Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C et al.. Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes. Genes Cells 3: 751-763

Genes to Cells (Impact Factor: 2.81). 10/1998; 3(11):751 - 763. DOI: 10.1046/j.1365-2443.1998.00227.x
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Nedd4 is a ubiquitin-protein ligase containing a calcium/lipid-binding domain, multiple WW domains and a C-terminal Hect domain, which is required for both the ubiquitin transfer and the association with E2 ubiquitin-conjugating enzymes. Nedd4 has been reported to be involved in the selective ubiquitination of some regulatory proteins in transcription and membrane transport.ResultsThree mRNA species for human Nedd4 were found to be 6.4-, 7.8- and 9.5-kb in size, and their expression patterns varied among normal tissues and cancer cell lines, indicating the tissue- and cell-specificities of Nedd4 expression. The Nedd4 protein, ≈120 kDa in weight, was found in the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery, of human cultured cells. Neural differentiation induced not only the down-regulation of Nedd4 but also the localization of the protein to both the cytoplasm and neurites. To identify the ubiquitination pathway that is linked to Nedd4, we demonstrated that specific E2 enzymes, including human Ubc4, UbcH5B, UbcH5C, UbcH6 and UbcH7, could transfer ubiquitin molecules to Nedd4 at the active cysteine residue, whereas E6AP accepted ubiquitins from Ubc4, UbcH5B, UbcH5C and UbcH7. Furthermore, nuclear localization of N-terminal deletion mutant Nedd4 enabled us to investigate the interaction between Nedd4 and E2 enzyme (Ubc4 or UbcH7) in the cell. The simultaneous expression of the full-length Nedd4 and E2 enzyme revealed that both proteins mostly colocalized in the cytoplasmic periphery, while the N-terminal deleted Nedd4 induced the nuclear and perinuclear colocalization with E2 enzyme.Conclusion
Our findings suggested that Nedd4 plays an important role in the cell regulation, including neural differentiation through cooperation with specific E2 ubiquitination pathways.

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Available from: Hisashi Koga, Oct 06, 2014
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    • "Biologically, NEDD4 is an E3 ubiquitin ligase composed of a C2 domain, three or four WW domains and an ubiquitin ligase Hect domain [19]. NEDD4 is highly expressed in the skin, skeletal muscle, the liver, the bladder, placenta and cancer cell lines [14], [20]. Previously studies demonstrate that phosphatase and tensin homolog (PTEN) [21], insulin-like growth factor I receptor (IGF-IR) [22] and SMAD4 [23] are substrates of NEDD4, which have been reported to be associated with keloid. "
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    ABSTRACT: Keloid is benign fibroproliferative dermal tumors with unknown etiology. Recently, a genome-wide association study (GWAS) in Japanese population has identified 3 susceptibility loci (rs873549 at 1q41, rs940187 and rs1511412 at 3q22.3, rs8032158 at 15p21.3) for keloid. In order to examine whether these susceptibility loci are associated with keloid in the Chinese Han population, twelve previously reported SNPs were selected for replication in 714 cases and 2,944 controls by using Sequenom MassArray system. We found three SNPs in two regions showed significant association with keloid in the Chinese Han population: 1q41 (rs873549, P = 3.03×10(-33), OR = 2.05, 95% CI: 1.82-2.31 and rs1442440, P = 9.85×10(-18), OR = 0.56, 95% CI: 0.49-0.64, respectively) and 15q21.3 (rs2271289 located in NEDD4, P = 1.02×10(-11), OR = 0.66, 95% CI: 0.58-0.74). We also detected one risk haplotype AG (P = 1.36×10(-31), OR = 2.02) and two protective haplotypes of GA and AA (GA, P = 1.94×10(-19), OR = 0.53, AA, P = 0.00043, OR = 0.78, respectively) from the two SNPs (rs873549 and rs1442440). Our study confirmed two previously reported loci 1q41 and 15q21.3 for keloid in the Chinese Han population, which suggested the common genetic factor predisposing to the development of keloid shared by the Chinese Han and Japanese populations.
