This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2.
Subunit:
Interacts with UBE2E3 (By similarity). Interacts with NDFIP1 and NDFIP2 (By similarity); this interaction activates the E3 ubiquitin-protein ligase. Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7. The phosphorylated form interacts with 14-3-3 proteins. Interacts with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with WNK1. Interacts with SGK1. Interacts (via C2 domain) with NPC2.
Subcellular Location:
Cytoplasm. Note=May be recruited to exosomes by NDFIP1.
Tissue Specificity:
Ubiquitously expressed, with highest levels in prostate, pancreas and kidney.
Post-translational modifications:
Phosphorylated by SGK1 or PKA; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation.
Auto-ubiquitinated.
Similarity:
Contains 1 C2 domain.
Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.
Contains 4 WW domains.
SWISS:
Q96PU5
Gene ID:
23327
Database links:
Entrez Gene: 23327 Human
Entrez Gene: 83814 Mouse
Entrez Gene: 291553 Rat
Entrez Gene: 399396 Xenopus laevis
Omim: 606384 Human
SwissProt: Q96PU5 Human
SwissProt: Q8CFI0 Mouse
Unigene: 185677 Human
Unigene: 98668 Mouse
Unigene: 72824 Rat
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