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Mothers against decapentaplegic homolog 6 (MAD homolog 6) (Mothers against DPP homolog 6) (SMAD family member 6) (SMAD 6) (Smad6) (hSMAD6)

 SMAD6_HUMAN             Reviewed;         496 AA.
O43541; A9J6M5; O43654; Q15799; Q7Z7L4; Q96E31; Q9UKZ3;
04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
03-OCT-2006, sequence version 2.
02-DEC-2020, entry version 194.
RecName: Full=Mothers against decapentaplegic homolog 6;
Short=MAD homolog 6;
Short=Mothers against DPP homolog 6;
AltName: Full=SMAD family member 6;
Short=SMAD 6;
Short=Smad6;
Short=hSMAD6;
Name=SMAD6; Synonyms=MADH6;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
PubMed=8673135; DOI=10.1038/ng0796-347;
Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., Kern S.E.,
Hamilton S.R., Willson J.K.V., Markowitz S.D., Kinzler K.W.,
Vogelstein B.V.;
"Mad-related genes in the human.";
Nat. Genet. 13:347-349(1996).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), FUNCTION, INTERACTION WITH ACVR1B;
BMPR1B; SMAD1 AND TGFBR1, AND MUTAGENESIS OF GLY-471 AND 478-ARG--ARG-496.
TISSUE=T-cell;
PubMed=9436979; DOI=10.1101/gad.12.2.186;
Hata A., Lagna G., Massague J., Hemmati-Brivanlou A.;
"Smad6 inhibits BMP/Smad1 signaling by specifically competing with the
Smad4 tumor suppressor.";
Genes Dev. 12:186-197(1998).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
TISSUE=Placenta;
PubMed=9712726; DOI=10.1006/bbrc.1998.9170;
Afrakhte M., Moren A., Jossan S., Itoh S., Sampath K., Westermark B.,
Heldin C.H., Heldin N.E., ten Dijke P.;
"Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members.";
Biochem. Biophys. Res. Commun. 249:505-511(1998).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM A).
Hagiwara K., Freeman A.H., McMenamin M.G., Bennett W.P., Nagashima M.,
Minter A.R., Yang K., Takenoshita S., Harris C.C.;
Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM D).
TISSUE=Prostatic carcinoma;
Konrad L., Scheiber J.A., Brandt H., Eickelberg O., Hofmann R.;
"Identification of a new SMAD6 variant in human.";
Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
TISSUE=Uterus;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project:
the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM B).
Hagiwara K., Freeman A.A.H., McMenamin M.G., Bennett W.P., Yang K.,
Takenoshita S., Harris C.C.;
"Determination of the genomic structure of human Smad3, Smad6 and Smad7 and
the cloning of the human Smad3 promoter.";
Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases.
[8]
REVIEW.
PubMed=9759503; DOI=10.1146/annurev.biochem.67.1.753;
Massague J.;
"TGF-beta signal transduction.";
Annu. Rev. Biochem. 67:753-791(1998).
[9]
REVIEW.
PubMed=10647776; DOI=10.1016/s1359-6101(99)00012-x;
Verschueren K., Huylebroeck D.;
"Remarkable versatility of Smad proteins in the nucleus of transforming
growth factor-beta activated cells.";
Cytokine Growth Factor Rev. 10:187-199(1999).
[10]
REVIEW.
PubMed=10708948; DOI=10.1016/s1359-6101(99)00024-6;
Wrana J.L., Attisano L.;
"The Smad pathway.";
Cytokine Growth Factor Rev. 11:5-13(2000).
[11]
REVIEW.
PubMed=10708949; DOI=10.1016/s1359-6101(99)00025-8;
Miyazono K.;
"TGF-beta signaling by Smad proteins.";
Cytokine Growth Factor Rev. 11:15-22(2000).
[12]
INTERACTION WITH HOXC8.
PubMed=10722652; DOI=10.1074/jbc.275.12.8267;
Bai S., Shi X., Yang X., Cao X.;
"Smad6 as a transcriptional corepressor.";
J. Biol. Chem. 275:8267-8270(2000).
[13]
FUNCTION (ISOFORM B).
PubMed=11284962; DOI=10.1046/j.1440-169x.2001.00562.x;
Krishnan P., King M.W., Neff A.W., Sandusky G.E., Bierman K.L.,
Grinnell B., Smith R.C.;
"Human truncated Smad 6 (Smad 6s) inhibits the BMP pathway in Xenopus
laevis.";
Dev. Growth Differ. 43:115-132(2001).
