SMAD6_HUMAN
ID SMAD6_HUMAN Reviewed; 496 AA.
AC O43541; A9J6M5; O43654; Q15799; Q7Z7L4; Q96E31; Q9UKZ3;
DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Mothers against decapentaplegic homolog 6;
DE Short=MAD homolog 6;
DE Short=Mothers against DPP homolog 6;
DE AltName: Full=SMAD family member 6;
DE Short=SMAD 6;
DE Short=Smad6;
DE Short=hSMAD6;
GN Name=SMAD6; Synonyms=MADH6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RX PubMed=8673135; DOI=10.1038/ng0796-347;
RA Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., Kern S.E.,
RA Hamilton S.R., Willson J.K.V., Markowitz S.D., Kinzler K.W.,
RA Vogelstein B.V.;
RT "Mad-related genes in the human.";
RL Nat. Genet. 13:347-349(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), FUNCTION, INTERACTION WITH ACVR1B;
RP BMPR1B; SMAD1 AND TGFBR1, AND MUTAGENESIS OF GLY-471 AND 478-ARG--ARG-496.
RC TISSUE=T-cell;
RX PubMed=9436979; DOI=10.1101/gad.12.2.186;
RA Hata A., Lagna G., Massague J., Hemmati-Brivanlou A.;
RT "Smad6 inhibits BMP/Smad1 signaling by specifically competing with the
RT Smad4 tumor suppressor.";
RL Genes Dev. 12:186-197(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
RC TISSUE=Placenta;
RX PubMed=9712726; DOI=10.1006/bbrc.1998.9170;
RA Afrakhte M., Moren A., Jossan S., Itoh S., Sampath K., Westermark B.,
RA Heldin C.H., Heldin N.E., ten Dijke P.;
RT "Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members.";
RL Biochem. Biophys. Res. Commun. 249:505-511(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM A).
RA Hagiwara K., Freeman A.H., McMenamin M.G., Bennett W.P., Nagashima M.,
RA Minter A.R., Yang K., Takenoshita S., Harris C.C.;
RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM D).
RC TISSUE=Prostatic carcinoma;
RA Konrad L., Scheiber J.A., Brandt H., Eickelberg O., Hofmann R.;
RT "Identification of a new SMAD6 variant in human.";
RL Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Uterus;
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 [7]
RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM B).
RA Hagiwara K., Freeman A.A.H., McMenamin M.G., Bennett W.P., Yang K.,
RA Takenoshita S., Harris C.C.;
RT "Determination of the genomic structure of human Smad3, Smad6 and Smad7 and
RT the cloning of the human Smad3 promoter.";
RL Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP REVIEW, AND FUNCTION.
RX PubMed=9759503; DOI=10.1146/annurev.biochem.67.1.753;
RA Massague J.;
RT "TGF-beta signal transduction.";
RL Annu. Rev. Biochem. 67:753-791(1998).
RN [9]
RP REVIEW, AND FUNCTION.
RX PubMed=10647776; DOI=10.1016/s1359-6101(99)00012-x;
RA Verschueren K., Huylebroeck D.;
RT "Remarkable versatility of Smad proteins in the nucleus of transforming
RT growth factor-beta activated cells.";
RL Cytokine Growth Factor Rev. 10:187-199(1999).
RN [10]
RP REVIEW, AND FUNCTION.
RX PubMed=10708948; DOI=10.1016/s1359-6101(99)00024-6;
RA Wrana J.L., Attisano L.;
RT "The Smad pathway.";
RL Cytokine Growth Factor Rev. 11:5-13(2000).
RN [11]
RP REVIEW, AND FUNCTION.
RX PubMed=10708949; DOI=10.1016/s1359-6101(99)00025-8;
RA Miyazono K.;
RT "TGF-beta signaling by Smad proteins.";
RL Cytokine Growth Factor Rev. 11:15-22(2000).
RN [12]
RP INTERACTION WITH HOXC8.
