ID:SMUF2_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase SMURF2; Short=hSMURF2; EC=6.3.2.-; AltName: Full=SMAD ubiquitination regulatory factor 2; AltName: Full=SMAD-specific E3 ubiquitin-protein ligase 2; 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. Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1. Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3. In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation. Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2. Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level. ENZYME REGULATION: Activated by NDFIP1- and NDFIP2-binding. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Interacts (via WW domains) with SMAD1. Interacts (via WW domains) with SMAD2 (via PY-motif). Interacts (via WW domains) with SMAD3 (via PY-motif). Interacts with SMAD6. Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF- beta receptor and regulates its degradation. Does not interact with SMAD4; SMAD4 lacks a PY-motif. Interacts with AIMP1. Interacts with STAMBP and RNF11. Interacts with NDFIP1 and NDFIP2 (Probable); this interaction activates the E3 ubiquitin-protein ligase. INTERACTION: Self; NbExp=5; IntAct=EBI-396727, EBI-396727; Q9Y3C5:RNF11; NbExp=3; IntAct=EBI-396727, EBI-396669; P0CG47:UBB; NbExp=4; IntAct=EBI-396727, EBI-413034; SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cell membrane. Membrane raft. Note=Cytoplasmic in the presence of SMAD7. Co-localizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts. TISSUE SPECIFICITY: Widely expressed. DOMAIN: The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3). DOMAIN: The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. PTM: Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome. SIMILARITY: Contains 1 C2 domain. SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. SIMILARITY: Contains 3 WW domains.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9HAU4
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BioCarta from NCI Cancer Genome Anatomy Project h_EfpPathway - Estrogen-responsive protein Efp controls cell cycle and breast tumors growth
Reactome (by CSHL, EBI, and GO)
Protein Q9HAU4 (Reactome details) participates in the following event(s):
R-HSA-2176445 SMURF2 binds SMAD2 R-HSA-4641134 SMURF2 binds AXIN R-HSA-173542 SMURF2 ubiquitinates SMAD2 R-NUL-2176393 SMURF2 ubiquitinates Smad7 and phosphorylated TGFBR1 R-HSA-178208 SMAD7 binds to SMURF2 R-HSA-2179274 SMURF2 binds SMAD3 phosphorylated in the linker region R-HSA-2179276 SMURF2 monoubiquitinates SMAD3 R-NUL-2169043 Smad7:SMURF2 binds phosphorylated TGFBR1 R-NUL-2167888 Smad7:SMURF2 complex translocates to the cytosol R-HSA-2167876 SMAD7:SMURF2 complex translocates to the cytosol R-HSA-4641129 AXIN is ubiquitinated by SMURF2 R-HSA-4608854 SMURF1/2 are recruited to the DVL2:PARD6A complex R-HSA-5632646 SMURF1/2 bind PTCH1 R-HSA-5635865 SMURF1/2 dissociates from ub-PTCH1 R-HSA-983157 Interaction of E3 with substrate and E2-Ub complex R-HSA-983147 Release of E3 from polyubiquitinated substrate R-HSA-2169050 SMURFs/NEDD4L ubiquitinate phosphorylated TGFBR1 and SMAD7 R-HSA-2186741 SMAD2/3 activation induces binding of RNF111/SMURF2 to SKI/SKIL R-HSA-2186747 Ubiquitination of SKI/SKIL by RNF111/SMURF2 R-HSA-201821 I-Smad binds to type I receptor, preventing Smad1/5/8 from being activated R-HSA-5632648 SMURF1/2 ubiquitinates PTCH1 R-HSA-983140 Transfer of Ub from E2 to substrate and release of E2 R-HSA-178218 SMAD7:SMURF complex binds to phosphorylated TGFBR1 R-HSA-8952419 SMURFs ubiquitinate RUNX3 R-HSA-6781764 USP15 deubiquitinates SMAD1,SMAD2,SMAD3, SMAD7:SMURF,KEAP1 R-HSA-4608852 SMURF1/2 ubiquitinates PRICKLE1 R-HSA-2173788 Downregulation of TGF-beta receptor signaling R-HSA-4641257 Degradation of AXIN R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity R-HSA-4608870 Asymmetric localization of PCP proteins R-HSA-5632684 Hedgehog 'on' state R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation R-HSA-2173789 TGF-beta receptor signaling activates SMADs R-HSA-201681 TCF dependent signaling in response to WNT R-HSA-2173793 Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer R-HSA-201451 Signaling by BMP R-HSA-4086400 PCP/CE pathway R-HSA-5358351 Signaling by Hedgehog R-HSA-983169 Class I MHC mediated antigen processing & presentation R-HSA-170834 Signaling by TGF-beta Receptor Complex R-HSA-195721 Signaling by WNT R-HSA-8941858 Regulation of RUNX3 expression and activity R-HSA-212436 Generic Transcription Pathway R-HSA-5689880 Ub-specific processing proteases R-HSA-9006936 Signaling by TGF-beta family members R-HSA-3858494 Beta-catenin independent WNT signaling R-HSA-162582 Signal Transduction R-HSA-1280218 Adaptive Immune System R-HSA-8878159 Transcriptional regulation by RUNX3 R-HSA-73857 RNA Polymerase II Transcription R-HSA-5688426 Deubiquitination R-HSA-168256 Immune System R-HSA-74160 Gene expression (Transcription) R-HSA-597592 Post-translational protein modification R-HSA-392499 Metabolism of proteins
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