UniProt functional annotation for P46934



	UniProt functional annotation for P46934

UniProt code: P46934.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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: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. 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. 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. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). {ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:18562292, ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:21399620, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:23644597, ECO:0000269|PubMed:25631046}.

Function: (Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding. {ECO:0000269|PubMed:12559917}.

Catalytic activity: Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.26; Evidence={ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:21399620};

Activity regulation: Activated by NDFIP1- and NDFIP2-binding. {ECO:0000250}.

Pathway: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:23644597}.

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, PMEPAI 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 (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). Interacts with OTUD7B. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (PubMed:20559325, PubMed:24379409). Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B (PubMed:22096579). Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (PubMed:21191027). Interacts with ZBTB7B (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250, ECO:0000250|UniProtKB:P46935, ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:18562292, ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:20559325, ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:21399620, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:22096579, ECO:0000269|PubMed:22179831, ECO:0000269|PubMed:23665454, ECO:0000269|PubMed:23873930, ECO:0000269|PubMed:24379409}.

Subunit: (Microbial infection) Interacts with viral proteins that contain a late-budding motif P-P-P-Y. This interaction is essential for viral particle budding of many retroviruses, like HTLV-1 Gag and MLV Gag. Interacts with Herpes simplex virus 2 (HHV-2) protein UL56; this interaction induces NEDD4 degradation (PubMed:18353951). Interacts with Ebola virus protein VP40 (PubMed:12559917). {ECO:0000269|PubMed:12559917, ECO:0000269|PubMed:14581525, ECO:0000269|PubMed:18353951}.

Subcellular location: Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. 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. {ECO:0000250, ECO:0000269|PubMed:18819914}.

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). {ECO:0000250, ECO:0000269|PubMed:21191027}.

Ptm: Auto-ubiquitinated. {ECO:0000250}.

Miscellaneous: A cysteine residue is required for ubiquitin-thioester formation.

Sequence caution: Sequence=BAA07655.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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: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. 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. 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. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). {ECO:0000269\|PubMed:11598133, ECO:0000269\|PubMed:17218260, ECO:0000269\|PubMed:18305167, ECO:0000269\|PubMed:18562292, ECO:0000269\|PubMed:20086093, ECO:0000269\|PubMed:21399620, ECO:0000269\|PubMed:21765395, ECO:0000269\|PubMed:23644597, ECO:0000269\|PubMed:25631046}.



Function:		(Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding. {ECO:0000269\|PubMed:12559917}.


Catalytic activity:		Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.26; Evidence={ECO:0000269\|PubMed:17218260, ECO:0000269\|PubMed:21399620};
Activity regulation:		Activated by NDFIP1- and NDFIP2-binding. {ECO:0000250}.
Pathway:		Protein modification; protein ubiquitination. {ECO:0000269\|PubMed:23644597}.
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, PMEPAI 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 (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). Interacts with OTUD7B. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (PubMed:20559325, PubMed:24379409). Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B (PubMed:22096579). Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (PubMed:21191027). Interacts with ZBTB7B (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250, ECO:0000250\|UniProtKB:P46935, ECO:0000269\|PubMed:11598133, ECO:0000269\|PubMed:17218260, ECO:0000269\|PubMed:18305167, ECO:0000269\|PubMed:18562292, ECO:0000269\|PubMed:20086093, ECO:0000269\|PubMed:20159449, ECO:0000269\|PubMed:20559325, ECO:0000269\|PubMed:21191027, ECO:0000269\|PubMed:21399620, ECO:0000269\|PubMed:21765395, ECO:0000269\|PubMed:22096579, ECO:0000269\|PubMed:22179831, ECO:0000269\|PubMed:23665454, ECO:0000269\|PubMed:23873930, ECO:0000269\|PubMed:24379409}.
Subunit:		(Microbial infection) Interacts with viral proteins that contain a late-budding motif P-P-P-Y. This interaction is essential for viral particle budding of many retroviruses, like HTLV-1 Gag and MLV Gag. Interacts with Herpes simplex virus 2 (HHV-2) protein UL56; this interaction induces NEDD4 degradation (PubMed:18353951). Interacts with Ebola virus protein VP40 (PubMed:12559917). {ECO:0000269\|PubMed:12559917, ECO:0000269\|PubMed:14581525, ECO:0000269\|PubMed:18353951}.
Subcellular location:		Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. 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. {ECO:0000250, ECO:0000269\|PubMed:18819914}.
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). {ECO:0000250, ECO:0000269\|PubMed:21191027}.
Ptm:		Auto-ubiquitinated. {ECO:0000250}.
Miscellaneous:		A cysteine residue is required for ubiquitin-thioester formation.
Sequence caution:		Sequence=BAA07655.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};