SMURF2
Domain
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.
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 (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, PubMed:21791611). 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.
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
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).
Tissue Specificity
Widely expressed.
Cellular localization
- Nucleus
- Cytoplasm
- Cell membrane
- Membrane raft
- Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts.
Alternative names
E3 ubiquitin-protein ligase SMURF2, hSMURF2, HECT-type E3 ubiquitin transferase SMURF2, SMAD ubiquitination regulatory factor 2, SMAD-specific E3 ubiquitin-protein ligase 2, SMURF2