NEDD4

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Neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase
Protein NEDD4 PDB 2KPZ.png
Rendering based on PDB 2KPZ.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NEDD4 ; NEDD4-1; RPF1
External IDs OMIM602278 MGI97297 HomoloGene136740 GeneCards: NEDD4 Gene
EC number 6.3.2.-
RNA expression pattern
PBB GE NEDD4 213012 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4734 17999
Ensembl ENSG00000069869 ENSMUSG00000032216
UniProt P46934 P46935
RefSeq (mRNA) NM_001284338 NM_010890
RefSeq (protein) NP_001271267 NP_035020
Location (UCSC) Chr 15:
56.12 – 56.29 Mb
Chr 9:
72.66 – 72.75 Mb
PubMed search [1] [2]

E3 ubiquitin-protein ligase NEDD4 also known as neural precursor cell expressed developmentally down-regulated protein 4 (NEDD-4) is an enzyme that in humans is encoded by the NEDD4 gene.[1][2] NEDD4 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel (ENaC) in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and lead to salt retention and hypertension occur.

Neural precursor cell expressed developmentally down-regulated gene 4, NEDD4 (NEDD4-1), is an E3 ubiquitin ligase enzyme that targets proteins for ubiquitination. NEDD4 is a highly conserved gene in eukaryotes, and is the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, consisting of 9 members in humans (NEDD4, NEDD4-2(NEDD4L), ITCH, SMURF1, SMURF2, WWP1, WWP2, NEDL1 AND NEDDL2).[3][4][5] NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis.

NEDD4 protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro. In vivo NEDD4 is involved in the regulation of a diverse range of processes, including insulin-like growth factor signalling, neuronal architecture and viral budding. NEDD4 is an essential protein for animal development and survival.[6]

Structure[edit]

The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependant phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain.[7] The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.[8] The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.[9] The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate.[3]

Expression[edit]

The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein.[10] The mouse Nedd4 gene is located on chromosome 9.[1] NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle.[11] The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.[1][11]

Function[edit]

In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels.[12][13][14][15]

NEDD4 mediates ubiquitination and subsequent down-regulation of components of the epidermal growth factor (EGF) signalling pathway, such as HER3 and HER4 EGF receptors, and ACK.[16][17][18]

The fibroblast growth factor receptor 1 (FGFR1) undergoes NEDD4 mediated ubiquitination and down-regulation, and interestingly contains a novel site (VL***PSR) that binds the C2 and WW3 domain of NEDD4.[19]

There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses,[5] and NEDD4 also interacts with components of the endocytic machinery required for budding.[20]

NEDD4 can also function independently of its ubiquitin ligase activity. NEDD4 interacts with VEGFR2, leading to the degradation of VEGFR2 irrespective of whether the HECT domain is catalytically active.[21]

NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity.[13] However, in vivo studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.[22][23][24]

Regulation[edit]

NEDD4 activity can be regulated by auto-inhibition, whereby the C2 domain binds to the HECT domain to create an inhibitory conformation of the protein.[25] This auto-inhibitory conformation can be disrupted by the presence of calcium, by proteins that bind to NEDD4 to prevent this conformation, or by phosphorylation of NEDD4 at specific tyrosine residues to activate NEDD4 ubiquitin ligase activity.[25][26]

The NDFIP1 and NDFIP2 proteins function as adaptor proteins that can facilitate NEDD4 binding to substrates that lack PY motifs, as well as a role in binding NEDD4 to abrogate auto-inhibition.[27][28] NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.[29]

Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.[30] Ras signalling also up-regulates NEDD4 transcription.[31]

Physiological significance[edit]

In vivo, NEDD4 is involved in the regulation of insulin and insulin-like growth factor (IGF-1) signalling by regulating the amount of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) on the cell surface.[6][32]

The deletion of NEDD4 in mice leads to a reduced number of effector T-cells, and a slower T-cell response to antigen, suggesting that NEDD4 may function to convert naïve T-cells into activated T-cells.[33]

NEDD4 plays an important role in neuronal development, and is responsible for the formation and arborisation of dendrites in neurons by forming a signalling complex with TINK and Rap2A.[34] It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.[35][36]

NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking.[37][38] The in vivo role of NEDD4 in PTEN regulation is less clear. There is some evidence from NEDD4 deficient mice that NEDD4 does not target PTEN for degradation or trafficking.[6][39][40] However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.[31][41][42][43][44] NEDD4 regulation of PTEN may only occur in specific biological contexts.

