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Nedd4  -  neural precursor cell expressed,...

Mus musculus

Synonyms: AA959633, AL023035, AU019897, E3 ubiquitin-protein ligase NEDD4, E430025J12Rik, ...
 
 
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Disease relevance of Nedd4

 

High impact information on Nedd4

  • The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels [4].
  • It recently has been shown that epithelial Na(+) channels are controlled by a receptor for intracellular Na(+), a G protein (G(o)), and a ubiquitin-protein ligase (Nedd4) [5].
  • In the present paper, we show that Nedd4 mediates the ubiquitin-dependent down-regulation of Na+ channel activity in response to increased intracellular Na+ [6].
  • Thus, binding of Nedd4 by the PY motifs would appear to be part of a physiological control system for down-regulation of Na+ channel activity [6].
  • Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+ [6].
 

Biological context of Nedd4

  • We have mapped the mouse Nedd4 gene to chromosome 9 using an interspecific backcross panel [7].
  • Primary cultures, which closely mimic in vivo chondrogenesis, were also used to demonstrate the stage-specific expression of Nedd4 during early skeletal development [8].
  • Subsequent stimulation or homotypic cell adhesion promotes membrane translocation of Itch and the related protein Nedd4, resulting in PKCtheta and PLCgamma1 degradation [9].
  • A mutant IGF-IR in which the serines at positions 1280--1283 have been mutated to alanine does not protect from apoptosis and fails to translocate Nedd4 or Raf-1 to the mitochondria [10].
  • Based on previous observations in yeast, we propose that N4WBP5 may act as an adaptor for Nedd4-like proteins and their putative targets to control ubiquitin-dependent protein sorting and trafficking [11].
 

Anatomical context of Nedd4

 

Associations of Nedd4 with chemical compounds

  • We have isolated a mouse cDNA clone containing the C2 domain of mouse Nedd4, a ubiquitin protein ligase (E3) that also contains a hect (homologous to the E6-AP carboxyl-terminus) domain and three WW domains [13].
  • Grb10 interacting with Nedd4 was not ubiquitinated in vivo, raising the possibility that this interaction may be used to target other proteins, like tyrosine kinase receptors, for ubiquitination [13].
  • Nedd4-2, but not Nedd4, is negatively regulated by serum- and glucocorticoid-inducible kinase 1, an aldosterone-induced kinase, providing an attractive mechanism for the stimulatory effect of aldosterone on Na+ transport [14].
  • DeltaNp63alpha is sumoylated and ubiquitinated both in HEK293 cells and in zebrafish embryos, and Nedd4 promotes ubiquitination and instability of DeltaNp63alpha protein, with lysine residue 637 serving as a potential alternative sumoylation and ubiquitination site that is crucial for DeltaNp63alpha destabilization [15].
  • Here we show that Nedd4, a ubiquitin-protein ligase containing multiple WW domains and a calcium/lipid-binding domain, is also cleaved during apoptosis induced by a variety of stimuli including Fas-ligation, gamma-radiation, tumor necrosis factor-alpha, C-8 ceramide, and etoposide treatment [16].
 

Other interactions of Nedd4

  • The interaction with Grb10 in the two-hybrid system was confirmed using the full-length Nedd4, and it was abolished by deleting the last 148 amino acids of Grb10, a region that includes the SH2 domain and the newly identified BPS domain [13].
  • Ubiquitination of the IGF-IR in p6/Grb10 cells is severely impaired by overexpression of a catalytically inactive Nedd4 mutant (Nedd4-CS), which also stabilizes the receptor [17].
  • This is the first demonstration of regulation of stability of a tyrosine kinase receptor by the Nedd4 (HECT) family of E3 ligases [17].
  • By site-directed mutagenesis, one of the in vitro caspase cleavage sites in mouse Nedd4 was mapped to a DQPD237 downward arrow sequence, which is conserved between mouse, rat, and human proteins [16].
  • The 14.3.3/Raf-1/Nedd4 pathway is operative in the presence or absence of the insulin receptor substrate-1 [10].
 

