Human Gene NEDD4 (ENST00000338963.6) from GENCODE V44
Description: Homo sapiens NEDD4 E3 ubiquitin protein ligase (NEDD4), transcript variant 2, mRNA. (from RefSeq NM_198400) RefSeq Summary (NM_198400): This gene is the founding member of the NEDD4 family of HECT ubiquitin ligases that function in the ubiquitin proteasome system of protein degradation. The encoded protein contains an N-terminal calcium and phospholipid binding C2 domain followed by multiple tryptophan-rich WW domains and, a C-terminal HECT ubiquitin ligase catalytic domain. It plays critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumor suppressor PTEN. [provided by RefSeq, Jul 2016]. Gencode Transcript: ENST00000338963.6 Gencode Gene: ENSG00000069869.17 Transcript (Including UTRs) Position: hg38 chr15:55,826,922-55,917,131 Size: 90,210 Total Exon Count: 22 Strand: - Coding Region Position: hg38 chr15:55,829,897-55,916,831 Size: 86,935 Coding Exon Count: 22
ID:NEDD4_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase NEDD4; EC=6.3.2.-; AltName: Full=Cell proliferation-inducing gene 53 protein; AltName: Full=Neural precursor cell expressed developmentally down-regulated protein 4; Short=NEDD-4; FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in the pathway leading to the degradation of VEGFR- 2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding (By similarity). PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G. Binds, in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH that contain the PPSY motif. Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, TMEPAI and PRRG2 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interaction with PTEN is questionable according to PubMed:18562292. Interacts with viral proteins that contain a late- budding motif P-P-P-Y. This interaction is essential for viral particle budding of a lot of retroviruses, like HTLV-1 Gag and MLV Gag. Interacts (via C2 domain) with GRB10 (via SH2 domain). Interacts with ERBB4 (By similarity). Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4. Interacts (via WW3 domain) with TNK2; EGF promotes this interaction. Interacts (via WW3 domain) with FGFR1 (via C-terminus). INTERACTION: O95166:GABARAP; NbExp=6; IntAct=EBI-726944, EBI-712001; Q9H0R8:GABARAPL1; NbExp=6; IntAct=EBI-726944, EBI-746969; P60520:GABARAPL2; NbExp=3; IntAct=EBI-726944, EBI-720116; Q99732:LITAF; NbExp=4; IntAct=EBI-726944, EBI-725647; P60484:PTEN; NbExp=4; IntAct=EBI-726944, EBI-696162; SUBCELLULAR LOCATION: Cytoplasm (By similarity). Cell membrane; Peripheral membrane protein (By similarity). Note=Recruited to the plasma membrane by GRB10. Once complexed with GRB10 and IGF1R, follows IGF1R internalization, remaining associated with early endosomes. Uncouples from IGF1R-containing endosomes before the sorting of the receptor to the lysosomal compartment (By similarity). May be recruited to exosomes by NDFIP1. DOMAIN: The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, TMEPAI, NDFIP1 and PRRG2 (By similarity). PTM: Auto-ubiquitinated (By similarity). MISCELLANEOUS: A cysteine residue is required for ubiquitin- thioester formation. SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. SIMILARITY: Contains 4 WW domains. SEQUENCE CAUTION: Sequence=BAA07655.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P46934
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0006511 ubiquitin-dependent protein catabolic process GO:0006622 protein targeting to lysosome GO:0007041 lysosomal transport GO:0007399 nervous system development GO:0010766 negative regulation of sodium ion transport GO:0010768 negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage GO:0014068 positive regulation of phosphatidylinositol 3-kinase signaling GO:0016032 viral process GO:0016241 regulation of macroautophagy GO:0016567 protein ubiquitination GO:0019089 transmission of virus GO:0030948 negative regulation of vascular endothelial growth factor receptor signaling pathway GO:0031175 neuron projection development GO:0031623 receptor internalization GO:0032801 receptor catabolic process GO:0034644 cellular response to UV GO:0034765 regulation of ion transmembrane transport GO:0042391 regulation of membrane potential GO:0042921 glucocorticoid receptor signaling pathway GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway GO:0044111 development involved in symbiotic interaction GO:0045732 positive regulation of protein catabolic process GO:0046824 positive regulation of nucleocytoplasmic transport GO:0048814 regulation of dendrite morphogenesis GO:0050847 progesterone receptor signaling pathway GO:0051592 response to calcium ion GO:0070534 protein K63-linked ubiquitination GO:1901016 regulation of potassium ion transmembrane transporter activity GO:2000650 negative regulation of sodium ion transmembrane transporter activity
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04120 - Ubiquitin mediated proteolysis hsa04144 - Endocytosis
Reactome (by CSHL, EBI, and GO)
Protein P46934 (Reactome details) participates in the following event(s):
R-HSA-1169399 Interaction of ISG15 with NEDD4 and inhibition of Ebola virus budding R-HSA-1973956 NEDD4 binds ERBB4jmAcyt1s80 dimer R-HSA-1977296 NEDD4 ubiquitinates ERBB4jmAcyt1s80 dimer R-HSA-983157 Interaction of E3 with substrate and E2-Ub complex R-HSA-983147 Release of E3 from polyubiquitinated substrate R-HSA-6807134 NEDD4, WWP2, CHIP and XIAP polyubiquitinate PTEN R-HSA-983140 Transfer of Ub from E2 to substrate and release of E2 R-HSA-6807106 PTEN undergoes monoubiquitination R-HSA-1169408 ISG15 antiviral mechanism R-HSA-1253288 Downregulation of ERBB4 signaling R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation R-HSA-1169410 Antiviral mechanism by IFN-stimulated genes R-HSA-1236394 Signaling by ERBB4 R-HSA-8948751 Regulation of PTEN stability and activity R-HSA-983169 Class I MHC mediated antigen processing & presentation R-HSA-8948747 Regulation of PTEN localization R-HSA-913531 Interferon Signaling R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-6807070 PTEN Regulation R-HSA-1280218 Adaptive Immune System R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-162582 Signal Transduction R-HSA-1257604 PIP3 activates AKT signaling R-HSA-168256 Immune System R-HSA-9006925 Intracellular signaling by second messengers
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