SMUF2_MOUSE
ID SMUF2_MOUSE Reviewed; 748 AA.
AC A2A5Z6; A2A5Z7; Q5IRE6;
DT 16-DEC-2008, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=E3 ubiquitin-protein ligase SMURF2;
DE EC=2.3.2.26 {ECO:0000250|UniProtKB:Q9HAU4};
DE AltName: Full=HECT-type E3 ubiquitin transferase SMURF2;
DE AltName: Full=SMAD ubiquitination regulatory factor 2;
DE AltName: Full=SMAD-specific E3 ubiquitin-protein ligase 2;
GN Name=Smurf2 {ECO:0000312|MGI:MGI:1913563};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC STRAIN=129/SvJ;
RX PubMed=15820682; DOI=10.1016/j.cell.2005.01.035;
RA Yamashita M., Ying S.X., Zhang G.M., Li C., Cheng S.Y., Deng C.X.,
RA Zhang Y.E.;
RT "Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis
RT by targeting MEKK2 for degradation.";
RL Cell 121:101-113(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP INDUCTION BY TNF SIGNALING PATHWAY ACTIVATION.
RX PubMed=16373342; DOI=10.1074/jbc.m509430200;
RA Kaneki H., Guo R., Chen D., Yao Z., Schwarz E.M., Zhang Y.E., Boyce B.F.,
RA Xing L.;
RT "Tumor necrosis factor promotes Runx2 degradation through up-regulation of
RT Smurf1 and Smurf2 in osteoblasts.";
RL J. Biol. Chem. 281:4326-4333(2006).
RN [6]
RP STABILIZATION BY AIMP1.
RX PubMed=18448069; DOI=10.1016/j.bbrc.2008.04.099;
RA Lee Y.S., Han J.M., Son S.H., Choi J.W., Jeon E.J., Bae S.-C., Park Y.I.,
RA Kim S.;
RT "AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2.";
RL Biochem. Biophys. Res. Commun. 371:395-400(2008).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an
CC E2 ubiquitin-conjugating enzyme in the form of a thioester and then
CC directly transfers the ubiquitin to targeted substrates. Interacts with
CC SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-
CC beta receptor ubiquitin-dependent degradation, thereby down-regulating
CC TGF-beta signaling. In addition, interaction with SMAD7 activates
CC autocatalytic degradation, which is prevented by interaction with
CC AIMP1. Also forms a stable complex with TGF-beta receptor-mediated
CC phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for
CC ubiquitination and proteasome-mediated degradation. SMAD2 may recruit
CC substrates, such as SNON, for ubiquitin-dependent degradation.
CC Negatively regulates TGFB1-induced epithelial-mesenchymal transition
CC and myofibroblast differentiation. {ECO:0000250|UniProtKB:Q9HAU4}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.26; Evidence={ECO:0000250|UniProtKB:Q9HAU4};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts (via WW domains) with SMAD1. Interacts (via WW
CC domains) with SMAD2 (via PY-motif). Interacts (via WW domains) with
CC SMAD3 (via PY-motif). Interacts with SMAD6. Interacts with SMAD7 (via
CC PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor
CC and regulates its degradation. Does not interact with SMAD4; SMAD4
CC lacks a PY-motif. Interacts with AIMP1 (By similarity). Interacts with
CC NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein
CC ligase (By similarity). Interacts with TTC3 (By similarity).
CC {ECO:0000250|UniProtKB:Q9HAU4}.
CC -!- INTERACTION:
CC A2A5Z6; O14641: DVL2; Xeno; NbExp=8; IntAct=EBI-2348309, EBI-740850;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9HAU4}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9HAU4}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9HAU4}. Membrane raft
CC {ECO:0000250|UniProtKB:Q9HAU4}. Note=Cytoplasmic in the presence of
CC SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane
CC rafts. {ECO:0000250|UniProtKB:Q9HAU4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=A2A5Z6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=A2A5Z6-2; Sequence=VSP_036055, VSP_036056;
CC -!- INDUCTION: Up-regulated about ten-fold by activation of the TNF-
CC signaling pathway in vitro. {ECO:0000269|PubMed:16373342}.
CC -!- DOMAIN: The second and third WW domains are responsible for interaction
CC with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3). {ECO:0000250}.
CC -!- DOMAIN: The C2 domain is involved in autoinhibition of the catalytic
CC activity by interacting with the HECT domain. {ECO:0000250}.
CC -!- PTM: Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and
CC UBE2D1 (By similarity). Ubiquitinated by the SCF(FBXL15) complex and
CC TTC3, leading to its degradation by the proteasome (By similarity).
CC 'Lys-48'-linked polyubiquitination mediated by TRAF4 at Lys-119 leads
CC to SMURF2 proteasomal degradation (By similarity).
CC {ECO:0000250|UniProtKB:Q9HAU4}.
CC -!- MISCELLANEOUS: Level decreases under the suppression of SCYE1,
CC suggesting that AIMP1 stabilizes SMURF2. {ECO:0000269|PubMed:18448069}.
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DR EMBL; AY685230; AAV87906.1; -; mRNA.
DR EMBL; AL593847; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466558; EDL34316.1; -; Genomic_DNA.
DR EMBL; BC138786; AAI38787.1; -; mRNA.
DR EMBL; BC138788; AAI38789.1; -; mRNA.
DR CCDS; CCDS25564.1; -. [A2A5Z6-1]
DR RefSeq; NP_079757.2; NM_025481.2. [A2A5Z6-1]
DR RefSeq; XP_006533999.1; XM_006533936.3. [A2A5Z6-2]
DR AlphaFoldDB; A2A5Z6; -.