    PLoS ONE 05/2013; 8(5):e62377. DOI:10.1371/journal.pone.0062377 · 3.23 Impact Factor
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    • "The subcellular localization of both Nedd4 and Nedd4-2 is diffusely cytoplasmic (Anan et al., 1998) and localization of Nedd4 proteins to the cytoplasm is dependent on the presence of the N-terminal portion of the protein. In cells overexpressing an N-terminal mutant of Nedd4, the distribution of the protein is primarily peri-nuclear (Anan et al., 1998). Interestingly, both Nedd4 and Nedd4-2 have also been detected in exosomes (Putz et al., 2008), this finding expands the role for Nedd4 proteins in exosome biogenesis and raises new questions regarding the functions "
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    ABSTRACT: Ubiquitination of proteins by the Nedd4 family of ubiquitin ligases is a significant mechanism in protein trafficking and degradation and provides for tight spatiotemporal regulation. Ubiquitination is gaining increasing recognition as a central mechanism underpinning the regulation of neuronal development and homeostasis in the brain. This review will focus on the Nedd4 and Nedd4-2 E3 ubiquitin ligases that are implicated in an increasing number of neuronal protein-protein interactions. Understanding of the contribution of Nedd4 and Nedd4-2 in regulating key functions in the brain is shedding new light on the ubiquitination signal not only in orchestrating degradation events but also in protein trafficking. Furthermore, the description of several novel Nedd4/4-2 targets in neurons is changing the way we conceptualize how neurons maintain normal function and how this is altered in disease.
    The international journal of biochemistry & cell biology 12/2012; 45(3). DOI:10.1016/j.biocel.2012.12.006 · 4.05 Impact Factor
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    • "t of UbcH7 in controlling PTEN levels requires further investigation . UbcH7 interacts with several E3 ligases , including Parkin ( Shimura et al . , 2000 ) , Cbl ( Yokouchi et al . , 1999 ; Zheng et al . , 2000 ) , E6 - AP ( Nuber et al . , 1998 ; Huang et al . , 1999 ) , NK - lytic – associated molecule ( Fortier and Kornbluth , 2006 ) , NEDD4 ( Anan et al . , 1998 ; Wang et al . , 2007 ) , TRIAD - 1 ( Marteijn et al . , 2005 ) , Smurf2 ( Ogunjimi et al . , 2005 ) , TRAF6 ( Geetha et al . , 2005 ) , and components of the SCF complex ( Staropoli et al . , 2003 ; Oh et al . , 2004 ) . Additionally UbcH7 can bind to the E3 ligase BRCA - 1 but does not catalyze its self - ubiquitinating activity ( Brz"
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    ABSTRACT: Timely degradation of regulatory proteins by the ubiquitin proteolytic pathway (UPP) is an established paradigm of cell cycle regulation during the G2/M and G1/S transitions. Less is known about roles for the UPP during S phase. Here we present evidence that dynamic cell cycle-dependent changes in levels of UbcH7 regulate entrance into and progression through S phase. In diverse cell lines, UbcH7 protein levels are dramatically reduced in S phase but are fully restored by G2. Knockdown of UbcH7 increases the proportion of cells in S phase and doubles the time to traverse S phase, whereas UbcH7 overexpression reduces the proportion of cells in S phase. These data suggest a role for UbcH7 targets in the completion of S phase and entry into G2. Notably, UbcH7 knockdown was coincident with elevated levels of the checkpoint kinase Chk1 but not Chk2. These results argue that UbcH7 promotes S phase progression to G2 by modulating the intra-S phase checkpoint mediated by Chk1. Furthermore, UbcH7 levels appear to be regulated by a UPP. Together the data identify novel roles for the UPP, specifically UbcH7 in the regulation of S phase transit time as well as in cell proliferation.
    Molecular biology of the cell 11/2008; 20(1):1-9. DOI:10.1091/mbc.E08-01-0036 · 4.47 Impact Factor
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