RX PubMed=10722652; DOI=10.1074/jbc.275.12.8267;
RA Bai S., Shi X., Yang X., Cao X.;
RT "Smad6 as a transcriptional corepressor.";
RL J. Biol. Chem. 275:8267-8270(2000).
RN [13]
RP FUNCTION (ISOFORM B).
RX PubMed=11284962; DOI=10.1046/j.1440-169x.2001.00562.x;
RA Krishnan P., King M.W., Neff A.W., Sandusky G.E., Bierman K.L.,
RA Grinnell B., Smith R.C.;
RT "Human truncated Smad 6 (Smad 6s) inhibits the BMP pathway in Xenopus
RT laevis.";
RL Dev. Growth Differ. 43:115-132(2001).
RN [14]
RP INTERACTION WITH STAMBP.
RX PubMed=11483516; DOI=10.1093/emboj/20.15.4132;
RA Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S.;
RT "Promoting bone morphogenetic protein signaling through negative regulation
RT of inhibitory Smads.";
RL EMBO J. 20:4132-4142(2001).
RN [15]
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 [16]
RP INTERACTION WITH AXIN1.
RX PubMed=16601693; DOI=10.1038/sj.emboj.7601057;
RA Liu W., Rui H., Wang J., Lin S., He Y., Chen M., Li Q., Ye Z., Zhang S.,
RA Chan S.C., Chen Y.-G., Han J., Lin S.-C.;
RT "Axin is a scaffold protein in TGF-beta signaling that promotes degradation
RT of Smad7 by Arkadia.";
RL EMBO J. 25:1646-1658(2006).
RN [17]
RP FUNCTION, AND INTERACTION WITH PELI1.
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 [18]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRKX, MUTAGENESIS OF
RP SER-435, AND PHOSPHORYLATION AT SER-435.
RX PubMed=16491121; DOI=10.1038/sj.onc.1209436;
RA Glesne D., Huberman E.;
RT "Smad6 is a protein kinase X phosphorylation substrate and is required for
RT HL-60 cell differentiation.";
RL Oncogene 25:4086-4098(2006).
RN [19]
RP INVOLVEMENT IN CONGENITAL CARDIOVASCULAR MALFORMATIONS, INVOLVEMENT IN
RP AOVD2, VARIANT THR-325, VARIANTS AOVD2 LEU-415 AND PHE-484,
RP CHARACTERIZATION OF VARIANTS AOVD2 LEU-415 AND PHE-484, AND FUNCTION.
RX PubMed=22275001; DOI=10.1002/humu.22030;
RA Tan H.L., Glen E., Topf A., Hall D., O'Sullivan J.J., Sneddon L., Wren C.,
RA Avery P., Lewis R.J., ten Dijke P., Arthur H.M., Goodship J.A.,
RA Keavney B.D.;
RT "Nonsynonymous variants in the SMAD6 gene predispose to congenital
RT cardiovascular malformation.";
RL Hum. Mutat. 33:720-727(2012).
RN [20]
RP UBIQUITINATION AT LYS-173, AND MUTAGENESIS OF LYS-173.
RX PubMed=23455153; DOI=10.1038/emboj.2013.38;
RA Zhang X., Zhang J., Bauer A., Zhang L., Selinger D.W., Lu C.X.,
RA Ten Dijke P.;
RT "Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated
RT monoubiquitination of SMAD6.";
RL EMBO J. 32:996-1007(2013).
RN [21]
RP INVOLVEMENT IN CRS7, AND VARIANTS CRS7 223-GLN--ARG-496 DEL; LYS-287;
RP ALA-306; LEU-323; 374-GLU--ARG-496 DEL; CYS-390; 407-GLU--ARG-496 DEL;
RP CYS-465 AND THR-490.
