SMAD6_MOUSE
ID SMAD6_MOUSE Reviewed; 495 AA.
AC O35182; Q9CW62;
DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=Mothers against decapentaplegic homolog 6;
DE Short=MAD homolog 6;
DE Short=Mothers against DPP homolog 6;
DE AltName: Full=Mad homolog 7;
DE AltName: Full=SMAD family member 6;
DE Short=SMAD 6;
DE Short=Smad6;
GN Name=Smad6; Synonyms=Madh6, Madh7, Msmad6;
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].
RC TISSUE=Lung;
RX PubMed=9335505; DOI=10.1038/39355;
RA Imamura T., Takase M., Nishihara A., Oeda E., Hanai J., Kawabata M.,
RA Miyazono K.;
RT "Smad6 inhibits signalling by the TGF-beta superfamily.";
RL Nature 389:622-626(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 174-495.
RC STRAIN=C57BL/6J; TISSUE=Lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP INTERACTION WITH RNF111.
RX PubMed=14657019; DOI=10.1093/emboj/cdg632;
RA Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A.,
RA Ebina M., Nukiwa T., Miyazawa K., Imamura T., Miyazono K.;
RT "Arkadia amplifies TGF-beta superfamily signaling through degradation of
RT Smad7.";
RL EMBO J. 22:6458-6470(2003).
RN [4]
RP INTERACTION WITH WWP1, AND UBIQUITINATION.
RX PubMed=15221015; DOI=10.1038/sj.onc.1207885;
RA Komuro A., Imamura T., Saitoh M., Yoshida Y., Yamori T., Miyazono K.,
RA Miyazawa K.;
RT "Negative regulation of transforming growth factor-beta (TGF-beta)
RT signaling by WW domain-containing protein 1 (WWP1).";
RL Oncogene 23:6914-6923(2004).
RN [5]
RP INTERACTION WITH NEDD4L.
RX PubMed=15496141; DOI=10.1042/bj20040738;
RA Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K., Miyazono K.,
RA Imamura T.;
RT "NEDD4-2 (neural precursor cell expressed, developmentally down-regulated
RT 4-2) negatively regulates TGF-beta (transforming growth factor-beta)
RT signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta
RT type I receptor.";
RL Biochem. J. 386:461-470(2005).
RN [6]
RP FUNCTION, INTERACTION WITH PELI1, AND INDUCTION.
RX PubMed=16951688; DOI=10.1038/ni1383;
RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
RA Kim I.H., Kim S.J., Park S.H.;
RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
RT signaling through direct interaction with the adapter Pellino-1.";
RL Nat. Immunol. 7:1057-1065(2006).
RN [7]
RP METHYLATION AT ARG-74 AND ARG-81, AND MUTAGENESIS OF ARG-74.
RX PubMed=23747011; DOI=10.1016/j.molcel.2013.05.004;
RA Xu J., Wang A.H., Oses-Prieto J., Makhijani K., Katsuno Y., Pei M., Yan L.,
RA Zheng Y.G., Burlingame A., Bruckner K., Derynck R.;
RT "Arginine Methylation Initiates BMP-Induced Smad Signaling.";
RL Mol. Cell 51:5-19(2013).
RN [8]
RP UBIQUITINATION.
RX PubMed=23610558; DOI=10.1371/journal.pbio.1001538;
RA Kelly C.E., Thymiakou E., Dixon J.E., Tanaka S., Godwin J., Episkopou V.;
RT "Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon
RT extension.";
RL PLoS Biol. 11:E1001538-E1001538(2013).
CC -!- FUNCTION: Transforming growth factor-beta superfamily receptors
CC signaling occurs through the Smad family of intracellular mediators.
CC SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates
CC signaling downstream of type I transforming growth factor-beta (By
CC similarity). Acts as a mediator of TGF-beta and BMP anti-inflammatory
CC activities. Suppresses IL1R-TLR signaling through its direct
CC interaction with PEL1, preventing NF-kappa-B activation, nuclear
CC transport and NF-kappa-B-mediated expression of pro-inflammatory genes
CC (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing
CC with SMAD4 for receptor-activated SMAD1-binding. Binds to regulatory
CC elements in target promoter regions (By similarity).
CC {ECO:0000250|UniProtKB:O43541, ECO:0000269|PubMed:16951688}.
CC -!- SUBUNIT: Interacts with NEDD4L. Interacts with WWP1. Interacts with
CC STAMBP and PRKX (By similarity). Interacts with RNF111 and AXIN1.