The role of NEDD4 in negatively regulating tumour suppressor proteins is consistent with the frequent overexpression of NEDD4 in many different types of human cancers.[45][46] Decreased levels of NEDD4 have also been associated with some cancers, including neuroblastoma and pancreatic cancer where the NEDD4 directly targets the respective oncoproteins N-Myc and c-Myc associated with these cancers for degradation.[47]

See also[edit]

References[edit]

  1. ^ a b c Kumar S, Harvey KF, Kinoshita M, Copeland NG, Noda M, Jenkins NA (May 1997). "cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene". Genomics 40 (3): 435–43. doi:10.1006/geno.1996.4582. PMID 9073511. 
  2. ^ Imhof MO, McDonnell DP (Jul 1996). "Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors". Mol Cell Biol 16 (6): 2594–605. PMC 231250. PMID 8649367. 
  3. ^ a b Rotin D, Kumar S (2009). "Physiological functions of the HECT family of ubiquitin ligases". Nat. Rev. Mol. Cell Biol. 10 (6): 398–409. doi:10.1038/nrm2690. PMID 19436320. 
  4. ^ Scheffner M, Kumar S (2014). "Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects". Biochim. Biophys. Acta 1843 (1): 61–74. doi:10.1016/j.bbamcr.2013.03.024. PMID 23545411. 
  5. ^ a b 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. doi:10.1038/cdd.2009.84. PMC 2818775. PMID 19557014. 
  6. ^ a b c Cao XR, Lill NL, Boase N, Shi PP, Croucher DR, Shan H, Qu J, Sweezer EM, Place T, Kirby PA, Daly RJ, Kumar S, Yang B (2008). "Nedd4 controls animal growth by regulating IGF-1 signaling". Sci Signal 1 (38): ra5. doi:10.1126/scisignal.1160940. PMC 2833362. PMID 18812566. 
  7. ^ Harvey KF, Kumar S (1999). "Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions". Trends Cell Biol. 9 (5): 166–9. PMID 10322449. 
  8. ^ Dunn R, Klos DA, Adler AS, Hicke L (2004). "The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo". J. Cell Biol. 165 (1): 135–44. doi:10.1083/jcb.200309026. PMC 2172079. PMID 15078904. 
  9. ^ Sudol M, Chen HI, Bougeret C, Einbond A, Bork P (1995). "Characterization of a novel protein-binding module--the WW domain". FEBS Lett. 369 (1): 67–71. PMID 7641887. 
  10. ^ "NEDD4 neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase [Homo sapiens (human)]". NCBI. 
  11. ^ a b Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes Cells 3 (11): 751–63. PMID 9990509. 
  12. ^ Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D (1996). "WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome". EMBO J. 15 (10): 2371–80. PMC 450167. PMID 8665844. 
  13. ^ a b Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, Cook DI (1998). "Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 7169–73. PMC 22776. PMID 9618557. 
  14. ^ Rougier JS, Albesa M, Abriel H, Viard P (2011). "Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels". J. Biol. Chem. 286 (11): 8829–38. doi:10.1074/jbc.M110.166520. PMC 3059038. PMID 21220429. 
  15. ^ Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, Kumar S (2004). "Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2". J. Biol. Chem. 279 (28): 28930–5. doi:10.1074/jbc.M402820200. PMID 15123669. 
  16. ^ Zeng F, Xu J, Harris RC (2009). "Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells". FASEB J. 23 (6): 1935–45. doi:10.1096/fj.08-121947. PMC 2698660. PMID 19193720. 
  17. ^ Huang Z, Choi BK, Mujoo K, Fan X, Fa M, Mukherjee S, Owiti N, Zhang N, An Z (2014). "The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling". Oncogene. doi:10.1038/onc.2014.56. PMID 24662824. 
