Mothers against decapentaplegic homolog 7 (MAD homolog 7) (Mothers against DPP homolog 7) (Mothers against decapentaplegic homolog 8) (MAD homolog 8) (Mothers against DPP homolog 8) (SMAD family member 7) (SMAD 7) (Smad7)

 SMAD7_MOUSE             Reviewed;         426 AA.
 O35253; O88709;
 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
 01-JAN-1998, sequence version 1.
 02-DEC-2020, entry version 188.
 RecName: Full=Mothers against decapentaplegic homolog 7;
          Short=MAD homolog 7;
          Short=Mothers against DPP homolog 7;
 AltName: Full=Mothers against decapentaplegic homolog 8;
          Short=MAD homolog 8;
          Short=Mothers against DPP homolog 8;
 AltName: Full=SMAD family member 7;
          Short=SMAD 7;
          Short=Smad7;
 Name=Smad7; Synonyms=Madh7, Madh8;
 Mus musculus (Mouse).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
 Murinae; Mus; Mus.
 NCBI_TaxID=10090;
 [1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
 TISSUE=Placenta;
 PubMed=9335507; DOI=10.1038/39369;
 Nakao A., Afrakhte M., Moren A., Nakayama T., Christian J.L., Heuchel R.,
 Itoh S., Kawabata M., Heldin N.-E., Heldin C.-H., ten Dijke P.;
 "Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta
 signalling.";
 Nature 389:631-635(1997).
 [2]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
 TISSUE=Embryo;
 Kitamura K., Okazaki K.;
 "Characterization of a novel mouse homologue of Mad, Smad7, that can
 mediate TGF-beta family signalling.";
 Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
 [3]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
 TISSUE=Embryo;
 Kitamura K., Okazaki K.;
 "Isolation of cDNAs encoding mouse homologues of Mad (Smad7 and Smad7B)
 that can mediate TGF-beta family signalling.";
 Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
 [4]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
 PubMed=10828018;
 Kitamura K., Aota S., Sakamoto R., Yoshikawa S.I., Okazaki K.;
 "Smad7 selectively interferes with different pathways of activin signaling
 and inhibits erythroid leukemia cell differentiation.";
 Blood 95:3371-3379(2000).
 [5]
 PHOSPHORYLATION AT SER-249, MUTAGENESIS OF SER-249, AND SUBCELLULAR
 LOCATION.
 PubMed=11278814; DOI=10.1074/jbc.m011019200;
 Pulaski L., Landstrom M., Heldin C.-H., Souchelnytskyi S.;
 "Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory
 role in transforming growth factor-beta-dependent signaling but affects
 Smad7-dependent transcriptional activation.";
 J. Biol. Chem. 276:14344-14349(2001).
 [6]
 INTERACTION WITH RNF111, AND UBIQUITINATION.
 PubMed=14657019; DOI=10.1093/emboj/cdg632;
 Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A.,
 Ebina M., Nukiwa T., Miyazawa K., Imamura T., Miyazono K.;
 "Arkadia amplifies TGF-beta superfamily signaling through degradation of
 Smad7.";
 EMBO J. 22:6458-6470(2003).
 [7]
 INTERACTION WITH WWP1, AND UBIQUITINATION.
 PubMed=15221015; DOI=10.1038/sj.onc.1207885;
 Komuro A., Imamura T., Saitoh M., Yoshida Y., Yamori T., Miyazono K.,
 Miyazawa K.;
 "Negative regulation of transforming growth factor-beta (TGF-beta)
 signaling by WW domain-containing protein 1 (WWP1).";
 Oncogene 23:6914-6923(2004).
 [8]
 INTERACTION WITH NEDD4L, AND SUBCELLULAR LOCATION.
 PubMed=15496141; DOI=10.1042/bj20040738;
 Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K., Miyazono K.,
 Imamura T.;
 "NEDD4-2 (neural precursor cell expressed, developmentally down-regulated
 4-2) negatively regulates TGF-beta (transforming growth factor-beta)
 signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta
 type I receptor.";
 Biochem. J. 386:461-470(2005).
 [9]
 UBIQUITINATION.
 PubMed=23610558; DOI=10.1371/journal.pbio.1001538;
 Kelly C.E., Thymiakou E., Dixon J.E., Tanaka S., Godwin J., Episkopou V.;
 "Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon
 extension.";
 PLoS Biol. 11:E1001538-E1001538(2013).
 -!- FUNCTION: Antagonist of signaling by TGF-beta (transforming growth
     factor) type 1 receptor superfamily members; has been shown to inhibit
     TGF-beta (Transforming growth factor) and activin signaling by
     associating with their receptors thus preventing SMAD2 access.