Analytical, diagnostic and therapeutic context of Nedd4

References

  1. Itchy, a Nedd4 ubiquitin ligase, downregulates latent membrane protein 2A activity in B-cell signaling. Ikeda, A., Caldwell, R.G., Longnecker, R., Ikeda, M. J. Virol. (2003) [Pubmed]
  2. Role of Nedd4 and ubiquitination of Rous sarcoma virus Gag in budding of virus-like particles from cells. Vana, M.L., Tang, Y., Chen, A., Medina, G., Carter, C., Leis, J. J. Virol. (2004) [Pubmed]
  3. APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles. Dussart, S., Douaisi, M., Courcoul, M., Bessou, G., Vigne, R., Decroly, E. J. Mol. Biol. (2005) [Pubmed]
  4. The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Dinudom, A., Fotia, A.B., Lefkowitz, R.J., Young, J.A., Kumar, S., Cook, D.I. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Na(+)-H(+) exchange in salivary secretory cells is controlled by an intracellular Na(+) receptor. Ishibashi, H., Dinudom, A., Harvey, K.F., Kumar, S., Young, J.A., Cook, D.I. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Dinudom, A., Harvey, K.F., Komwatana, P., Young, J.A., Kumar, S., Cook, D.I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Kumar, S., Harvey, K.F., Kinoshita, M., Copeland, N.G., Noda, M., Jenkins, N.A. Genomics (1997) [Pubmed]
  8. Analysis of Nedd4 expression during skeletal development in the mouse limb. Weston, A.D., Underhill, T.M. Mech. Dev. (2000) [Pubmed]
  9. A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling. Heissmeyer, V., Macián, F., Varma, R., Im, S.H., García-Cozar, F., Horton, H.F., Byrne, M.C., Feske, S., Venuprasad, K., Gu, H., Liu, Y.C., Dustin, M.L., Rao, A. Novartis Found. Symp. (2005) [Pubmed]
  10. Anti-apoptotic signaling of the insulin-like growth factor-I receptor through mitochondrial translocation of c-Raf and Nedd4. Peruzzi, F., Prisco, M., Morrione, A., Valentinis, B., Baserga, R. J. Biol. Chem. (2001) [Pubmed]
  11. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. Harvey, K.F., Shearwin-Whyatt, L.M., Fotia, A., Parton, R.G., Kumar, S. J. Biol. Chem. (2002) [Pubmed]
  12. Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch. Flasza, M., Nguyen Huu, N.S., Mazaleyrat, S., Clémence, S., Villemant, C., Clarke, R., Baron, M. Mol. Membr. Biol. (2006) [Pubmed]
  13. mGrb10 interacts with Nedd4. Morrione, A., Plant, P., Valentinis, B., Staub, O., Kumar, S., Rotin, D., Baserga, R. J. Biol. Chem. (1999) [Pubmed]
  14. New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis. Thomas, C.P., Itani, O.A. Curr. Opin. Nephrol. Hypertens. (2004) [Pubmed]
  15. Destabilization of DeltaNp63alpha by Nedd4-mediated ubiquitination and Ubc9-mediated sumoylation, and its implications on dorsoventral patterning of the zebrafish embryo. Bakkers, J., Camacho-Carvajal, M., Nowak, M., Kramer, C., Danger, B., Hammerschmidt, M. Cell Cycle (2005) [Pubmed]
  16. Caspase-mediated cleavage of the ubiquitin-protein ligase Nedd4 during apoptosis. Harvey, K.F., Harvey, N.L., Michael, J.M., Parasivam, G., Waterhouse, N., Alnemri, E.S., Watters, D., Kumar, S. J. Biol. Chem. (1998) [Pubmed]
  17. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Vecchione, A., Marchese, A., Henry, P., Rotin, D., Morrione, A. Mol. Cell. Biol. (2003) [Pubmed]
  18. Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4. Jolliffe, C.N., Harvey, K.F., Haines, B.P., Parasivam, G., Kumar, S. Biochem. J. (2000) [Pubmed]
  19. All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na+. Harvey, K.F., Dinudom, A., Komwatana, P., Jolliffe, C.N., Day, M.L., Parasivam, G., Cook, D.I., Kumar, S. J. Biol. Chem. (1999) [Pubmed]
  20. Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4. Timmins, J., Schoehn, G., Ricard-Blum, S., Scianimanico, S., Vernet, T., Ruigrok, R.W., Weissenhorn, W. J. Mol. Biol. (2003) [Pubmed]
 
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