  18. ^ Lin Q, Wang J, Childress C, Sudol M, Carey DJ, Yang W (2010). "HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK". Mol. Cell. Biol. 30 (6): 1541–54. doi:10.1128/MCB.00013-10. PMC 2832494. PMID 20086093. 
  19. ^ Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D (2011). "Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function". EMBO J. 30 (16): 3259–73. doi:10.1038/emboj.2011.234. PMC 3160656. PMID 21765395. 
  20. ^ Sette P, Jadwin JA, Dussupt V, Bello NF, Bouamr F (2010). "The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif". J. Virol. 84 (16): 8181–92. doi:10.1128/JVI.00634-10. PMC 2916511. PMID 20519395. 
  21. ^ Murdaca J, Treins C, Monthouël-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S (2004). "Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation". J. Biol. Chem. 279 (25): 26754–61. doi:10.1074/jbc.M311802200. PMID 15060076. 
  22. ^ Kamynina E, Tauxe C, Staub O (2001). "Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation". Am. J. Physiol. Renal Physiol. 281 (3): F469–77. PMID 11502596. 
  23. ^ Fotia AB, Dinudom A, Shearwin KE, Koch JP, Korbmacher C, Cook DI, Kumar S (2003). "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels". FASEB J. 17 (1): 70–2. doi:10.1096/fj.02-0497fje. PMID 12424229. 
  24. ^ Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S (2011). "Respiratory distress and perinatal lethality in Nedd4-2-deficient mice". Nat Commun 2: 287. doi:10.1038/ncomms1284. PMC 3104547. PMID 21505443. 
  25. ^ a b Wang J, Peng Q, Lin Q, Childress C, Carey D, Yang W (2010). "Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition". J. Biol. Chem. 285 (16): 12279–88. doi:10.1074/jbc.M109.086405. PMC 2852967. PMID 20172859. 
  26. ^ Mund T, Pelham HR (2009). "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins". EMBO Rep. 10 (5): 501–7. doi:10.1038/embor.2009.30. PMC 2680872. PMID 19343052. 
  27. ^ Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S (2006). "Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins". Bioessays 28 (6): 617–28. doi:10.1002/bies.20422. PMID 16700065. 
  28. ^ Mund T, Pelham HR (2010). "Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2". Proc. Natl. Acad. Sci. U.S.A. 107 (25): 11429–34. doi:10.1073/pnas.0911714107. PMC 2895104. PMID 20534535. 
  29. ^ Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS (2009). "Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons". Proc. Natl. Acad. Sci. U.S.A. 106 (36): 15489–94. doi:10.1073/pnas.0904880106. PMC 2741278. PMID 19706893. 
  30. ^ Kwak YD, Wang B, Li JJ, Wang R, Deng Q, Diao S, Chen Y, Xu R, Masliah E, Xu H, Sung JJ, Liao FF (2012). "Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration". J. Neurosci. 32 (32): 10971–81. doi:10.1523/JNEUROSCI.1836-12.2012. PMC 3681290. PMID 22875931. 
  31. ^ a b Zeng T, Wang Q, Fu J, Lin Q, Bi J, Ding W, Qiao Y, Zhang S, Zhao W, Lin H, Wang M, Lu B, Deng X, Zhou D, Yin Z, Wang HR (May 2014). "Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis". Cell Rep 7 (3): 871–82. doi:10.1016/j.celrep.2014.03.045. PMID 24746824. 
  32. ^ Fan CD, Lum MA, Xu C, Black JD, Wang X (2013). "Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response". J. Biol. Chem. 288 (3): 1674–84. doi:10.1074/jbc.M112.416339. PMC 3548477. PMID 23195959. 
  33. ^ Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM (2008). "Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells". Nat. Immunol. 9 (12): 1356–63. doi:10.1038/ni.1670. PMC 2935464. PMID 18931680. 