[14]
INTERACTION WITH STAMBP.
PubMed=11483516; DOI=10.1093/emboj/20.15.4132;
Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S.;
"Promoting bone morphogenetic protein signaling through negative regulation
of inhibitory Smads.";
EMBO J. 20:4132-4142(2001).
[15]
INTERACTION WITH RNF111.
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).
[16]
INTERACTION WITH AXIN1.
PubMed=16601693; DOI=10.1038/sj.emboj.7601057;
Liu W., Rui H., Wang J., Lin S., He Y., Chen M., Li Q., Ye Z., Zhang S.,
Chan S.C., Chen Y.-G., Han J., Lin S.-C.;
"Axin is a scaffold protein in TGF-beta signaling that promotes degradation
of Smad7 by Arkadia.";
EMBO J. 25:1646-1658(2006).
[17]
FUNCTION, AND INTERACTION WITH PELI1.
PubMed=16951688; DOI=10.1038/ni1383;
Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S.,
Kim I.H., Kim S.J., Park S.H.;
"Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor
signaling through direct interaction with the adapter Pellino-1.";
Nat. Immunol. 7:1057-1065(2006).
[18]
FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRKX, MUTAGENESIS OF
SER-435, AND PHOSPHORYLATION AT SER-435.
PubMed=16491121; DOI=10.1038/sj.onc.1209436;
Glesne D., Huberman E.;
"Smad6 is a protein kinase X phosphorylation substrate and is required for
HL-60 cell differentiation.";
Oncogene 25:4086-4098(2006).
[19]
INVOLVEMENT IN CONGENITAL CARDIOVASCULAR MALFORMATIONS, VARIANT THR-325,
VARIANTS AOVD2 LEU-415 AND PHE-484, AND CHARACTERIZATION OF VARIANTS AOVD2
LEU-415 AND PHE-484.
PubMed=22275001; DOI=10.1002/humu.22030;
Tan H.L., Glen E., Topf A., Hall D., O'Sullivan J.J., Sneddon L., Wren C.,
Avery P., Lewis R.J., ten Dijke P., Arthur H.M., Goodship J.A.,
Keavney B.D.;
"Nonsynonymous variants in the SMAD6 gene predispose to congenital
cardiovascular malformation.";
Hum. Mutat. 33:720-727(2012).
[20]
UBIQUITINATION AT LYS-173, AND MUTAGENESIS OF LYS-173.
PubMed=23455153; DOI=10.1038/emboj.2013.38;
Zhang X., Zhang J., Bauer A., Zhang L., Selinger D.W., Lu C.X.,
Ten Dijke P.;
"Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated
monoubiquitination of SMAD6.";
EMBO J. 32:996-1007(2013).
[21]
INVOLVEMENT IN CRS7, AND VARIANTS CRS7 223-GLN--ARG-496 DEL; LYS-287;
ALA-306; LEU-323; 374-GLU--ARG-496 DEL; CYS-390; 407-GLU--ARG-496 DEL;
CYS-465 AND THR-490.
PubMed=27606499; DOI=10.7554/elife.20125;
Timberlake A.T., Choi J., Zaidi S., Lu Q., Nelson-Williams C., Brooks E.D.,
Bilguvar K., Tikhonova I., Mane S., Yang J.F., Sawh-Martinez R.,
Persing S., Zellner E.G., Loring E., Chuang C., Galm A., Hashim P.W.,
Steinbacher D.M., DiLuna M.L., Duncan C.C., Pelphrey K.A., Zhao H.,
Persing J.A., Lifton R.P.;
"Two locus inheritance of non-syndromic midline craniosynostosis via rare
SMAD6 and common BMP2 alleles.";
Elife 5:0-0(2016).
-!- FUNCTION: Acts as a mediator of TGF-beta and BMP antiflammatory
activity. Suppresses IL1R-TLR signaling through its direct interaction
with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-
kappa-B-mediated expression of proinflammatory genes. May block the
BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-
activated SMAD1-binding. Binds to regulatory elements in target
promoter regions. {ECO:0000269|PubMed:16491121,
ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:9436979}.
