E3 ubiquitin-protein ligase NEDD4; cell proliferation-inducing gene 53 protein; neural cell expressed developmentally down-regulated protein 4; NEDD-4 (NEDD4, KIAA0093, NEDD4-1, PIG53)

Function: - E3 ubiquitin-protein ligase - accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester & directly transfers the ubiquitin to targeted substrates - role in the pathway leading to degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity - monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization & degradation in lysosomes - ubiquitinates FGFR1, leading to receptor internalization & degradation in lysosomes - polyubiquitination of PTEN ? - role in ubiquitination of ERBB4 intracellular domain E4ICD - part of a signaling complex composed of NEDD4, RAP2A & TNIK which regulates neuronal dendrite extension & arborization during development - ubiquitinates TNK2 & regulates EGF-induced degradation of EGFR & TNF2 - activated by NDFIP1- & NDFIP2-binding - protein modification; protein ubiquitination - auto-ubiquitinated (putative) - interacts with UBE2D2 - binds SCNN1A, SCNN1B & SCNN1G - binds, in vitro, through the WW2 & WW3 domains, to neural isoforms of ENAH that contain the PPSY motif - interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, TMEPAI & PRRG2 (putative) - interacts with NDFIP1 & NDFIP2 - interaction activates the E3 ubiquitin-protein ligase & may induce its recruitment to exosomes - interaction with PTEN is questionable - interacts (via C2 domain) with GRB10 (via SH2 domain) - interacts with ERBB4 (putative) - interacts with TNIK; allows TNIK-dependent recruitment of RAP2A & its ubiquitination by NEDD4 - interacts (via WW3 domain) with TNK2 - EGF promotes this interaction - interacts (via WW3 domain) with FGFR1 (via C-terminus) Structure: - the WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, TMEPAI, NDFIP1 & PRRG2 (putative) - contains 1 HECT domain (E6AP-type E3 ubiquitin-protein ligase domain) - contains 4 WW domains - a Cys is required for ubiquitin-thioester formation Compartment: - cytoplasm (putative) - plasma membrane (putative) - recruited to the plasma membrane by GRB10 - once complexed with GRB10 & IGF1R, follows IGF1R internalization, remaining associated with early endosomes - uncouples from IGF1R-containing endosomes before the sorting of the receptor to the lysosomal compartment - may be recruited to exosomes by NDFIP1 Alternative splicing: named isoforms=4 Pathology: - role in budding of many viruses - interacts with viral proteins that contain a late-budding motif P-P-P-Y - interaction is essential for viral particle budding of retroviruses

Related

E3 ubiquitin-protein ligase NEDD4-like; NEDD4.2; Nedd4-2 (NEDD4L, KIAA0439, NEDL3) NEDD4 family-interacting protein Nedd4-binding protein NEDD4-like E3 ubiquitin-protein ligase WWP1; atrophin-1-interacting protein 5; AIP5; TGIF-interacting ubiquitin ligase 1; Tiul1; WW domain-containing protein 1 (WWP1) NEDD4-like E3 ubiquitin-protein ligase WWP2; atrophin-1-interacting protein 2; AIP2; WW domain-containing protein 2 (WWP2) neural precursor cell expressed developmentally downregulated (NEDD) protein

General

phosphoprotein E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein

Properties

SIZE: entity length = 1319 aa MW = 149 kD COMPARTMENT: lysosome cytoplasm MOTIF: serine-rich region {68-215} MOTIF: serine residue (SEVERAL) Mediates interaction with TNIK {578-981} MOTIF: WW domain (W/rsp5/WWP domain) {610-643} Thr phosphorylation site {T648} Ser phosphorylation site {S670} Ser phosphorylation site {S747} WW domain (W/rsp5/WWP domain) {767-800} WW domain (W/rsp5/WWP domain) {840-873} WW domain (W/rsp5/WWP domain) {892-925} HECT domain {984-1318} MOTIF: cysteine residue {C1286}

Database Correlations

OMIM 602278 UniProt P46934 PFAM correlations Entrez Gene 4734 Kegg hsa:4734

References

UniProt :accession P46934