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 (PubMed:11016919). Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby down-regulating TGF-beta signaling (PubMed:11163210, PubMed:12717440). In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1 (PubMed:18448069). Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation (PubMed:11016919, PubMed:11158580, PubMed:11389444). SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation (PubMed:11389444). Negatively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation (PubMed:30696809). (Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding. 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. Interacts (via WW domains) with SMAD1 (PubMed:11158580). Interacts (via WW domains) with SMAD2 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts (via WW domains) with SMAD3 (via PY-motif) (PubMed:11158580, PubMed:11389444). Interacts with SMAD6 (PubMed:11158580). Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation (PubMed:11163210, PubMed:11158580, PubMed:33673144, PubMed:16061177, PubMed:16641086). Does not interact with SMAD4; SMAD4 lacks a PY-motif (PubMed:11158580). Interacts with AIMP1 (PubMed:18448069). Interacts with SNON (PubMed:11389444). Interacts with STAMBP and RNF11 (PubMed:14562029, PubMed:14755250). May interact with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin-protein ligase activity. Interacts with TTC3 (Probable). (Microbial infection) Interacts (via WW domains) with EBOV and MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like particle budding. Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts. Widely expressed. The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3). The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. (Microbial infection) The WW domains mediate binding with matrix protein VP40. Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the SCF(FBXL15) complex and TTC3, leading to its degradation by the proteasome (PubMed:21572392, PubMed:30696809). 'Lys-48'-linked polyubiquitination mediated by TRAF4 at Lys-119 leads to SMURF2 proteasomal degradation (PubMed:31076633).