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{{PBB|geneid=4734}} {{PBB|geneid=4734}}
'''E3 ubiquitin-protein ligase NEDD4''' also known as '''neural precursor cell expressed developmentally down-regulated protein 4''' (NEDD-4) is an ] that in humans is encoded by the ''NEDD4'' ].<ref name="pmid9073511">{{cite journal | author = Kumar S, Harvey KF, Kinoshita M, Copeland NG, Noda M, Jenkins NA | title = cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene | journal = Genomics | volume = 40 | issue = 3 | pages = 435–43 | date = May 1997 | pmid = 9073511 | pmc = | doi = 10.1006/geno.1996.4582 }}</ref><ref name="pmid8649367">{{cite journal | author = Imhof MO, McDonnell DP | title = Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors | journal = Mol Cell Biol | volume = 16 | issue = 6 | pages = 2594–605 | date = Jul 1996 | pmid = 8649367 | pmc = 231250 | doi = }}</ref> NEDD4 has been shown to ] and therefore down regulate the ] (ENaC) in the ] of the ], therefore opposing the actions of ] and increasing ]. In ] NEDD4 is unable to bind to the ] and lead to salt retention and hypertension occur. '''E3 ubiquitin-protein ligase NEDD4''' also known as '''neural precursor cell expressed developmentally down-regulated protein 4''' (NEDD-4) is an ] that in humans is encoded by the ''NEDD4'' ].<ref name="Kumar_1997">{{cite journal | author = Kumar S, Harvey KF, Kinoshita M, Copeland NG, Noda M, Jenkins NA | title = cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene | journal = Genomics | volume = 40 | issue = 3 | pages = 435–43 | date = May 1997 | pmid = 9073511 | pmc = | doi = 10.1006/geno.1996.4582 }}</ref><ref name="pmid8649367">{{cite journal | author = Imhof MO, McDonnell DP | title = Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors | journal = Mol Cell Biol | volume = 16 | issue = 6 | pages = 2594–605 | date = Jul 1996 | pmid = 8649367 | pmc = 231250 | doi = }}</ref> NEDD4 has been shown to ] and therefore down regulate the ] (ENaC) in the ] of the ], therefore opposing the actions of ] and increasing ]. In ] NEDD4 is unable to bind to the ] 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 ] that targets proteins for ]. ''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(]), ITCH, SMURF1, SMURF2, WWP1, WWP2, NEDL1 AND NEDDL2).<ref>Rotin, D. and S. Kumar, Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol, 2009. 10(6): p. 398-409.</ref><ref>Scheffner, M. and S. Kumar, Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim Biophys Acta, 2014. 1843(1): p. 61-74.</ref><ref>Yang, B. and S. Kumar, Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ, 2010. 17(1): p. 68-77.</ref><ref>Boase, N. and S. Kumar, NEDD4: The founding member of a family of ubiquitin-protein ligases. Gene, 2014. In submission.</ref> NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis. Neural precursor cell expressed developmentally down-regulated gene 4, NEDD4 (NEDD4-1), is an E3 ubiquitin ligase ] that targets proteins for ]. ''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(]), ITCH, SMURF1, SMURF2, WWP1, WWP2, NEDL1 AND NEDDL2).<ref name="Rotin_2009">{{cite journal | author = Rotin D, Kumar S | title = Physiological functions of the HECT family of ubiquitin ligases | journal = Nat. Rev. Mol. Cell Biol. | volume = 10 | issue = 6 | pages = 398–409 | year = 2009 | pmid = 19436320 | doi = 10.1038/nrm2690 }}</ref><ref name="pmid23545411">{{cite journal | author = Scheffner M, Kumar S | title = Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects | journal = Biochim. Biophys. Acta | volume = 1843 | issue = 1 | pages = 61–74 | year = 2014 | pmid = 23545411 | doi = 10.1016/j.bbamcr.2013.03.024 }}</ref><ref name="Yang_2010">{{cite journal | author = Yang B, Kumar S | title = Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions | journal = Cell Death Differ. | volume = 17 | issue = 1 | pages = 68–77 | year = 2010 | pmid = 19557014 | pmc = 2818775 | doi = 10.1038/cdd.2009.84 }}</ref> 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.<ref>Cao, X.R., et al., Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal, 2008. 1(38): p. ra5.</ref> 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.<ref name="Cao_2008">{{cite journal | author = 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 | title = Nedd4 controls animal growth by regulating IGF-1 signaling | journal = Sci Signal | volume = 1 | issue = 38 | pages = ra5 | year = 2008 | pmid = 18812566 | pmc = 2833362 | doi = 10.1126/scisignal.1160940 }}</ref>