RX PubMed=27606499; DOI=10.7554/elife.20125;
RA Timberlake A.T., Choi J., Zaidi S., Lu Q., Nelson-Williams C., Brooks E.D.,
RA Bilguvar K., Tikhonova I., Mane S., Yang J.F., Sawh-Martinez R.,
RA Persing S., Zellner E.G., Loring E., Chuang C., Galm A., Hashim P.W.,
RA Steinbacher D.M., DiLuna M.L., Duncan C.C., Pelphrey K.A., Zhao H.,
RA Persing J.A., Lifton R.P.;
RT "Two locus inheritance of non-syndromic midline craniosynostosis via rare
RT SMAD6 and common BMP2 alleles.";
RL Elife 5:0-0(2016).
RN [22]
RP INVOLVEMENT IN RUS, VARIANTS RUS 115-TRP--ARG-496 DEL; LEU-187; SER-205;
RP ASN-267; 279-TYR--ARG-496 DEL; 315-GLU--ARG-496 DEL; PRO-339;
RP 350-TYR--ARG-496 DEL; ARG-370; 447-GLN--ARG-496 DEL AND ASP-471, AND
RP VARIANTS 75-ARG--ARG-496 DEL; 130-SER--ARG-496 DEL AND 300-TYR--ARG-496
RP DEL.
RX PubMed=31138930; DOI=10.1038/s41436-019-0552-8;
RA Yang Y., Zheng Y., Li W., Li L., Tu M., Zhao L., Mei H., Zhu G., Zhu Y.;
RT "SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis.";
RL Genet. Med. 21:2577-2585(2019).
RN [23]
RP VARIANTS AOVD2 14-TRP--ARG-496 DEL; ALA-204; GLY-231; PRO-231 AND GLU-335.
RX PubMed=30796334; DOI=10.1038/s41431-019-0363-z;
RA Luyckx I., MacCarrick G., Kempers M., Meester J., Geryl C., Rombouts O.,
RA Peeters N., Claes C., Boeckx N., Sakalihasan N., Jacquinet A., Hoischen A.,
RA Vandeweyer G., Van Lent S., Saenen J., Van Craenenbroeck E., Timmermans J.,
RA Duijnhouwer A., Dietz H., Van Laer L., Loeys B., Verstraeten A.;
RT "Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic
RT valve-related aortopathy.";
RL Eur. J. Hum. Genet. 27:1044-1053(2019).
RN [24]
RP VARIANT AOVD2 GLY-ILE-391 INS, CHARACTERIZATION OF AOVD2 GLY-ILE-391 INS
RP AND PHE-484, AND FUNCTION.
RX PubMed=30848080; DOI=10.1002/mgg3.620;
RA Park J.E., Park J.S., Jang S.Y., Park S.H., Kim J.W., Ki C.S., Kim D.K.;
RT "A novel SMAD6 variant in a patient with severely calcified bicuspid aortic
RT valve and thoracic aortic aneurysm.";
RL Mol. Genet. Genomic Med. 7:e620-e620(2019).
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
CC (PubMed:9436979, PubMed:16951688, PubMed:22275001, PubMed:9759503,
CC PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:30848080).
CC Acts as a mediator of TGF-beta and BMP anti-inflammatory activities.
CC Suppresses IL1R-TLR signaling through its direct interaction with PEL1,
CC preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-
CC mediated expression of pro-inflammatory genes (PubMed:16951688). Blocks
CC the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-
CC activated SMAD1-binding (PubMed:9436979, PubMed:30848080). Binds to
CC regulatory elements in target promoter regions (PubMed:16491121).
CC {ECO:0000269|PubMed:16491121, ECO:0000269|PubMed:16951688,
CC ECO:0000269|PubMed:22275001, ECO:0000269|PubMed:30848080,
CC ECO:0000269|PubMed:9436979, ECO:0000303|PubMed:10647776,
CC ECO:0000303|PubMed:10708948, ECO:0000303|PubMed:10708949,
CC ECO:0000303|PubMed:9759503}.