-!- SUBUNIT: Interacts with NEDD4L (By similarity). Interacts with WWP1 (By
similarity). Interacts with STAMBP and PRKX. Interacts with RNF111 and
AXIN1. Interacts with TGF-beta type I receptor superfamily members,
including ACVR1B, BMPR1B and TGFBR1. In response to BMP2, but not to
TGFB treatment, interacts with SMAD1, but not with SMAD2, nor with
SMAD4; this interaction may inhibit SMAD1 binding to SMAD4. Interacts
with HOXC8 and HOXC9. Interacts with PELI1; this interaction interferes
with PELI1 complex formation with TRAF6, IRAK1, IRAK4 and MYD88 in
response to IL1B and hence negatively regulates IL1R-TLR signaling.
{ECO:0000250, ECO:0000269|PubMed:10722652, ECO:0000269|PubMed:11483516,
ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16491121,
ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:16951688,
ECO:0000269|PubMed:9436979}.
-!- INTERACTION:
O43541; P51817: PRKX; NbExp=5; IntAct=EBI-976374, EBI-4302903;
O43541; Q13950: RUNX2; NbExp=3; IntAct=EBI-976374, EBI-976402;
O43541; Q15797: SMAD1; NbExp=4; IntAct=EBI-976374, EBI-1567153;
O43541; O43541: SMAD6; NbExp=2; IntAct=EBI-976374, EBI-976374;
O43541-2; O95630: STAMBP; NbExp=2; IntAct=EBI-4324970, EBI-396676;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16491121}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=A;
IsoId=O43541-1; Sequence=Displayed;
Name=B; Synonyms=Smad 6S;
IsoId=O43541-2; Sequence=VSP_006179, VSP_006180;
Name=D;
IsoId=O43541-4; Sequence=VSP_035489, VSP_035490;
-!- TISSUE SPECIFICITY: Ubiquitous in various organs, with higher levels in
lung. Isoform B is up-regulated in diseased heart tissue.
-!- PTM: Phosphorylated by BMP type 1 receptor kinase and by PRKX.
{ECO:0000269|PubMed:16491121}.
-!- PTM: Monoubiquitinated at Lys-173 by the E2/E3 hybrid ubiquitin-protein
ligase UBE2O, leading to reduced binding affinity for the activated BMP
type I receptor ACVR1/ALK2, thereby enhancing BMP7 and regulating
adipocyte differentiation (PubMed:23455153). Ubiquitinated by WWP1 (By
similarity). Ubiquitinated by RNF165, promoting proteasomal
degradation, leading to enhance the BMP-Smad signaling (By similarity).
{ECO:0000250|UniProtKB:O35182, ECO:0000269|PubMed:23455153}.
-!- PTM: Arginine methylation by PRMT1, which is recruited by BMPR2,
initiates BMP-Induced signaling and induces dissociation from the
BMPR1B receptor at the cell surface leading to derepress downstream
Smad1/Smad5 signaling. {ECO:0000250|UniProtKB:O35182}.
-!- DISEASE: Aortic valve disease 2 (AOVD2) [MIM:614823]: A common defect
in the aortic valve in which two rather than three leaflets are
present. It is often associated with aortic valve calcification,
stenosis and insufficiency. In extreme cases, the blood flow may be so
restricted that the left ventricle fails to grow, resulting in
hypoplastic left heart syndrome. {ECO:0000269|PubMed:22275001}.
Note=The disease is caused by mutations affecting the gene represented
in this entry. SMAD6 variants may contribute to increased risk of
congenital cardiovascular malformations (CVM). CVM is a major cause of
mortality and morbidity in childhood. In most sporadic cases that
cannot be attributed to particular malformation syndromes or
teratogenic exposures, there remains a substantial excess familial
risk, indicating a significant genetic contribution to disease
susceptibility (PubMed:22275001). {ECO:0000269|PubMed:22275001}.
-!- DISEASE: Craniosynostosis 7 (CRS7) [MIM:617439]: A form of
craniosynostosis, a primary abnormality of skull growth involving
premature fusion of one or more cranial sutures. The growth velocity of
the skull often cannot match that of the developing brain resulting in
an abnormal head shape and, in some cases, increased intracranial
pressure, which must be treated promptly to avoid permanent
neurodevelopmental disability. {ECO:0000269|PubMed:27606499}.
Note=Disease susceptibility is associated with variations affecting the
gene represented in this entry. Rare heterozygous SMAD6 variants are
strongly associated with non-syndromic midline craniosynostosis and
confer a very high risk for disease development, in the presence of a
common risk allele (rs1884302) near the BMP2 locus.