== Structure == == Structure ==
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.<ref>Harvey, K.F. and S. Kumar, Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions. Trends Cell Biol, 1999. 9(5): p. 166-9.</ref> The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.<ref>Dunn, R., et al., The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo. J Cell Biol, 2004. 165(1): p. 135-44.</ref> The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.<ref>Sudol, M., et al., Characterization of a novel protein-binding module--the WW domain. FEBS Lett, 1995. 369(1): p. 67-71.</ref> 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.<ref>Rotin, D. and S. Kumar, Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol, 2009. 10(6): p. 398-409.</ref> 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.<ref name="pmid10322449">{{cite journal | author = Harvey KF, Kumar S | title = Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions | journal = Trends Cell Biol. | volume = 9 | issue = 5 | pages = 166–9 | year = 1999 | pmid = 10322449 | doi = }}</ref> The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.<ref name="pmid15078904">{{cite journal | author = Dunn R, Klos DA, Adler AS, Hicke L | title = The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo | journal = J. Cell Biol. | volume = 165 | issue = 1 | pages = 135–44 | year = 2004 | pmid = 15078904 | pmc = 2172079 | doi = 10.1083/jcb.200309026 }}</ref> The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.<ref name="pmid7641887">{{cite journal | author = Sudol M, Chen HI, Bougeret C, Einbond A, Bork P | title = Characterization of a novel protein-binding module--the WW domain | journal = FEBS Lett. | volume = 369 | issue = 1 | pages = 67–71 | year = 1995 | pmid = 7641887 | doi = }}</ref> 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.<ref name="Rotin_2009"/>


== Expression == == Expression ==
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.<ref>http://www.ncbi.nlm.nih.gov/gene/4734.</ref> The mouse ''Nedd4'' gene is located on chromosome 9.<ref>Kumar, S., et al., cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics, 1997. 40(3): p. 435-43.</ref> NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle.<ref>Anan, T., et al., Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes. Genes Cells, 1998. 3(11): p. 751-63.</ref> The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.<ref>Kumar, S., et al., cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics, 1997. 40(3): p. 435-43.</ref><ref>Anan, T., et al., Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes. Genes Cells, 1998. 3(11): p. 751-63.</ref> 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.<ref name="url_NEDD_NCBI_gene">{{cite web | url = http://www.ncbi.nlm.nih.gov/gene/4734 | title = NEDD4 neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase | publisher = NCBI }}</ref> The mouse ''Nedd4'' gene is located on chromosome 9.<ref name="Kumar_1997"/> NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle.<ref name="Anan_1998">{{cite journal | author = Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M | title = Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes | journal = Genes Cells | volume = 3 | issue = 11 | pages = 751–63 | year = 1998 | pmid = 9990509 | doi = | url = }}</ref> The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.<ref name="Kumar_1997"/><ref name="Anan_1998"/>


== Function == == Function ==
''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.<ref>Staub, O., et al., WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J, 1996. 15(10): p. 2371-80</ref><ref>Dinudom, A., et al., Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Proc Natl Acad Sci U S A, 1998. 95(12): p. 7169-73.</ref><ref>Rougier, J.S., et al., 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, 2011. 286(11): p. 8829-38.</ref><ref>Fotia, A.B., et al., Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J Biol Chem, 2004. 279(28): p. 28930-5.</ref> ''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.<ref name="pmid8665844">{{cite journal | author = Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D | title = WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome | journal = EMBO J. | volume = 15 | issue = 10 | pages = 2371–80 | year = 1996 | pmid = 8665844 | pmc = 450167 | doi = }}</ref><ref name="Dinudom_1998">{{cite journal | author = Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, Cook DI | title = Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+ | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 12 | pages = 7169–73 | year = 1998 | pmid = 9618557 | pmc = 22776 | doi = }}</ref><ref name="pmid21220429">{{cite journal | author = Rougier JS, Albesa M, Abriel H, Viard P | title = Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels | journal = J. Biol. Chem. | volume = 286 | issue = 11 | pages = 8829–38 | year = 2011 | pmid = 21220429 | pmc = 3059038 | doi = 10.1074/jbc.M110.166520 }}</ref><ref name="pmid15123669">{{cite journal | author = Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, Kumar S | title = Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2 | journal = J. Biol. Chem. | volume = 279 | issue = 28 | pages = 28930–5 | year = 2004 | pmid = 15123669 | doi = 10.1074/jbc.M402820200 }}</ref>