CC Interacts with TGF-beta type I receptor superfamily members, including
CC ACVR1B, BMPR1B and TGFBR1. In response to BMP2 treatment, interacts
CC with SMAD1; this interaction may inhibit SMAD1-binding to SMAD4.
CC Interacts with HOXC8 and HOXC9 (By similarity). Interacts with PELI1;
CC this interaction interferes with PELI1 complex formation with TRAF6,
CC IRAK1, IRAK4 and MYD88 in response to IL1B and hence negatively
CC regulates IL1R-TLR signaling. {ECO:0000250,
CC ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:15221015,
CC ECO:0000269|PubMed:15496141, ECO:0000269|PubMed:16951688}.
CC -!- INTERACTION:
CC O35182; O35625: Axin1; NbExp=2; IntAct=EBI-4321242, EBI-2365912;
CC O35182; P36898: Bmpr1b; NbExp=2; IntAct=EBI-4321242, EBI-7107883;
CC O35182; Q9JIF0: Prmt1; NbExp=3; IntAct=EBI-4321242, EBI-519055;
CC O35182; Q9C0C9: UBE2O; Xeno; NbExp=4; IntAct=EBI-4321242, EBI-2339946;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Ubiquitous in various organs, with higher levels in
CC lung.
CC -!- INDUCTION: By TGF-beta and BMP4. {ECO:0000269|PubMed:16951688}.
CC -!- PTM: Monoubiquitinated at Lys-174 by the E2/E3 hybrid ubiquitin-protein
CC ligase UBE2O, leading to reduced binding affinity for the activated BMP
CC type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating
CC adipocyte differentiation (By similarity). Ubiquitinated by WWP1
CC (PubMed:15221015). Ubiquitinated by RNF165, promoting proteasomal
CC degradation, leading to enhance the BMP-Smad signaling
CC (PubMed:23610558). {ECO:0000250|UniProtKB:O43541,
CC ECO:0000269|PubMed:15221015, ECO:0000269|PubMed:23610558}.
CC -!- PTM: Arginine methylation by PRMT1, which is recruited by BMPR2,
CC initiates BMP-Induced signaling and induces dissociation from the
CC BMPR1B receptor at the cell surface leading to derepress downstream
CC Smad1/Smad5 signaling. {ECO:0000269|PubMed:23747011}.
CC -!- PTM: Phosphorylated by BMP type 1 receptor kinase and by PRKX.
CC {ECO:0000250|UniProtKB:O43541}.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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DR EMBL; AF010133; AAB81351.1; -; mRNA.
DR EMBL; AK004671; BAB23460.1; -; mRNA.
DR CCDS; CCDS23273.1; -.
DR RefSeq; NP_032568.3; NM_008542.3.
DR RefSeq; XP_006510885.1; XM_006510822.2.
DR AlphaFoldDB; O35182; -.
DR SMR; O35182; -.
DR BioGRID; 201279; 11.
DR IntAct; O35182; 189.
DR MINT; O35182; -.
DR STRING; 10090.ENSMUSP00000036285; -.
DR iPTMnet; O35182; -.
DR PhosphoSitePlus; O35182; -.
DR PaxDb; O35182; -.
DR PRIDE; O35182; -.
DR ProteomicsDB; 261255; -.
DR Antibodypedia; 13795; 581 antibodies from 37 providers.
DR DNASU; 17130; -.
DR Ensembl; ENSMUST00000041029; ENSMUSP00000036285; ENSMUSG00000036867.
DR GeneID; 17130; -.
DR KEGG; mmu:17130; -.
DR UCSC; uc009qbk.2; mouse.
DR CTD; 4091; -.
DR MGI; MGI:1336883; Smad6.
DR VEuPathDB; HostDB:ENSMUSG00000036867; -.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000158146; -.
DR HOGENOM; CLU_026736_2_1_1; -.
DR InParanoid; O35182; -.
DR OMA; CLFKERD; -.
DR OrthoDB; 395665at2759; -.
DR PhylomeDB; O35182; -.
DR TreeFam; TF314923; -.
DR Reactome; R-MMU-201451; Signaling by BMP.
DR BioGRID-ORCS; 17130; 4 hits in 77 CRISPR screens.
DR ChiTaRS; Smad6; mouse.
DR PRO; PR:O35182; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; O35182; protein.
DR Bgee; ENSMUSG00000036867; Expressed in right lung and 187 other tissues.
DR ExpressionAtlas; O35182; baseline and differential.
DR Genevisible; O35182; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0070410; F:co-SMAD binding; ISO:MGI.
DR GO; GO:0070411; F:I-SMAD binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070412; F:R-SMAD binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0140416; F:transcription regulator inhibitor activity; ISO:MGI.
