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. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF (By similarity). Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. 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. Activated by NDFIP1- and NDFIP2-binding. Protein modification; protein ubiquitination. Binds SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2, DRPLA and adenovirus type 2 PIII. Interacts with TGIF (By similarity). Binds KLF2 AND HIVEP3. Interacts with RNF11. Interacts with SPART. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (By similarity). Interacts with ERBB4 isoforms JM-B CYT-1 and JM-A CYT-1. Does not interact with ERB4 isoform JMA-A CYT-2. Interacts with SMAD1, SMAD2, SMAD3, SMAD5, SMAD6, SMAD7, TGFBR1 AND TGFBR2. Associates with the TGFBR1:TGFBR2 receptor complex in presence of SMAD7. Interacts with SKIL isoform 1. Interacts with TP63 isoform 1 and isoform 2. Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3 (By similarity). The WW domains mediate interaction with PPxY motif-containing proteins. Auto-ubiquitinated and ubiquitinated by RNF11. Chimera. The second part of the clone maps to another chromosome.