NEDD4
Domain
The WW domains mediate interaction with PPxY motif-containing proteins (PubMed:21191027). The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (By similarity).
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 (PubMed:19920177, PubMed:21399620, PubMed:23644597). 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 (PubMed:21765395). Promotes ubiquitination of RAPGEF2 (PubMed:11598133). 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 (PubMed:20086093). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Ubiquitinates DAZAP2, leading to its proteasomal degradation (PubMed:11342538). Ubiquitinates POLR2A (PubMed:19920177). Functions as a platform to recruit USP13 to form an NEDD4-USP13 deubiquitination complex that plays a critical role in cleaving the 'Lys-48'-linked ubiquitin chains of VPS34 and then stabilizing VPS34, thus promoting the formation of autophagosomes (PubMed:32101753).
(Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding.
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
Undergoes 'Lys-29'-linked auto-ubiquitination at Lys-1279 and serves as a scaffold for recruiting USP13 to form an NEDD4-USP13 deubiquitination complex.
Cellular localization
- Cytoplasm
- Nucleus
- Cell membrane
- Peripheral membrane protein
- 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).
Alternative names
KIAA0093, NEDD4-1, RPF1, PIG53, NEDD4, E3 ubiquitin-protein ligase NEDD4, Cell proliferation-inducing gene 53 protein, HECT-type E3 ubiquitin transferase NEDD4, Neural precursor cell expressed developmentally down-regulated protein 4, NEDD-4