DR GO; GO:0070698; F:type I activin receptor binding; ISO:MGI.
DR GO; GO:0034713; F:type I transforming growth factor beta receptor binding; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0035904; P:aorta development; IMP:MGI.
DR GO; GO:0003180; P:aortic valve morphogenesis; ISO:MGI.
DR GO; GO:0030509; P:BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0060948; P:cardiac vascular smooth muscle cell development; TAS:DFLAT.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0031589; P:cell-substrate adhesion; ISS:UniProtKB.
DR GO; GO:0060976; P:coronary vasculature development; IMP:MGI.
DR GO; GO:0060977; P:coronary vasculature morphogenesis; TAS:DFLAT.
DR GO; GO:0045444; P:fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0003170; P:heart valve development; IMP:MGI.
DR GO; GO:0006955; P:immune response; ISO:MGI.
DR GO; GO:0003183; P:mitral valve morphogenesis; IMP:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0030279; P:negative regulation of ossification; IMP:BHF-UCL.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; ISO:MGI.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; ISO:MGI.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI.
DR GO; GO:0003148; P:outflow tract septum morphogenesis; IMP:BHF-UCL.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IMP:BHF-UCL.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; TAS:DFLAT.
DR GO; GO:0003184; P:pulmonary valve morphogenesis; IMP:BHF-UCL.
DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
DR GO; GO:0034616; P:response to laminar fluid shear stress; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISO:MGI.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0001657; P:ureteric bud development; IEP:UniProtKB.
DR GO; GO:0042310; P:vasoconstriction; TAS:DFLAT.
DR GO; GO:0003281; P:ventricular septum development; IMP:MGI.
DR GO; GO:0007352; P:zygotic specification of dorsal/ventral axis; ISO:MGI.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR001132; SMAD_dom_Dwarfin-type.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036578; SMAD_MH1_sf.
DR PANTHER; PTHR13703; PTHR13703; 1.
DR Pfam; PF03165; MH1; 1.
DR Pfam; PF03166; MH2; 1.
DR SMART; SM00523; DWA; 1.
DR SMART; SM00524; DWB; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 1.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 1: Evidence at protein level;
KW DNA-binding; Isopeptide bond; Metal-binding; Methylation; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc.
FT CHAIN 1..495
FT /note="Mothers against decapentaplegic homolog 6"
FT /id="PRO_0000090870"
FT DOMAIN 149..276
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 332..495
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 1..115
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 133..161
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 206
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 248
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 261
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 266
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 74
FT /note="Dimethylated arginine; alternate"
FT /evidence="ECO:0000269|PubMed:23747011"
FT MOD_RES 74
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0000269|PubMed:23747011"
FT MOD_RES 81
FT /note="Dimethylated arginine; alternate"
FT /evidence="ECO:0000269|PubMed:23747011"
FT MOD_RES 81
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0000269|PubMed:23747011"
FT MOD_RES 436
FT /note="Phosphoserine; by PRKX; in vitro"
FT /evidence="ECO:0000250|UniProtKB:O43541,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT CROSSLNK 174
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O43541"
FT MUTAGEN 74
FT /note="R->A: Strongly decreased methylation."
FT /evidence="ECO:0000269|PubMed:23747011"
FT CONFLICT 176..177
FT /note="VT -> AQ (in Ref. 2; BAB23460)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 495 AA; 53714 MW; D9282D42B120C507 CRC64;
MFRSKRSGLV RRLWRSRVVP DREEGSGGGG GVDEDGSLGS RAEPAPRARE GGGCSRSEVR
SVAPRRPRDA VGPRGAAIAG RRRRTGGLPR PVSESGAGAG GSPLDVAEPG GPGWLPESDC
ETVTCCLFSE RDAAGAPRDS GDPQARQSPE PEEGGGPRSR EARSRLLLLE QELKTVTYSL
LKRLKERSLD TLLEAVESRG GVPGGCVLVP RADLRLGGQP APPQLLLGRL FRWPDLQHAV
ELKPLCGCHS FTAAADGPTV CCNPYHFSRL CGPESPPPPY SRLSPPDQYK PLDLSDSTLS
YTETEATNSL ITAPGEFSDA SMSPDATKPS HWCSVAYWEH RTRVGRLYAV YDQAVSIFYD
LPQGSGFCLG QLNLEQRSES VRRTRSKIGF GILLSKEPDG VWAYNRGEHP IFVNSPTLDA
PGGRALVVRK VPPGYSIKVF DFERSGLLQH ADAAHGPYDP HSVRISFAKG WGPCYSRQFI
TSCPCWLEIL LNNHR