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.<ref>Zeng, F., J. Xu, and R.C. Harris, Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells. FASEB J, 2009. 23(6): p. 1935-45.</ref><ref>Huang, Z., et al., The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling. Oncogene, 2014: p. Epub 24 March 2014.</ref><ref>Lin, Q., et al., HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK. Mol Cell Biol, 2010. 30(6): p. 1541-54.</ref> 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.<ref name="pmid19193720">{{cite journal | author = Zeng F, Xu J, Harris RC | title = Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells | journal = FASEB J. | volume = 23 | issue = 6 | pages = 1935–45 | year = 2009 | pmid = 19193720 | pmc = 2698660 | doi = 10.1096/fj.08-121947 }}</ref><ref name="pmid24662824">{{cite journal | author = Huang Z, Choi BK, Mujoo K, Fan X, Fa M, Mukherjee S, Owiti N, Zhang N, An Z | title = The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling | journal = Oncogene | volume = | issue = | pages = | year = 2014 | pmid = 24662824 | doi = 10.1038/onc.2014.56 }}</ref><ref name="pmid20086093">{{cite journal | author = Lin Q, Wang J, Childress C, Sudol M, Carey DJ, Yang W | title = HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK | journal = Mol. Cell. Biol. | volume = 30 | issue = 6 | pages = 1541–54 | year = 2010 | pmid = 20086093 | pmc = 2832494 | doi = 10.1128/MCB.00013-10 }}</ref>


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.<ref>Persaud, A., et al., Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J, 2011. 30(16): p. 3259-73.</ref> 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.<ref name="pmid21765395">{{cite journal | author = Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D | title = Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function | journal = EMBO J. | volume = 30 | issue = 16 | pages = 3259–73 | year = 2011 | pmid = 21765395 | pmc = 3160656 | doi = 10.1038/emboj.2011.234 }}</ref>


There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses<ref>Yang, B. and S. Kumar, Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ, 2010. 17(1): p. 68-77.</ref>, and NEDD4 also interacts with components of the endocytic machinery required for budding.<ref>Sette, P., et al., The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif. J Virol, 2010. 84(16): p. 8181-92.</ref> There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses,<ref name="Yang_2010"/> and NEDD4 also interacts with components of the endocytic machinery required for budding.<ref name="pmid20519395">{{cite journal | author = Sette P, Jadwin JA, Dussupt V, Bello NF, Bouamr F | title = The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif | journal = J. Virol. | volume = 84 | issue = 16 | pages = 8181–92 | year = 2010 | pmid = 20519395 | pmc = 2916511 | doi = 10.1128/JVI.00634-10 }}</ref>


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.<ref>Murdaca, J., et al., Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem, 2004. 279(25): p. 26754-61.</ref> 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.<ref name="pmid15060076">{{cite journal | author = Murdaca J, Treins C, Monthouël-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S | title = Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation | journal = J. Biol. Chem. | volume = 279 | issue = 25 | pages = 26754–61 | year = 2004 | pmid = 15060076 | doi = 10.1074/jbc.M311802200 }}</ref>


NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity.<ref>Dinudom, A., et al., Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Proc Natl Acad Sci U S A, 1998. 95(12): p. 7169-73.</ref> However, ''in vivo'' studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.<ref>Kamynina, E., C. Tauxe, and O. Staub, Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation. Am J Physiol Renal Physiol, 2001. 281(3): p. F469-77.</ref><ref>Fotia, A.B., et al., The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB J, 2003. 17(1): p. 70-2.</ref><ref>Boase, N.A., et al., Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nat Commun, 2011. 2: p. 287.</ref> NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity.<ref name="Dinudom_1998"/> However, ''in vivo'' studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.<ref name="pmid11502596">{{cite journal | author = Kamynina E, Tauxe C, Staub O | title = Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation | journal = Am. J. Physiol. Renal Physiol. | volume = 281 | issue = 3 | pages = F469–77 | year = 2001 | pmid = 11502596 | doi = }}</ref><ref name="pmid12424229">{{cite journal | author = Fotia AB, Dinudom A, Shearwin KE, Koch JP, Korbmacher C, Cook DI, Kumar S | title = The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels | journal = FASEB J. | volume = 17 | issue = 1 | pages = 70–2 | year = 2003 | pmid = 12424229 | doi = 10.1096/fj.02-0497fje }}</ref><ref name="pmid21505443">{{cite journal | author = Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S | title = Respiratory distress and perinatal lethality in Nedd4-2-deficient mice | journal = Nat Commun | volume = 2 | issue = | pages = 287 | year = 2011 | pmid = 21505443 | pmc = 3104547 | doi = 10.1038/ncomms1284 }}</ref>