{ECO:0000269|PubMed:27606499}.
-!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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EMBL; U59914; AAC50792.1; -; mRNA.
EMBL; AF035528; AAB94137.1; -; mRNA.
EMBL; AF043640; AAC00497.1; -; mRNA.
EMBL; AF037469; AAC82331.1; -; mRNA.
EMBL; AF041065; AAF14343.1; -; Genomic_DNA.
EMBL; AF041062; AAF14343.1; JOINED; Genomic_DNA.
EMBL; AF041063; AAF14343.1; JOINED; Genomic_DNA.
EMBL; AF041064; AAF14343.1; JOINED; Genomic_DNA.
EMBL; AM909653; CAP20377.1; -; mRNA.
EMBL; BC012986; AAH12986.1; -; mRNA.
EMBL; AF101474; AAF06841.1; -; Genomic_DNA.
CCDS; CCDS10221.1; -. [O43541-1]
RefSeq; NP_005576.3; NM_005585.4. [O43541-1]
RefSeq; XP_011519863.1; XM_011521561.2. [O43541-2]
SMR; O43541; -.
BioGRID; 110266; 49.
CORUM; O43541; -.
DIP; DIP-36708N; -.
IntAct; O43541; 14.
MINT; O43541; -.
STRING; 9606.ENSP00000288840; -.
iPTMnet; O43541; -.
PhosphoSitePlus; O43541; -.
BioMuta; SMAD6; -.
MassIVE; O43541; -.
MaxQB; O43541; -.
PaxDb; O43541; -.
PeptideAtlas; O43541; -.
PRIDE; O43541; -.
ProteomicsDB; 49038; -. [O43541-1]
ProteomicsDB; 49039; -. [O43541-2]
ProteomicsDB; 49040; -. [O43541-4]
Antibodypedia; 13795; 567 antibodies.
Ensembl; ENST00000288840; ENSP00000288840; ENSG00000137834. [O43541-1]
Ensembl; ENST00000557916; ENSP00000452955; ENSG00000137834. [O43541-4]
GeneID; 4091; -.
KEGG; hsa:4091; -.
UCSC; uc002aqf.4; human. [O43541-1]
CTD; 4091; -.
DisGeNET; 4091; -.
EuPathDB; HostDB:ENSG00000137834.14; -.
GeneCards; SMAD6; -.
HGNC; HGNC:6772; SMAD6.
HPA; ENSG00000137834; Tissue enhanced (lung).
MalaCards; SMAD6; -.
MIM; 602931; gene.
MIM; 614823; phenotype.
MIM; 617439; phenotype.
neXtProt; NX_O43541; -.
OpenTargets; ENSG00000137834; -.
Orphanet; 402075; Familial bicuspid aortic valve.
PharmGKB; PA30529; -.
eggNOG; KOG3701; Eukaryota.
GeneTree; ENSGT00940000158146; -.
HOGENOM; CLU_026736_2_1_1; -.
InParanoid; O43541; -.
OMA; CKSFGAQ; -.
OrthoDB; 395665at2759; -.
PhylomeDB; O43541; -.
TreeFam; TF314923; -.
PathwayCommons; O43541; -.
Reactome; R-HSA-201451; Signaling by BMP.
Reactome; R-HSA-8941326; RUNX2 regulates bone development.
SignaLink; O43541; -.
SIGNOR; O43541; -.
BioGRID-ORCS; 4091; 19 hits in 866 CRISPR screens.
ChiTaRS; SMAD6; human.
GeneWiki; Mothers_against_decapentaplegic_homolog_6; -.
GenomeRNAi; 4091; -.
Pharos; O43541; Tbio.
PRO; PR:O43541; -.
Proteomes; UP000005640; Chromosome 15.
RNAct; O43541; protein.
Bgee; ENSG00000137834; Expressed in upper lobe of lung and 224 other tissues.
ExpressionAtlas; O43541; baseline and differential.
Genevisible; O43541; HS.
GO; GO:0005737; C:cytoplasm; TAS:BHF-UCL.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
GO; GO:0016604; C:nuclear body; IDA:HPA.
GO; GO:0000790; C:nuclear chromatin; ISA:NTNU_SB.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0032991; C:protein-containing complex; IDA:MGI.
GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
GO; GO:0070410; F:co-SMAD binding; IPI:BHF-UCL.
GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IBA:GO_Central.
GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
GO; GO:0140416; F:DNA-binding transcription factor inhibitor activity; IDA:BHF-UCL.
GO; GO:0070411; F:I-SMAD binding; IPI:BHF-UCL.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0070412; F:R-SMAD binding; IPI:BHF-UCL.
GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
GO; GO:0008134; F:transcription factor binding; IBA:GO_Central.
GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; IDA:UniProtKB.
GO; GO:0070698; F:type I activin receptor binding; IDA:BHF-UCL.
GO; GO:0034713; F:type I transforming growth factor beta receptor binding; IDA:BHF-UCL.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
GO; GO:0035904; P:aorta development; IEA:Ensembl.
GO; GO:0003180; P:aortic valve morphogenesis; IMP:BHF-UCL.
GO; GO:0030509; P:BMP signaling pathway; IDA:UniProtKB.
GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
GO; GO:0031589; P:cell-substrate adhesion; IMP:UniProtKB.
GO; GO:0060976; P:coronary vasculature development; IEA:Ensembl.
GO; GO:0045444; P:fat cell differentiation; IDA:UniProtKB.
GO; GO:0006955; P:immune response; IMP:BHF-UCL.
GO; GO:0003183; P:mitral valve morphogenesis; ISS:BHF-UCL.
GO; GO:0043066; P:negative regulation of apoptotic process; IMP:BHF-UCL.
GO; GO:0030514; P:negative regulation of BMP signaling pathway; IDA:BHF-UCL.
GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:BHF-UCL.
GO; GO:0030279; P:negative regulation of ossification; ISS:BHF-UCL.
GO; GO:0045668; P:negative regulation of osteoblast differentiation; IMP:BHF-UCL.
GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; IDA:BHF-UCL.
GO; GO:0010991; P:negative regulation of SMAD protein complex assembly; IDA:BHF-UCL.
GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
GO; GO:0003148; P:outflow tract septum morphogenesis; ISS:BHF-UCL.
GO; GO:1902895; P:positive regulation of pri-miRNA transcription by RNA polymerase II; IEA:Ensembl.
GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
GO; GO:0003184; P:pulmonary valve morphogenesis; ISS:BHF-UCL.
GO; GO:0043627; P:response to estrogen; IEA:Ensembl.
GO; GO:0034616; P:response to laminar fluid shear stress; IEP:BHF-UCL.
GO; GO:0032496; P:response to lipopolysaccharide; IDA:ARUK-UCL.
GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IBA:GO_Central.
GO; GO:0001657; P:ureteric bud development; IEA:Ensembl.
GO; GO:0003281; P:ventricular septum development; IEA:Ensembl.
GO; GO:0007352; P:zygotic specification of dorsal/ventral axis; 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;
Alternative splicing; Craniosynostosis; Disease mutation; DNA-binding;
Isopeptide bond; Metal-binding; Methylation; Nucleus; Phosphoprotein;
Polymorphism; Reference proteome; Transcription; Transcription regulation;
Ubl conjugation; Zinc.
CHAIN 1..496
/note="Mothers against decapentaplegic homolog 6"
/id="PRO_0000090869"
DOMAIN 148..275
/note="MH1"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
DOMAIN 331..496
/note="MH2"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
COMPBIAS 25..33
/note="Poly-Gly"
COMPBIAS 82..85
/note="Poly-Arg"
COMPBIAS 165..168
/note="Poly-Leu"
COMPBIAS 251..254
/note="Poly-Ala"
COMPBIAS 275..278
/note="Poly-Pro"
METAL 205
/note="Zinc"
/evidence="ECO:0000250"
METAL 247
/note="Zinc"
/evidence="ECO:0000250"
METAL 260
/note="Zinc"
/evidence="ECO:0000250"
METAL 265
/note="Zinc"
/evidence="ECO:0000250"
MOD_RES 75
/note="Dimethylated arginine; alternate"
/evidence="ECO:0000250|UniProtKB:O35182"
MOD_RES 75
/note="Omega-N-methylarginine; alternate"
/evidence="ECO:0000250|UniProtKB:O35182"
MOD_RES 82
/note="Dimethylated arginine; alternate"
/evidence="ECO:0000250|UniProtKB:O35182"
MOD_RES 82
/note="Omega-N-methylarginine; alternate"
/evidence="ECO:0000250|UniProtKB:O35182"
MOD_RES 435
/note="Phosphoserine; by PRKX; in vitro"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
