Kumar S. Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions. Trends Cell Biol. 1999;9(5):166–9.CrossRefPubMedGoogle Scholar
  16. Harvey KF, Shearwin-Whyatt LM, Fotia A, Parton RG, Kumar S. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J Biol Chem. 2002;277(11):9307–17.CrossRefPubMedGoogle Scholar
  17. Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, et al. Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci USA. 2009;106(36):15489–94.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Itani OA, Campbell JR, Herrero J, Snyder PM, Thomas CP. Alternate promoters and variable splicing lead to hNedd4-2 isoforms with a C2 domain and varying number of WW domains. Am J Physiol Renal Physiol. 2003;285(5):F916–29.CrossRefPubMedGoogle Scholar
  19. Itani OA, Stokes JB, Thomas CP. Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. Am J Physiol Renal Physiol. 2005;289(2):F334–46.CrossRefPubMedGoogle Scholar
  20. Kamynina E, Debonneville C, Bens M, Vandewalle A, Staub O. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J. 2001;15(1):204–14.CrossRefPubMedGoogle Scholar
  21. Kimura T, Kawabe H, Jiang C, Zhang W, Xiang YY, Lu C, et al. Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease. Proc Natl Acad Sci U S A. 2011;108(8):3216–21.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Knight KK, Olson DR, Zhou R, Snyder PM. Liddle’s syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage. Proc Natl Acad Sci USA. 2006;103(8):2805–8.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Konstas AA, Shearwin-Whyatt LM, Fotia AB, Degger B, Riccardi D, Cook DI, et al. Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. J Biol Chem. 2002;277(33):29406–16.CrossRefPubMedGoogle Scholar
  24. Krzystanek K, Rasmussen HB, Grunnet M, Staub O, Olesen SP, Abriel H, et al. Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels. Heart Rhythm. 2012;9(3):440–8.CrossRefPubMedGoogle Scholar
  25. Kumar S, Tomooka Y, Noda M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem Biophys Res Commun. 1992;185(3):1155–61.CrossRefPubMedGoogle Scholar
  26. Laedermann CJ, Cachemaille M, Kirschmann G, Pertin M, Gosselin RD, Chang I, et al. Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain. J Clin Invest. 2013;123(7):3002–13.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Lee IH, Dinudom A, Sanchez-Perez A, Kumar S, Cook DI. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 2007;282(41):29866–73.CrossRefPubMedGoogle Scholar
  28. Mund T, Pelham HR. Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins. EMBO Rep. 2009;10(5):501–7.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Nagaki K, Yamamura H, Shimada S, Saito T, Hisanaga S, Taoka M, et al. 14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels. Biochemistry. 2006;45(21):6733–40.CrossRefPubMedGoogle Scholar
  30. Oberfeld B, Ruffieux-Daidie D, Vitagliano JJ, Pos KM, Verrey F, Staub O. Ubiquitin-specific protease 2-45 (Usp2-45) binds to epithelial Na+ channel (ENaC)-ubiquitylating enzyme Nedd4-2. Am J Physiol Renal Physiol. 2011;301(1):F189–96.CrossRefPubMedGoogle Scholar
  31. Pouly D, Debonneville A, Ruffieux-Daidie D, Maillard M, Abriel H, Loffing J, et al. Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure. Am J Physiol Renal Physiol. 2013;305(1):F21–30.CrossRefPubMedGoogle Scholar
  32. Ronzaud C, Loffing-Cueni D, Hausel P, Debonneville A, Malsure SR, Fowler-Jaeger N, et al. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. J Clin Invest. 2013;123(2):657–65.PubMedPubMedCentralGoogle Scholar
  33. Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol. 2009;10(6):398–409.CrossRefPubMedGoogle Scholar
  34. Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. Bioessays. 2006;28(6):617–28.CrossRefPubMedGoogle Scholar
  35. Shi PP, Cao XR, Sweezer EM, Kinney TS, Williams NR, Husted RF, et al. Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. Am J Physiol Renal Physiol. 2008;295(2):F462–70.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Snyder PM, Olson DR, Kabra R, Zhou R, Steines JC. cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2. J Biol Chem. 2004;279(44):45753–8.CrossRefPubMedGoogle Scholar
  37. van Bemmelen MX, Rougier JS, Gavillet B, Apotheloz F, Daidie D, Tateyama M, et al. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res. 2004;95(3):284–91.CrossRefPubMedGoogle Scholar
  38. Yang B, Kumar S. Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ. 2010;17(1):68–77.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Yip K, Kolesnikoff N, Hauschild N, Biggs L, Lopez A, Galli S, et al. The Nedd4-2-Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation. Nat Commun. 2016;7:13198.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Yu T, Calvo L, Anta B, Lopez-Benito S, Lopez-Bellido R, Vicente-Garcia C, et al. In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA. J Neurosci. 2014;34(17):6098–106.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Yu T, Calvo L, Anta B, Lopez-Benito S, Southon E, Chao MV, et al. Regulation of trafficking of activated TrkA is critical for NGF-mediated functions. Traffic. 2011;12(4):521–34.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Cancer BiologyUniversity of South AustraliaAdelaideAustralia