== Regulation' == == Regulation ==
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.<ref>Wang, J., et al., Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition. J Biol Chem, 2010. 285(16): p. 12279-88.</ref> 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.<ref>Wang, J., et al., Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition. J Biol Chem, 2010. 285(16): p. 12279-88.</ref><ref>Mund, T. and H.R. Pelham, Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins. EMBO Rep, 2009. 10(5): p. 501-7.</ref><ref>Persaud, A., et al., Tyrosine phosphorylation of NEDD4 activates its ubiquitin ligase activity. Sci Signal, 2014. 7(346): p. ra95.</ref> 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.<ref name="Wang_2010">{{cite journal | author = Wang J, Peng Q, Lin Q, Childress C, Carey D, Yang W | title = Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition | journal = J. Biol. Chem. | volume = 285 | issue = 16 | pages = 12279–88 | year = 2010 | pmid = 20172859 | pmc = 2852967 | doi = 10.1074/jbc.M109.086405 }}</ref> 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.<ref name="Wang_2010"/><ref name="pmid19343052">{{cite journal | author = Mund T, Pelham HR | title = Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins | journal = EMBO Rep. | volume = 10 | issue = 5 | pages = 501–7 | year = 2009 | pmid = 19343052 | pmc = 2680872 | doi = 10.1038/embor.2009.30 }}</ref>


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.<ref>Shearwin-Whyatt, L., et al., Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. Bioessays, 2006. 28(6): p. 617-28.</ref><ref>Mund, T. and H.R. Pelham, Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2. Proc Natl Acad Sci U S A, 2010. 107(25): p. 11429-34.</ref> NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.<ref>Howitt, J., et al., Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A, 2009. 106(36): p. 15489-94.</ref> 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.<ref name="pmid16700065">{{cite journal | author = Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S | title = Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins | journal = Bioessays | volume = 28 | issue = 6 | pages = 617–28 | year = 2006 | pmid = 16700065 | doi = 10.1002/bies.20422 }}</ref><ref name="pmid20534535">{{cite journal | author = Mund T, Pelham HR | title = Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 25 | pages = 11429–34 | year = 2010 | pmid = 20534535 | pmc = 2895104 | doi = 10.1073/pnas.0911714107 }}</ref> NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.<ref name="pmid19706893">{{cite journal | author = Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS | title = Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 36 | pages = 15489–94 | year = 2009 | pmid = 19706893 | pmc = 2741278 | doi = 10.1073/pnas.0904880106 }}</ref>


Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.<ref>Kwak, Y.D., et al., Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration. J Neurosci, 2012. 32(32): p. 10971-81.</ref> Ras signalling also up-regulates NEDD4 transcription.<ref>Zeng, T., et al., Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis. Cell Rep, 2014. 7(3): p. 871-82.</ref> Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.<ref name="pmid22875931">{{cite journal | author = Kwak YD, Wang B, Li JJ, Wang R, Deng Q, Diao S, Chen Y, Xu R, Masliah E, Xu H, Sung JJ, Liao FF | title = Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration | journal = J. Neurosci. | volume = 32 | issue = 32 | pages = 10971–81 | year = 2012 | pmid = 22875931 | pmc = 3681290 | doi = 10.1523/JNEUROSCI.1836-12.2012 }}</ref> Ras signalling also up-regulates NEDD4 transcription.<ref name="Zeng_2014">{{cite journal | author = 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 | title = Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis | journal = Cell Rep | volume = 7 | issue = 3 | pages = 871–82 | year = 2014 | month = May | pmid = 24746824 | doi = 10.1016/j.celrep.2014.03.045 }}</ref>


