Protein: E3 ubiquitin-protein ligase NEDD4 (EC 2.3.2.26) (Cell proliferation-inducing gene 53 protein) (HECT-type E3 ubiquitin transferase NEDD4) (Neural precursor cell expressed developmentally down-regulated protein 4) (NEDD-4) (P46934)
Organism: Homo sapiens (Human)
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. Specifically ubiquitinates 'Lys-63' in target proteins. 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 (By similarity). Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. 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 (By similarity). Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development (By similarity). Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Ubiquitinates DAZAP2, leading to its proteasomal degradation. Ubiquitinates POLR2A.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:11342538}. Nucleus {ECO:0000269|PubMed:11342538}. Cell membrane {ECO:0000250|UniProtKB:P46935}; Peripheral membrane protein {ECO:0000250|UniProtKB:P46935}. Note=Predominantly cytoplasmic but also located in the nucleus (PubMed:11342538). 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 (PubMed:18819914). {ECO:0000250|UniProtKB:P46935, ECO:0000269|PubMed:11342538, ECO:0000269|PubMed:18819914}.
Interaction partners:
- NEDD4 family-interacting protein 1
- NEDD4 family-interacting protein 2
- Epithelial sodium channel subunit beta
- Polyubiquitin-C
- Ubiquitin-ribosomal protein eS31 fusion protein
- Arrestin domain-containing protein 3
- Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
- Ubiquitin-like protein ISG15
- Polyubiquitin-B
- Protein TMEPAI
Sequence:
MAQSLRLHFAARRSNTYPLSETSGDDLDSHVHMCFKRPTRISTSNVVQMKLTPRQTALAPLIKENVQSQERSSVPSSENVNKKSSCLQISLQPTRYSGYLQSSNVLADSDDASFTCILKDGIYSSAVVDNELNAVNDGHLVSSPAICSGSLSNFSTSDNGSYSSNGSDFGSCASITSGGSYTNSVISDSSSYTFPPSDDTFLGGNLPSDSTSNRSVPNRNTTPCEIFSRSTSTDPFVQDDLEHGLEIMKLPVSRNTKIPLKRYSSLVIFPRSPSTTRPTSPTSLCTLLSKGSYQTSHQFIISPSEIAHNEDGTSAKGFLSTAVNGLRLSKTICTPGEVRDIRPLHRKGSLQKKIVLSNNTPRQTVCEKSSEGYSCVSVHFTQRKAATLDCETTNGDCKPEMSEIKLNSDSEYIKLMHRTSACLPSSQNVDCQININGELERPHSQMNKNHGILRRSISLGGAYPNISCLSSLKHNCSKGGPSQLLIKFASGNEGKVDNLSRDSNRDCTNELSNSCKTRDDFLGQVDVPLYPLPTENPRLERPYTFKDFVLHPRSHKSRVKGYLRLKMTYLPKTSGSEDDNAEQAEELEPGWVVLDQPDAACHLQQQQEPSPLPPGWEERQDILGRTYYVNHESRRTQWKRPTPQDNLTDAENGNIQLQAQRAFTTRRQISEETESVDNRESSENWEIIREDEATMYSNQAFPSPPPSSNLDVPTHLAEELNARLTIFGNSAVSQPASSSNHSSRRGSLQAYTFEEQPTLPVLLPTSSGLPPGWEEKQDERGRSYYVDHNSRTTTWTKPTVQATVETSQLTSSQSSAGPQSQASTSDSGQQVTQPSEIEQGFLPKGWEVRHAPNGRPFFIDHNTKTTTWEDPRLKIPAHLRGKTSLDTSNDLGPLPPGWEERTHTDGRIFYINHNIKRTQWEDPRLENVAITGPAVPYSRDYKRKYEFFRRKLKKQNDIPNKFEMKLRRATVLEDSYRRIMGVKRADFLKARLWIEFDGEKGLDYGGVAREWFFLISKEMFNPYYGLFEYSATDNYTLQINPNSGLCNEDHLSYFKFIGRVAGMAVYHGKLLDGFFIRPFYKMMLHKPITLHDMESVDSEYYNSLRWILENDPTELDLRFIIDEELFGQTHQHELKNGGSEIVVTNKNKKEYIYLVIQWRFVNRIQKQMAAFKEGFFELIPQDLIKIFDENELELLMCGLGDVDVNDWREHTKYKNGYSANHQVIQWFWKAVLMMDSEKRIRLLQFVTGTSRVPMNGFAELYGSNGPQSFTVEQWGTPEKLPRAHTCFNRLDLPPYESFEELWDKLQMAIENTQGFDGVD