     Functions as an adapter to recruit SMURF2 to the TGF-beta receptor
     complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1,
     which promotes its dephosphorylation. Positively regulates PDPK1 kinase
     activity by stimulating its dissociation from the 14-3-3 protein YWHAQ
     which acts as a negative regulator. {ECO:0000250|UniProtKB:O15105}.
 -!- SUBUNIT: Interacts with COPS5. Interacts with STAMBP. Interacts with
     PPP1R15A (By similarity). Interacts with NEDD4L. Interacts with RNF111,
     AXIN1 and AXIN2. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1;
     SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates
     its degradation (By similarity). Interacts with WWP1. Interacts with
     PDPK1 (via PH domain) (By similarity). Ubiquitinated by WWP1.
     {ECO:0000250, ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:15221015,
     ECO:0000269|PubMed:15496141}.
 -!- INTERACTION:
     O35253; O35625: Axin1; NbExp=2; IntAct=EBI-5274835, EBI-2365912;
     O35253; Q923E4: Sirt1; NbExp=6; IntAct=EBI-5274835, EBI-1802585;
     O35253; Q9C0C9: UBE2O; Xeno; NbExp=2; IntAct=EBI-5274835, EBI-2339946;
 -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11278814,
     ECO:0000269|PubMed:15496141}. Cytoplasm {ECO:0000269|PubMed:11278814,
     ECO:0000269|PubMed:15496141}. Note=Interaction with NEDD4L or RNF111
     induces translocation from the nucleus to the cytoplasm
     (PubMed:15496141). TGF-beta stimulates its translocation from the
     nucleus to the cytoplasm. PDPK1 inhibits its translocation from the
     nucleus to the cytoplasm in response to TGF-beta (By similarity).
     {ECO:0000250|UniProtKB:O15105, ECO:0000269|PubMed:15496141}.
 -!- ALTERNATIVE PRODUCTS:
     Event=Alternative splicing; Named isoforms=2;
     Name=A;
       IsoId=O35253-1; Sequence=Displayed;
     Name=B;
       IsoId=O35253-2; Sequence=VSP_006181;
 -!- TISSUE SPECIFICITY: Ubiquitous in various organs, with higher levels in
     brain and kidney.
 -!- PTM: Phosphorylation on Ser-249 does not affect its stability, nuclear
     localization or inhibitory function in TGFB signaling; however it
     affects its ability to regulate transcription (PubMed:11278814).
     Phosphorylated by PDPK1 (By similarity). {ECO:0000250|UniProtKB:O15105,
     ECO:0000269|PubMed:11278814}.
 -!- PTM: Ubiquitinated by WWP1 (PubMed:15221015). Polyubiquitinated by
     RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation
     (PubMed:14657019). In response to TGF-beta, ubiquitinated by SMURF1;
     which promotes its degradation (By similarity). Ubiquitinated by
     RNF165, promoting proteasomal degradation, leading to enhance the BMP-
     Smad signaling (PubMed:23610558). {ECO:0000250|UniProtKB:O15105,
     ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:15221015,
     ECO:0000269|PubMed:23610558}.
 -!- PTM: Acetylation prevents ubiquitination and degradation mediated by
     SMURF1. {ECO:0000250|UniProtKB:O15105}.
 -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
 ---------------------------------------------------------------------------
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 EMBL; AF015260; AAB81353.1; -; mRNA.
 EMBL; AJ000550; CAA04182.1; -; mRNA.
 EMBL; AJ000551; CAA04183.1; -; mRNA.
 CCDS; CCDS37860.1; -. [O35253-1]
 RefSeq; NP_001036125.1; NM_001042660.1. [O35253-1]
 RefSeq; XP_006525766.1; XM_006525703.2. [O35253-2]
 BMRB; O35253; -.
 SMR; O35253; -.
 BioGRID; 201280; 27.
 IntAct; O35253; 8.
 MINT; O35253; -.
 STRING; 10090.ENSMUSP00000026999; -.
 iPTMnet; O35253; -.
 PhosphoSitePlus; O35253; -.
 PaxDb; O35253; -.
 PRIDE; O35253; -.
 Antibodypedia; 9268; 520 antibodies.
 Ensembl; ENSMUST00000026999; ENSMUSP00000026999; ENSMUSG00000025880. [O35253-1]
 Ensembl; ENSMUST00000168918; ENSMUSP00000129322; ENSMUSG00000025880. [O35253-1]
 GeneID; 17131; -.
 KEGG; mmu:17131; -.
 UCSC; uc008fqd.1; mouse. [O35253-1]
 UCSC; uc008fqe.2; mouse. [O35253-2]
 CTD; 4092; -.
 MGI; MGI:1100518; Smad7.
 eggNOG; KOG3701; Eukaryota.