CC -!- SUBUNIT: Interacts with NEDD4L (By similarity). Interacts with WWP1 (By
CC similarity). Interacts with STAMBP and PRKX. Interacts with RNF111 and
CC AXIN1. Interacts with TGF-beta type I receptor superfamily members,
CC including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to
CC TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with
CC SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts
CC with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes
CC with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in
CC response to IL1B and hence negatively regulates IL1R-TLR signaling.
CC {ECO:0000250, ECO:0000269|PubMed:10722652, ECO:0000269|PubMed:11483516,
CC ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16491121,
CC ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:16951688,
CC ECO:0000269|PubMed:9436979}.
CC -!- INTERACTION:
CC O43541; P51817: PRKX; NbExp=5; IntAct=EBI-976374, EBI-4302903;
CC O43541; Q13950: RUNX2; NbExp=3; IntAct=EBI-976374, EBI-976402;
CC O43541; Q15797: SMAD1; NbExp=4; IntAct=EBI-976374, EBI-1567153;
CC O43541; O43541: SMAD6; NbExp=2; IntAct=EBI-976374, EBI-976374;
CC O43541-2; O95630: STAMBP; NbExp=2; IntAct=EBI-4324970, EBI-396676;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16491121}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A;
CC IsoId=O43541-1; Sequence=Displayed;
CC Name=B; Synonyms=Smad 6S;
CC IsoId=O43541-2; Sequence=VSP_006179, VSP_006180;
CC Name=D;
CC IsoId=O43541-4; Sequence=VSP_035489, VSP_035490;
CC -!- TISSUE SPECIFICITY: Ubiquitous in various organs, with higher levels in
CC lung. Isoform B is up-regulated in diseased heart tissue.
CC -!- PTM: Phosphorylated by BMP type 1 receptor kinase and by PRKX.
CC {ECO:0000269|PubMed:16491121}.
CC -!- PTM: Monoubiquitinated at Lys-173 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 (PubMed:23455153). Ubiquitinated by WWP1 (By
CC similarity). Ubiquitinated by RNF165, promoting proteasomal
CC degradation, leading to enhance the BMP-Smad signaling (By similarity).
CC {ECO:0000250|UniProtKB:O35182, ECO:0000269|PubMed:23455153}.
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:0000250|UniProtKB:O35182}.
CC -!- DISEASE: Aortic valve disease 2 (AOVD2) [MIM:614823]: A common defect
CC in the aortic valve in which two rather than three leaflets are
CC present. It is often associated with aortic valve calcification,
CC stenosis and insufficiency. In extreme cases, the blood flow may be so
CC restricted that the left ventricle fails to grow, resulting in
CC hypoplastic left heart syndrome. {ECO:0000269|PubMed:22275001,
CC ECO:0000269|PubMed:30796334, ECO:0000269|PubMed:30848080}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. SMAD6 variants may contribute to increased risk of congenital
CC cardiovascular malformations (CVM). CVM is a major cause of mortality
CC and morbidity in childhood. In most sporadic cases that cannot be
CC attributed to particular malformation syndromes or teratogenic
CC exposures, there remains a substantial excess familial risk, indicating
CC a significant genetic contribution to disease susceptibility
CC (PubMed:22275001). {ECO:0000269|PubMed:22275001}.
CC -!- DISEASE: Craniosynostosis 7 (CRS7) [MIM:617439]: A form of
CC craniosynostosis, a primary abnormality of skull growth involving
CC premature fusion of one or more cranial sutures. The growth velocity of
CC the skull often cannot match that of the developing brain resulting in
CC an abnormal head shape and, in some cases, increased intracranial
CC pressure, which must be treated promptly to avoid permanent
CC neurodevelopmental disability. {ECO:0000269|PubMed:27606499}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry. Rare heterozygous SMAD6 variants are
CC strongly associated with non-syndromic midline craniosynostosis and
CC confer a very high risk for disease development, in the presence of a
CC common risk allele (rs1884302) near the BMP2 locus.