DR BMRB; A2A5Z6; -.
DR SMR; A2A5Z6; -.
DR BioGRID; 211376; 26.
DR IntAct; A2A5Z6; 16.
DR STRING; 10090.ENSMUSP00000090177; -.
DR iPTMnet; A2A5Z6; -.
DR PhosphoSitePlus; A2A5Z6; -.
DR EPD; A2A5Z6; -.
DR MaxQB; A2A5Z6; -.
DR PaxDb; A2A5Z6; -.
DR PeptideAtlas; A2A5Z6; -.
DR PRIDE; A2A5Z6; -.
DR ProteomicsDB; 257529; -. [A2A5Z6-1]
DR ProteomicsDB; 257530; -. [A2A5Z6-2]
DR Antibodypedia; 31598; 346 antibodies from 34 providers.
DR Ensembl; ENSMUST00000092517; ENSMUSP00000090177; ENSMUSG00000018363. [A2A5Z6-1]
DR Ensembl; ENSMUST00000103067; ENSMUSP00000099356; ENSMUSG00000018363. [A2A5Z6-2]
DR Ensembl; ENSMUST00000167787; ENSMUSP00000129269; ENSMUSG00000018363. [A2A5Z6-1]
DR GeneID; 66313; -.
DR KEGG; mmu:66313; -.
DR UCSC; uc007lzx.2; mouse. [A2A5Z6-1]
DR UCSC; uc007lzy.2; mouse. [A2A5Z6-2]
DR CTD; 64750; -.
DR MGI; MGI:1913563; Smurf2.
DR VEuPathDB; HostDB:ENSMUSG00000018363; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000155563; -.
DR HOGENOM; CLU_002173_1_1_1; -.
DR InParanoid; A2A5Z6; -.
DR OMA; TRPACEY; -.
DR PhylomeDB; A2A5Z6; -.
DR TreeFam; TF323658; -.
DR BRENDA; 2.3.2.26; 3474.
DR Reactome; R-MMU-201451; Signaling by BMP.
DR Reactome; R-MMU-2173788; Downregulation of TGF-beta receptor signaling.
DR Reactome; R-MMU-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-MMU-4608870; Asymmetric localization of PCP proteins.
DR Reactome; R-MMU-4641257; Degradation of AXIN.
DR Reactome; R-MMU-5632684; Hedgehog 'on' state.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-8941858; Regulation of RUNX3 expression and activity.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 66313; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Smurf2; mouse.
DR PRO; PR:A2A5Z6; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; A2A5Z6; protein.
DR Bgee; ENSMUSG00000018363; Expressed in cleaving embryo and 219 other tissues.
DR ExpressionAtlas; A2A5Z6; baseline and differential.
DR Genevisible; A2A5Z6; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0046332; F:SMAD binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISO:MGI.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI.
DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; ISO:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:MGI.
DR GO; GO:0030579; P:ubiquitin-dependent SMAD protein catabolic process; ISO:MGI.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 3.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 3.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 3.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 3.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 1.
DR PROSITE; PS50020; WW_DOMAIN_2; 3.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Cytoplasm; Isopeptide bond; Membrane;
KW Nucleus; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..748
FT /note="E3 ubiquitin-protein ligase SMURF2"
FT /id="PRO_0000358318"
FT DOMAIN 1..119
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 157..190
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 251..284
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 297..330
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 414..748
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT ACT_SITE 716
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT CROSSLNK 119
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9HAU4"
FT VAR_SEQ 18..30
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_036055"
FT VAR_SEQ 31
FT /note="R -> G (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_036056"
FT CONFLICT 130
FT /note="G -> V (in Ref. 1; AAV87906)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 748 AA; 86175 MW; 385AFA32D289D33F CRC64;
MSNPGGRRNG PVKLRLTVLC AKNLVKKDFF RLPDPFAKVV VDGSGQCHST DTVKNTLDPK
WNQHYDLYIG KSDSVTISVW NHKKIHKKQG AGFLGCVRLL SNAINRLKDT GYQRLDLCKL
GPNDNDTVRG QIVVSLQSRD RIGTGGQVVD CSRLFDNDLP DGWEERRTAS GRIQYLNHIT
RTTQWERPTR PASEYSSPGR PLSCFVDENT PITGTNGATC GHSSDPRLAE RRVRSQRHRN
YMSRTHLHTP PDLPEGYEQR TTQQGQVYFL HTQTGVSTWH DPRVPRDLSN INCEELGPLP
PGWEIRNTAT GRVYFVDHNN RTTQFTDPRL SANLHLVLNR QNQLKDQQQQ QVVPLCPDDT
ECLTVPRYKR DLVQKLKILR QELSQQQPQA GHCRIEVSRE EIFEESYRQV MKMRPKDLWK
RLMIKFRGEE GLDYGGVARE WLYLLSHEML NPYYGLFQYS RDDIYTLQIN PDSAVNPEHL
SYFHFVGRIM GMAVFHGHYI DGGFTLPFYK QLLGKSITLD DMELVDPDLH NSLVWILEND
ITGVLDHTFC VEHNAYGEII QHELKPNGKS IPVTEENKKE YVRLYVNWRF LRGIEAQFLA
LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVSDWKVN TRLKHCTPDS NVVKWFWKAV
EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI HQIDACTNNL PKAHTCFNRI
DIPPYESYEK LYEKLLTAIE ETCGFAVE
