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. Interacts with UBE2E3. Interacts with NDFIP1 and NDFIP2; 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. By androgens in prostate, and by albumin in kidney. Ubiquitously expressed, with highest levels in prostate, pancreas and kidney. Activated by NDFIP1- and NDFIP2-binding. 9 isoforms of the human protein are produced by alternative splicing. Note: This description may include information from UniProtKB.
Protein type: EC 6.3.2.-; Ubiquitin ligase; EC 18.104.22.168; Ligase; Ubiquitin conjugating system
Biological Process: protein monoubiquitination; proteasomal ubiquitin-dependent protein catabolic process; response to metal ion; viral reproduction; sodium ion transport; protein ubiquitination during ubiquitin-dependent protein catabolic process; protein ubiquitination; positive regulation of endocytosis; negative regulation of transcription from RNA polymerase II promoter; viral infectious cycle; excretion; response to salt stress; water homeostasis; transforming growth factor beta receptor signaling pathway; transmembrane transport; transcription initiation from RNA polymerase II promoter; cellular sodium ion homeostasis; transcription, DNA-dependent; ubiquitin-dependent protein catabolic process via the multivesicular body pathway; negative regulation of systemic arterial blood pressure; regulation of membrane potential; positive regulation of protein catabolic process; regulation of protein catabolic process; gene expression; negative regulation of transforming growth factor beta receptor signaling pathway
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.