CC {ECO:0000269|PubMed:27606499}.
CC -!- DISEASE: Radioulnar synostosis, non-syndromic (RUS) [MIM:179300]: An
CC autosomal dominant disease characterized by proximal fusion of the
CC radius and ulna resulting in extremely limited pronation and supination
CC of the forearm. There are two disease forms. Radioulnar synostosis type
CC 1 is characterized by a proximal fusion between the radius and ulna,
CC and the radial head is absent. Radioulnar synostosis type 2 is
CC characterized by a fusion just distal to the proximal radial epiphysis,
CC and congenital dislocation of the radial head. In radioulnar synostosis
CC type 2 there is also a restriction of extension at the elbow.
CC {ECO:0000269|PubMed:31138930}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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DR EMBL; U59914; AAC50792.1; -; mRNA.
DR EMBL; AF035528; AAB94137.1; -; mRNA.
DR EMBL; AF043640; AAC00497.1; -; mRNA.
DR EMBL; AF037469; AAC82331.1; -; mRNA.
DR EMBL; AF041065; AAF14343.1; -; Genomic_DNA.
DR EMBL; AF041062; AAF14343.1; JOINED; Genomic_DNA.
DR EMBL; AF041063; AAF14343.1; JOINED; Genomic_DNA.
DR EMBL; AF041064; AAF14343.1; JOINED; Genomic_DNA.
DR EMBL; AM909653; CAP20377.1; -; mRNA.
DR EMBL; BC012986; AAH12986.1; -; mRNA.
DR EMBL; AF101474; AAF06841.1; -; Genomic_DNA.
DR CCDS; CCDS10221.1; -. [O43541-1]
DR RefSeq; NP_005576.3; NM_005585.4. [O43541-1]
DR RefSeq; XP_011519863.1; XM_011521561.2. [O43541-2]
DR AlphaFoldDB; O43541; -.
DR SMR; O43541; -.
DR BioGRID; 110266; 51.
DR CORUM; O43541; -.
DR DIP; DIP-36708N; -.
DR IntAct; O43541; 17.
DR MINT; O43541; -.
DR STRING; 9606.ENSP00000288840; -.
DR iPTMnet; O43541; -.
DR PhosphoSitePlus; O43541; -.
DR BioMuta; SMAD6; -.
DR MassIVE; O43541; -.
DR MaxQB; O43541; -.
DR PaxDb; O43541; -.
DR PeptideAtlas; O43541; -.
DR PRIDE; O43541; -.
DR ProteomicsDB; 49038; -. [O43541-1]
DR ProteomicsDB; 49039; -. [O43541-2]
DR ProteomicsDB; 49040; -. [O43541-4]
DR Antibodypedia; 13795; 581 antibodies from 37 providers.
DR DNASU; 4091; -.
DR Ensembl; ENST00000288840.10; ENSP00000288840.5; ENSG00000137834.15. [O43541-1]
DR Ensembl; ENST00000557916.5; ENSP00000452955.1; ENSG00000137834.15. [O43541-4]
DR GeneID; 4091; -.
DR KEGG; hsa:4091; -.
DR MANE-Select; ENST00000288840.10; ENSP00000288840.5; NM_005585.5; NP_005576.3.
DR UCSC; uc002aqf.4; human. [O43541-1]
DR CTD; 4091; -.
DR DisGeNET; 4091; -.
DR GeneCards; SMAD6; -.
DR HGNC; HGNC:6772; SMAD6.
DR HPA; ENSG00000137834; Tissue enhanced (lung).
DR MalaCards; SMAD6; -.
DR MIM; 179300; phenotype.
DR MIM; 602931; gene.
DR MIM; 614823; phenotype.
DR MIM; 617439; phenotype.
DR neXtProt; NX_O43541; -.
DR OpenTargets; ENSG00000137834; -.
DR Orphanet; 402075; Familial bicuspid aortic valve.
DR PharmGKB; PA30529; -.