 GeneTree; ENSGT00940000159872; -.
 HOGENOM; CLU_026736_2_0_1; -.
 InParanoid; O35253; -.
 OMA; GCCMGKS; -.
 PhylomeDB; O35253; -.
 TreeFam; TF314923; -.
 Reactome; R-MMU-201451; Signaling by BMP.
 Reactome; R-MMU-2173788; Downregulation of TGF-beta receptor signaling.
 Reactome; R-MMU-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
 Reactome; R-MMU-5689880; Ub-specific processing proteases.
 BioGRID-ORCS; 17131; 4 hits in 19 CRISPR screens.
 ChiTaRS; Smad7; mouse.
 PRO; PR:O35253; -.
 Proteomes; UP000000589; Chromosome 18.
 RNAct; O35253; protein.
 Bgee; ENSMUSG00000025880; Expressed in lung and 311 other tissues.
 ExpressionAtlas; O35253; baseline and differential.
 Genevisible; O35253; MM.
 GO; GO:0005912; C:adherens junction; IEA:Ensembl.
 GO; GO:0016342; C:catenin complex; IEA:Ensembl.
 GO; GO:0005813; C:centrosome; ISO:MGI.
 GO; GO:0005737; C:cytoplasm; ISO:MGI.
 GO; GO:0005829; C:cytosol; ISO:MGI.
 GO; GO:0001650; C:fibrillar center; ISO:MGI.
 GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
 GO; GO:0005654; C:nucleoplasm; ISO:MGI.
 GO; GO:0005634; C:nucleus; IDA:MGI.
 GO; GO:0005886; C:plasma membrane; ISO:MGI.
 GO; GO:0032991; C:protein-containing complex; IDA:MGI.
 GO; GO:0048185; F:activin binding; ISO:MGI.
 GO; GO:0008013; F:beta-catenin binding; ISO:MGI.
 GO; GO:0005518; F:collagen binding; IPI:MGI.
 GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IBA:GO_Central.
 GO; GO:0140416; F:DNA-binding transcription factor inhibitor activity; ISO:MGI.
 GO; GO:0070411; F:I-SMAD binding; ISO:MGI.
 GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
 GO; GO:0008134; F:transcription factor binding; IBA:GO_Central.
 GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; ISO:MGI.
 GO; GO:0034713; F:type I transforming growth factor beta receptor binding; ISO:MGI.
 GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
 GO; GO:0034333; P:adherens junction assembly; ISO:MGI.
 GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
 GO; GO:0048844; P:artery morphogenesis; IMP:BHF-UCL.
 GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
 GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
 GO; GO:0034629; P:cellular protein-containing complex localization; ISO:MGI.
 GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEP:MGI.
 GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IMP:BHF-UCL.
 GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
 GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:MGI.
 GO; GO:1902731; P:negative regulation of chondrocyte proliferation; IDA:CACAO.
 GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:MGI.
 GO; GO:0030279; P:negative regulation of ossification; IDA:CACAO.
 GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
 GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; IMP:BHF-UCL.
 GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IMP:BHF-UCL.
 GO; GO:0031397; P:negative regulation of protein ubiquitination; ISO:MGI.
 GO; GO:0002725; P:negative regulation of T cell cytokine production; IMP:BHF-UCL.
 GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; IMP:BHF-UCL.
 GO; GO:2000317; P:negative regulation of T-helper 17 type immune response; IMP:BHF-UCL.
 GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; ISO:MGI.
 GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
 GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI.
 GO; GO:0051444; P:negative regulation of ubiquitin-protein transferase activity; ISO:MGI.
 GO; GO:0060389; P:pathway-restricted SMAD protein phosphorylation; IMP:BHF-UCL.
 GO; GO:0022409; P:positive regulation of cell-cell adhesion; IMP:BHF-UCL.
 GO; GO:1903043; P:positive regulation of chondrocyte hypertrophy; IDA:CACAO.
 GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:MGI.
 GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:MGI.
 GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
 GO; GO:0050821; P:protein stabilization; ISO:MGI.
 GO; GO:0032925; P:regulation of activin receptor signaling pathway; ISO:MGI.
 GO; GO:0055117; P:regulation of cardiac muscle contraction; IMP:BHF-UCL.
 GO; GO:0010717; P:regulation of epithelial to mesenchymal transition; ISO:MGI.
 GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI.
 GO; GO:0060373; P:regulation of ventricular cardiac muscle cell membrane depolarization; IC:BHF-UCL.
 GO; GO:0034616; P:response to laminar fluid shear stress; IEA:Ensembl.
 GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
 GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:MGI.
 GO; GO:0001657; P:ureteric bud development; IEP:UniProtKB.
 GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
 GO; GO:0060412; P:ventricular septum morphogenesis; IMP:BHF-UCL.
 Gene3D; 2.60.200.10; -; 1.
 Gene3D; 3.90.520.10; -; 1.
 InterPro; IPR013790; Dwarfin.
 InterPro; IPR003619; MAD_homology1_Dwarfin-type.
 InterPro; IPR013019; MAD_homology_MH1.
 InterPro; IPR017855; SMAD-like_dom_sf.
 InterPro; IPR001132; SMAD_dom_Dwarfin-type.
 InterPro; IPR008984; SMAD_FHA_dom_sf.
 InterPro; IPR036578; SMAD_MH1_sf.
 PANTHER; PTHR13703; PTHR13703; 1.
 Pfam; PF03165; MH1; 1.
 Pfam; PF03166; MH2; 1.
 SMART; SM00523; DWA; 1.
 SMART; SM00524; DWB; 1.
 SUPFAM; SSF49879; SSF49879; 1.
 SUPFAM; SSF56366; SSF56366; 1.
 PROSITE; PS51075; MH1; 1.
 PROSITE; PS51076; MH2; 1.
 1: Evidence at protein level;
 Acetylation; Alternative splicing; Cytoplasm; DNA-binding; Isopeptide bond;
 Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Transcription;
 Transcription regulation; Ubl conjugation; Zinc.
 CHAIN           1..426
                 /note="Mothers against decapentaplegic homolog 7"
                 /id="PRO_0000090873"
 DOMAIN          64..207
                 /note="MH1"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
 DOMAIN          261..426
                 /note="MH2"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
 REGION          208..217
                 /note="Important for interaction with SMURF2"
                 /evidence="ECO:0000250"
 MOTIF           208..211
                 /note="PY-motif"
                 /evidence="ECO:0000250"
 COMPBIAS        27..35
                 /note="Poly-Gly"
 COMPBIAS        49..56
                 /note="Poly-Gly"
 COMPBIAS        207..210
                 /note="Poly-Pro"
 METAL           125
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           180
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           192
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           197
                 /note="Zinc"
                 /evidence="ECO:0000250"
 MOD_RES         64
                 /note="N6-acetyllysine; alternate"
                 /evidence="ECO:0000250|UniProtKB:O15105"
 MOD_RES         70
                 /note="N6-acetyllysine; alternate"
                 /evidence="ECO:0000250|UniProtKB:O15105"
 MOD_RES         249
                 /note="Phosphoserine"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
                 ECO:0000269|PubMed:11278814"
 CROSSLNK        64
                 /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
                 G-Cter in ubiquitin); alternate"
                 /evidence="ECO:0000250|UniProtKB:O15105"
 CROSSLNK        70
                 /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
                 G-Cter in ubiquitin); alternate"
                 /evidence="ECO:0000250|UniProtKB:O15105"
 VAR_SEQ         223
                 /note="Missing (in isoform B)"
                 /evidence="ECO:0000303|PubMed:10828018, ECO:0000303|Ref.3"
                 /id="VSP_006181"
 MUTAGEN         249
                 /note="S->A: No effect on stability, nuclear localization
                 or inhibitory function in TGFB signaling. Abolishes
                 transcriptional activity."
                 /evidence="ECO:0000269|PubMed:11278814"
 MUTAGEN         249
                 /note="S->D: No effect."
                 /evidence="ECO:0000269|PubMed:11278814"
 CONFLICT        233
                 /note="A -> V (in Ref. 3 and 4)"
                 /evidence="ECO:0000305"
 SEQUENCE   426 AA;  46442 MW;  BEEE751371C0E0CF CRC64;
 MFRTKRSALV RRLWRSRAPG GEDEEEGVGG GGGGGELRGE GATDGRAYGA GGGGAGRAGC
 CLGKAVRGAK GHHHPHPPTS GAGAAGGAEA DLKALTHSVL KKLKERQLEL LLQAVESRGG
 TRTACLLLPG RLDCRLGPGA PASAQPAQPP SSYSLPLLLC KVFRWPDLRH SSEVKRLCCC
 ESYGKINPEL VCCNPHHLSR LCELESPPPP YSRYPMDFLK PTAGCPDAVP SSAETGGTNY
 LAPGGLSDSQ LLLEPGDRSH WCVVAYWEEK TRVGRLYCVQ EPSLDIFYDL PQGNGFCLGQ
 LNSDNKSQLV QKVRSKIGCG IQLTREVDGV WVYNRSSYPI FIKSATLDNP DSRTLLVHKV
 FPGFSIKAFD YEKAYSLQRP NDHEFMQQPW TGFTVQISFV KGWGQCYTRQ FISSCPCWLE
 VIFNSR

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