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

More general terms

• E3 ubiquitin ligase
• phosphoprotein

Additional terms

• 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

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4734
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4734
• OMIM: https://mirror.omim.org/entry/602278
• UniProt: http://www.uniprot.org/uniprot/P46934.html