DR VEuPathDB; HostDB:ENSG00000137834; -.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000158146; -.
DR HOGENOM; CLU_026736_2_1_1; -.
DR InParanoid; O43541; -.
DR OMA; CLFKERD; -.
DR OrthoDB; 395665at2759; -.
DR PhylomeDB; O43541; -.
DR TreeFam; TF314923; -.
DR PathwayCommons; O43541; -.
DR Reactome; R-HSA-201451; Signaling by BMP.
DR Reactome; R-HSA-8941326; RUNX2 regulates bone development.
DR SignaLink; O43541; -.
DR SIGNOR; O43541; -.
DR BioGRID-ORCS; 4091; 26 hits in 1099 CRISPR screens.
DR ChiTaRS; SMAD6; human.
DR GeneWiki; Mothers_against_decapentaplegic_homolog_6; -.
DR GenomeRNAi; 4091; -.
DR Pharos; O43541; Tbio.
DR PRO; PR:O43541; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; O43541; protein.
DR Bgee; ENSG00000137834; Expressed in right lung and 199 other tissues.
DR ExpressionAtlas; O43541; baseline and differential.
DR Genevisible; O43541; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; TAS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
DR GO; GO:0016604; C:nuclear body; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0070410; F:co-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0070411; F:I-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0070412; F:R-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0140416; F:transcription regulator inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0070698; F:type I activin receptor binding; IDA:BHF-UCL.
DR GO; GO:0034713; F:type I transforming growth factor beta receptor binding; IDA:BHF-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0035904; P:aorta development; IEA:Ensembl.
DR GO; GO:0003180; P:aortic valve morphogenesis; IMP:BHF-UCL.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0031589; P:cell-substrate adhesion; IMP:UniProtKB.
DR GO; GO:0060976; P:coronary vasculature development; IEA:Ensembl.
DR GO; GO:0045444; P:fat cell differentiation; IDA:UniProtKB.
DR GO; GO:0006955; P:immune response; IMP:BHF-UCL.
DR GO; GO:0003183; P:mitral valve morphogenesis; ISS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:BHF-UCL.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0030279; P:negative regulation of ossification; ISS:BHF-UCL.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0003148; P:outflow tract septum morphogenesis; ISS:BHF-UCL.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IEA:Ensembl.
DR GO; GO:0003184; P:pulmonary valve morphogenesis; ISS:BHF-UCL.
DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
DR GO; GO:0034616; P:response to laminar fluid shear stress; IEP:BHF-UCL.
DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:ARUK-UCL.
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; IEA:Ensembl.
DR GO; GO:0003281; P:ventricular septum development; IEA:Ensembl.
DR GO; GO:0007352; P:zygotic specification of dorsal/ventral axis; IMP:BHF-UCL.
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 Alternative splicing; Craniosynostosis; Disease variant; DNA-binding;
KW Isopeptide bond; Metal-binding; Methylation; Nucleus; Phosphoprotein;
KW Reference proteome; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc.