== Physiological significance == == Physiological significance ==
''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.<ref>Cao, X.R., et al., Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal, 2008. 1(38): p. ra5.</ref><ref>Fan, C.D., et al., 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, 2013. 288(3): p. 1674-84.</ref> ''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.<ref name="Cao_2008"/><ref name="pmid23195959">{{cite journal | author = Fan CD, Lum MA, Xu C, Black JD, Wang X | title = Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response | journal = J. Biol. Chem. | volume = 288 | issue = 3 | pages = 1674–84 | year = 2013 | pmid = 23195959 | pmc = 3548477 | doi = 10.1074/jbc.M112.416339 }}</ref>


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.<ref>Yang, B., et al., Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat Immunol, 2008. 9(12): p. 1356-63.</ref> 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.<ref name="pmid18931680">{{cite journal | author = Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM | title = Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells | journal = Nat. Immunol. | volume = 9 | issue = 12 | pages = 1356–63 | year = 2008 | pmid = 18931680 | pmc = 2935464 | doi = 10.1038/ni.1670 }}</ref>


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.<ref>Kawabe, H., et al., Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron, 2010. 65(3): p. 358-72.</ref> It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.<ref>Liu, Y., et al., Abnormal development of the neuromuscular junction in Nedd4-deficient mice. Dev Biol, 2009. 330(1): p. 153-66.</ref><ref>Wiszniak, S., et al., The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties. Dev Biol, 2013. 383(2): p. 186-200.</ref> 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.<ref name="pmid20159449">{{cite journal | author = 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 | title = Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development | journal = Neuron | volume = 65 | issue = 3 | pages = 358–72 | year = 2010 | pmid = 20159449 | pmc = 2825371 | doi = 10.1016/j.neuron.2010.01.007 }}</ref> It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.<ref name="pmid19345204">{{cite journal | author = Liu Y, Oppenheim RW, Sugiura Y, Lin W | title = Abnormal development of the neuromuscular junction in Nedd4-deficient mice | journal = Dev. Biol. | volume = 330 | issue = 1 | pages = 153–66 | year = 2009 | pmid = 19345204 | pmc = 2810636 | doi = 10.1016/j.ydbio.2009.03.023 }}</ref><ref name="pmid24080509">{{cite journal | author = Wiszniak S, Kabbara S, Lumb R, Scherer M, Secker G, Harvey N, Kumar S, Schwarz Q | title = The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties | journal = Dev. Biol. | volume = 383 | issue = 2 | pages = 186–200 | year = 2013 | pmid = 24080509 | doi = 10.1016/j.ydbio.2013.09.024 }}</ref>


NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN ''in vitro'', resulting in PTEN proteasomal degradation or trafficking.<ref>Wang, X., et al., NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell, 2007. 128(1): p. 129-39.</ref><ref>Trotman, L.C., et al., Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 2007. 128(1): p. 141-56.</ref> 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.<ref>Cao, X.R., et al., Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal, 2008. 1(38): p. ra5.</ref><ref>Fouladkou, F., et al., The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc Natl Acad Sci U S A, 2008. 105(25): p. 8585-90.</ref><ref>Hsia, H.E., et al., 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, 2014: p. Epub 25 Aug 2014.</ref> However, in other ''in vivo'' models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.<ref>Zeng, T., et al., Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis. Cell Rep, 2014. 7(3): p. 871-82.</ref><ref>Christie, K.J., J.A. Martinez, and D.W. Zochodne, Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN. Mol Cell Neurosci, 2012. 50(2): p. 179-92.</ref><ref>Drinjakovic, J., et al., E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron, 2010. 65(3): p. 341-57.</ref><ref>Hong, S.W., et al., p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN. Cell Death Differ, 2014. 21(1): p. 146-60.</ref><ref>Liu, J., et al., SCF(beta-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway. Oncotarget, 2014. 5(4): p. 1026-37.</ref> NEDD4 regulation of PTEN may only occur in specific biological contexts. NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN ''in vitro'', resulting in PTEN proteasomal degradation or trafficking.<ref name="pmid17218260">{{cite journal | author = 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 | title = NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN | journal = Cell | volume = 128 | issue = 1 | pages = 129–39 | year = 2007 | pmid = 17218260 | pmc = 1828909 | doi = 10.1016/j.cell.2006.11.039 }}</ref><ref name="pmid17218261">{{cite journal | author = 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 | title = Ubiquitination regulates PTEN nuclear import and tumor suppression | journal = Cell | volume = 128 | issue = 1 | pages = 141–56 | year = 2007 | pmid = 17218261 | pmc = 1855245 | doi = 10.1016/j.cell.2006.11.040 }}</ref> 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.<ref name="Cao_2008"/><ref name="pmid18562292">{{cite journal | author = Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D | title = The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 25 | pages = 8585–90 | year = 2008 | pmid = 18562292 | pmc = 2438405 | doi = 10.1073/pnas.0803233105 }}</ref><ref name="pmid25157163">{{cite journal | author = 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 | title = Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 111 | issue = 36 | pages = 13205–10 | year = 2014 | pmid = 25157163 | doi = 10.1073/pnas.1400737111 }}</ref> However, in other ''in vivo'' models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.<ref name="Zeng_2014"/><ref name="pmid22561198">{{cite journal | author = Christie KJ, Martinez JA, Zochodne DW | title = Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN | journal = Mol. Cell. Neurosci. | volume = 50 | issue = 2 | pages = 179–92 | year = 2012 | pmid = 22561198 | doi = 10.1016/j.mcn.2012.04.006 }}</ref><ref name="pmid20159448">{{cite journal | author = Drinjakovic J, Jung H, Campbell DS, Strochlic L, Dwivedy A, Holt CE | title = E3 ligase Nedd4 promotes axon branching by downregulating PTEN | journal = Neuron | volume = 65 | issue = 3 | pages = 341–57 | year = 2010 | pmid = 20159448 | pmc = 2862300 | doi = 10.1016/j.neuron.2010.01.017 }}</ref><ref name="pmid24141722">{{cite journal | author = 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 | title = p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN | journal = Cell Death Differ. | volume = 21 | issue = 1 | pages = 146–60 | year = 2014 | pmid = 24141722 | doi = 10.1038/cdd.2013.141 }}</ref><ref name="pmid24657926">{{cite journal | author = Liu J, Wan L, Liu P, Inuzuka H, Liu J, Wang Z, Wei W | title = SCF(β-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway | journal = Oncotarget | volume = 5 | issue = 4 | pages = 1026–37 | year = 2014 | pmid = 24657926 | pmc = 4011580 | doi = }}</ref> 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.<ref>Chen, C. and L.E. Matesic, The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev, 2007. 26(3-4): p. 587-604.</ref><ref>Ye, X., et al., NEDD4: A Promising Target for Cancer Therapy. Curr Cancer Drug Targets, 2014. 14(6): p. 549-56.</ref> 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.<ref>Liu, P.Y., et al., The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ, 2013. 20(3): p. 503-14.</ref> 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.<ref name="pmid17726579">{{cite journal | author = Chen C, Matesic LE | title = The Nedd4-like family of E3 ubiquitin ligases and cancer | journal = Cancer Metastasis Rev. | volume = 26 | issue = 3-4 | pages = 587–604 | year = 2007 | pmid = 17726579 | doi = 10.1007/s10555-007-9091-x }}</ref><ref name="pmid25088038">{{cite journal | author = Ye X, Wang L, Shang B, Wang Z, Wei W | title = NEDD4: a promising target for cancer therapy | journal = Curr Cancer Drug Targets | volume = 14 | issue = 6 | pages = 549–56 | year = 2014 | pmid = 25088038 | doi = }}</ref> 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.<ref name="pmid23175188">{{cite journal | author = 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 | title = The histone deacetylase SIRT2 stabilizes Myc oncoproteins | journal = Cell Death Differ. | volume = 20 | issue = 3 | pages = 503–14 | year = 2013 | pmid = 23175188 | pmc = 3569991 | doi = 10.1038/cdd.2012.147 }}</ref>


== See also == == See also ==

* ] * ]



== References == == References ==

Revision as of 18:56, 23 October 2014

Template:PBB 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. 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). 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.

Structure

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. The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates. The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors. 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.

Expression

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. The mouse Nedd4 gene is located on chromosome 9. NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle. The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.

Function

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.

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.

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.

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

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.

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

Regulation

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. 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.

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. NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.

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

Physiological significance

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.

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.

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. It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.

NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking. 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. However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN. 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. 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.

See also

References

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