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.
Biological Process: negative regulation of transcription from RNA polymerase II promoter; proteasomal ubiquitin-dependent protein catabolic process; protein polyubiquitination; protein ubiquitination; protein ubiquitination during ubiquitin-dependent protein catabolic process; regulation of membrane potential; response to metal ion; viral infectious cycle