FT CHAIN 1..496
FT /note="Mothers against decapentaplegic homolog 6"
FT /id="PRO_0000090869"
FT DOMAIN 148..275
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 331..496
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 1..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 136..156
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 205
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 247
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 260
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 265
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 75
FT /note="Dimethylated arginine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O35182"
FT MOD_RES 75
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O35182"
FT MOD_RES 82
FT /note="Dimethylated arginine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O35182"
FT MOD_RES 82
FT /note="Omega-N-methylarginine; alternate"
FT /evidence="ECO:0000250|UniProtKB:O35182"
FT MOD_RES 435
FT /note="Phosphoserine; by PRKX; in vitro"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
FT ECO:0000269|PubMed:16491121"
FT CROSSLNK 173
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23455153"
FT VAR_SEQ 1..261
FT /note="Missing (in isoform B)"
FT /evidence="ECO:0000303|PubMed:8673135"
FT /id="VSP_006179"
FT VAR_SEQ 262..273
FT /note="NPYHFSRLCGPE -> MSRMGKPIETQK (in isoform B)"
FT /evidence="ECO:0000303|PubMed:8673135"
FT /id="VSP_006180"
FT VAR_SEQ 318..338
FT /note="DASMSPDATKPSHWCSVAYWE -> AADAGIGSRGNRGLESSVPCS (in
FT isoform D)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_035489"
FT VAR_SEQ 339..496
FT /note="Missing (in isoform D)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_035490"
FT VARIANT 14..496
FT /note="Missing (in AOVD2)"
FT /evidence="ECO:0000269|PubMed:30796334"
FT /id="VAR_084468"
FT VARIANT 75..496
FT /note="Missing (probable disease-associated variant found
FT in a patient with radioulnar synostosis and macrocephaly;
FT associated with disease susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084469"
FT VARIANT 115..496
FT /note="Missing (in RUS; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084470"
FT VARIANT 130..496
FT /note="Missing (probable disease-associated variant found
FT in a patient with radioulnar synostosis and microcephaly;
FT associated with disease susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084471"
FT VARIANT 187
FT /note="S -> L (in RUS; unknown pathological significance;
FT dbSNP:rs1359442505)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084472"
FT VARIANT 204
FT /note="G -> A (in AOVD2; unknown pathological significance;
FT dbSNP:rs768542939)"
FT /evidence="ECO:0000269|PubMed:30796334"
FT /id="VAR_084473"
FT VARIANT 205
FT /note="C -> S (in RUS; unknown pathological significance;
FT dbSNP:rs1595757271)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084474"
FT VARIANT 223..496
FT /note="Missing (in CRS7; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_078924"
FT VARIANT 231
FT /note="R -> G (in AOVD2; unknown pathological significance;
FT dbSNP:rs1395007983)"
FT /evidence="ECO:0000269|PubMed:30796334"
FT /id="VAR_084475"
FT VARIANT 231
FT /note="R -> P (in AOVD2; unknown pathological significance;
FT dbSNP:rs1419095990)"
FT /evidence="ECO:0000269|PubMed:30796334"
FT /id="VAR_084476"
FT VARIANT 267
FT /note="S -> N (in RUS; unknown pathological significance;
FT dbSNP:rs1396117157)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084477"
FT VARIANT 279..496
FT /note="Missing (in RUS; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084478"
FT VARIANT 287
FT /note="E -> K (in CRS7; unknown pathological significance;
FT dbSNP:rs570279865)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_078925"
FT VARIANT 300..496
FT /note="Missing (probable disease-associated variant found
FT in a patient with radioulnar synostosis, pectus carinatum
FT and macrocephaly)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084479"