  34. ^ Kawabe H, Neeb A, Dimova K, Young SM, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N (2010). "Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development". Neuron 65 (3): 358–72. doi:10.1016/j.neuron.2010.01.007. PMC 2825371. PMID 20159449. 
  35. ^ Liu Y, Oppenheim RW, Sugiura Y, Lin W (2009). "Abnormal development of the neuromuscular junction in Nedd4-deficient mice". Dev. Biol. 330 (1): 153–66. doi:10.1016/j.ydbio.2009.03.023. PMC 2810636. PMID 19345204. 
  36. ^ Wiszniak S, Kabbara S, Lumb R, Scherer M, Secker G, Harvey N, Kumar S, Schwarz Q (2013). "The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties". Dev. Biol. 383 (2): 186–200. doi:10.1016/j.ydbio.2013.09.024. PMID 24080509. 
  37. ^ Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X (2007). "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN". Cell 128 (1): 129–39. doi:10.1016/j.cell.2006.11.039. PMC 1828909. PMID 17218260. 
  38. ^ Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP (2007). "Ubiquitination regulates PTEN nuclear import and tumor suppression". Cell 128 (1): 141–56. doi:10.1016/j.cell.2006.11.040. PMC 1855245. PMID 17218261. 
  39. ^ Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D (2008). "The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization". Proc. Natl. Acad. Sci. U.S.A. 105 (25): 8585–90. doi:10.1073/pnas.0803233105. PMC 2438405. PMID 18562292. 
  40. ^ Hsia HE, Kumar R, Luca R, Takeda M, Courchet J, Nakashima J, Wu S, Goebbels S, An W, Eickholt BJ, Polleux F, Rotin D, Wu H, Rossner MJ, Bagni C, Rhee JS, Brose N, Kawabe H (2014). "Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth". Proc. Natl. Acad. Sci. U.S.A. 111 (36): 13205–10. doi:10.1073/pnas.1400737111. PMID 25157163. 
  41. ^ Christie KJ, Martinez JA, Zochodne DW (2012). "Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN". Mol. Cell. Neurosci. 50 (2): 179–92. doi:10.1016/j.mcn.2012.04.006. PMID 22561198. 
  42. ^ Drinjakovic J, Jung H, Campbell DS, Strochlic L, Dwivedy A, Holt CE (2010). "E3 ligase Nedd4 promotes axon branching by downregulating PTEN". Neuron 65 (3): 341–57. doi:10.1016/j.neuron.2010.01.017. PMC 2862300. PMID 20159448. 
  43. ^ Hong SW, Moon JH, Kim JS, Shin JS, Jung KA, Lee WK, Jeong SY, Hwang JJ, Lee SJ, Suh YA, Kim I, Nam KY, Han S, Kim JE, Kim KP, Hong YS, Lee JL, Lee WJ, Choi EK, Lee JS, Jin DH, Kim TW (2014). "p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN". Cell Death Differ. 21 (1): 146–60. doi:10.1038/cdd.2013.141. PMID 24141722. 
  44. ^ Liu J, Wan L, Liu P, Inuzuka H, Liu J, Wang Z, Wei W (2014). "SCF(β-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway". Oncotarget 5 (4): 1026–37. PMC 4011580. PMID 24657926. 
  45. ^ Chen C, Matesic LE (2007). "The Nedd4-like family of E3 ubiquitin ligases and cancer". Cancer Metastasis Rev. 26 (3-4): 587–604. doi:10.1007/s10555-007-9091-x. PMID 17726579. 
  46. ^ Ye X, Wang L, Shang B, Wang Z, Wei W (2014). "NEDD4: a promising target for cancer therapy". Curr Cancer Drug Targets 14 (6): 549–56. PMID 25088038. 
  47. ^ Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, Ling D, Su SP, Nelson C, Chang DK, Koach J, Tee AE, Haber M, Norris MD, Toon C, Rooman I, Xue C, Cheung BB, Kumar S, Marshall GM, Biankin AV, Liu T (2013). "The histone deacetylase SIRT2 stabilizes Myc oncoproteins". Cell Death Differ. 20 (3): 503–14. doi:10.1038/cdd.2012.147. PMC 3569991. PMID 23175188. 

Further reading[edit]