FT VARIANT 306
FT /note="T -> A (in CRS7; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_077592"
FT VARIANT 315..496
FT /note="Missing (in RUS; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084480"
FT VARIANT 323
FT /note="P -> L (in CRS7; associated with disease
FT susceptibility; dbSNP:rs1374099442)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_077593"
FT VARIANT 325
FT /note="A -> T (found in a patient with congenital mitral
FT valve prolapse; dbSNP:rs199822239)"
FT /evidence="ECO:0000269|PubMed:22275001"
FT /id="VAR_068074"
FT VARIANT 335
FT /note="A -> E (in AOVD2; unknown pathological significance;
FT dbSNP:rs900988907)"
FT /evidence="ECO:0000269|PubMed:30796334"
FT /id="VAR_084481"
FT VARIANT 339
FT /note="H -> P (in RUS; unknown pathological significance;
FT dbSNP:rs142278375)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084482"
FT VARIANT 350..496
FT /note="Missing (in RUS; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084483"
FT VARIANT 370
FT /note="Q -> R (in RUS; unknown pathological significance;
FT dbSNP:rs1567115899)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084484"
FT VARIANT 374..496
FT /note="Missing (in CRS7; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_078926"
FT VARIANT 390
FT /note="G -> C (in CRS7; associated with disease
FT susceptibility; de novo mutation)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_077594"
FT VARIANT 391
FT /note="I -> IGI (in AOVD2; decreased inhibition of BMP
FT signaling pathway)"
FT /evidence="ECO:0000269|PubMed:30848080"
FT /id="VAR_084485"
FT VARIANT 407..496
FT /note="Missing (in CRS7; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_078927"
FT VARIANT 415
FT /note="P -> L (in AOVD2; decreased inhibition of BMP
FT signaling pathway; dbSNP:rs387907284)"
FT /evidence="ECO:0000269|PubMed:22275001"
FT /id="VAR_068075"
FT VARIANT 447..496
FT /note="Missing (in RUS; associated with disease
FT susceptibility)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084486"
FT VARIANT 465
FT /note="R -> C (in CRS7; associated with disease
FT susceptibility; dbSNP:rs761888345)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_077595"
FT VARIANT 471
FT /note="G -> D (in RUS; unknown pathological significance;
FT dbSNP:rs1595805424)"
FT /evidence="ECO:0000269|PubMed:31138930"
FT /id="VAR_084487"
FT VARIANT 484
FT /note="C -> F (in AOVD2; decreased inhibition of BMP
FT signaling pathway; dbSNP:rs387907283)"
FT /evidence="ECO:0000269|PubMed:22275001,
FT ECO:0000269|PubMed:30848080"
FT /id="VAR_068076"
FT VARIANT 490
FT /note="I -> T (in CRS7; associated with disease
FT susceptibility; dbSNP:rs1338294058)"
FT /evidence="ECO:0000269|PubMed:27606499"
FT /id="VAR_078928"
FT MUTAGEN 173
FT /note="K->R: Abolishes monoubiquitination by UBE2O."
FT /evidence="ECO:0000269|PubMed:23455153"
FT MUTAGEN 435
FT /note="S->A: Loss of in vitro phosphorylation by PRKX."
FT /evidence="ECO:0000269|PubMed:16491121"
FT MUTAGEN 471
FT /note="G->S: Loss of SMAD1-binding and of inhibition of
FT BMP-SMAD1 signaling. No effect on interaction with BMPR1B
FT and TGFBR1."
FT /evidence="ECO:0000269|PubMed:9436979"
FT MUTAGEN 478..496
FT /note="Missing: Loss of interaction with BMPR1B, TGFBR1 and
FT SMAD1."
FT /evidence="ECO:0000269|PubMed:9436979"
FT CONFLICT 21
FT /note="D -> N (in Ref. 2; AAB94137)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 496 AA; 53497 MW; A4B928AE2D34EBC2 CRC64;
MFRSKRSGLV RRLWRSRVVP DREEGGSGGG GGGDEDGSLG SRAEPAPRAR EGGGCGRSEV
RPVAPRRPRD AVGQRGAQGA GRRRRAGGPP RPMSEPGAGA GSSLLDVAEP GGPGWLPESD
CETVTCCLFS ERDAAGAPRD ASDPLAGAAL EPAGGGRSRE ARSRLLLLEQ ELKTVTYSLL
KRLKERSLDT LLEAVESRGG VPGGCVLVPR ADLRLGGQPA PPQLLLGRLF RWPDLQHAVE
LKPLCGCHSF AAAADGPTVC CNPYHFSRLC GPESPPPPYS RLSPRDEYKP LDLSDSTLSY
TETEATNSLI TAPGEFSDAS MSPDATKPSH WCSVAYWEHR TRVGRLYAVY DQAVSIFYDL
PQGSGFCLGQ LNLEQRSESV RRTRSKIGFG ILLSKEPDGV WAYNRGEHPI FVNSPTLDAP
GGRALVVRKV PPGYSIKVFD FERSGLQHAP EPDAADGPYD PNSVRISFAK GWGPCYSRQF
ITSCPCWLEI LLNNPR