ECO:0000269|PubMed:16491121"
CROSSLNK 173
/note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
G-Cter in ubiquitin)"
/evidence="ECO:0000269|PubMed:23455153"
VAR_SEQ 1..261
/note="Missing (in isoform B)"
/evidence="ECO:0000303|PubMed:8673135"
/id="VSP_006179"
VAR_SEQ 262..273
/note="NPYHFSRLCGPE -> MSRMGKPIETQK (in isoform B)"
/evidence="ECO:0000303|PubMed:8673135"
/id="VSP_006180"
VAR_SEQ 318..338
/note="DASMSPDATKPSHWCSVAYWE -> AADAGIGSRGNRGLESSVPCS (in
isoform D)"
/evidence="ECO:0000303|Ref.5"
/id="VSP_035489"
VAR_SEQ 339..496
/note="Missing (in isoform D)"
/evidence="ECO:0000303|Ref.5"
/id="VSP_035490"
VARIANT 223..496
/note="Missing (in CRS7; associated with disease
susceptibility)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_078924"
VARIANT 287
/note="E -> K (in CRS7; associated with disease
susceptibility; dbSNP:rs570279865)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_078925"
VARIANT 306
/note="T -> A (in CRS7; associated with disease
susceptibility)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_077592"
VARIANT 323
/note="P -> L (in CRS7; associated with disease
susceptibility; dbSNP:rs1374099442)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_077593"
VARIANT 325
/note="A -> T (found in a patient with congenital mitral
valve prolapse; dbSNP:rs199822239)"
/evidence="ECO:0000269|PubMed:22275001"
/id="VAR_068074"
VARIANT 374..496
/note="Missing (in CRS7; associated with disease
susceptibility)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_078926"
VARIANT 390
/note="G -> C (in CRS7; associated with disease
susceptibility; de novo mutation)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_077594"
VARIANT 407..496
/note="Missing (in CRS7; associated with disease
susceptibility)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_078927"
VARIANT 415
/note="P -> L (in AOVD2; results in significantly lower
activity than wild-type in inhibiting BMP signaling in a
transcriptional reporter assay; dbSNP:rs387907284)"
/evidence="ECO:0000269|PubMed:22275001"
/id="VAR_068075"
VARIANT 465
/note="R -> C (in CRS7; associated with disease
susceptibility; dbSNP:rs761888345)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_077595"
VARIANT 484
/note="C -> F (in AOVD2; results in significantly lower
activity than wild-type in inhibiting BMP signaling in a
transcriptional reporter assay; dbSNP:rs387907283)"
/evidence="ECO:0000269|PubMed:22275001"
/id="VAR_068076"
VARIANT 490
/note="I -> T (in CRS7; associated with disease
susceptibility; dbSNP:rs1338294058)"
/evidence="ECO:0000269|PubMed:27606499"
/id="VAR_078928"
MUTAGEN 173
/note="K->R: Abolishes monoubiquitination by UBE2O."
/evidence="ECO:0000269|PubMed:23455153"
MUTAGEN 435
/note="S->A: Loss of in vitro phosphorylation by PRKX."
/evidence="ECO:0000269|PubMed:16491121"
MUTAGEN 471
/note="G->S: Loss of SMAD1-binding and of inhibition of
BMP-SMAD1 signaling. No effect on interaction with BMPR1B
and TGFBR1."
/evidence="ECO:0000269|PubMed:9436979"
MUTAGEN 478..496
/note="Missing: Loss of interaction with BMPR1B, TGFBR1 and
SMAD1."
/evidence="ECO:0000269|PubMed:9436979"
CONFLICT 21
/note="D -> N (in Ref. 2; AAB94137)"
/evidence="ECO:0000305"
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


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E2187c ELISA kit Chicken,Gallus gallus,MAD homolog 6,MADH6,Mothers against decapentaplegic homolog 6,Mothers against DPP homolog 6,SMAD 6,SMAD family member 6,Smad6,SMAD6 96T
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Pathways :
WP2341: vitamin B1 (thiamin) biosynthesis and salvage pathway
WP2340: Thiamine (vitamin B1) biosynthesis and salvage
WP32: Translation Factors
WP1596: Iron Homeostasis
WP1045: TGF-beta Receptor Signaling Pathway
WP230: TGF Beta Signaling Pathway
WP258: TGF-beta Receptor Signaling Pathway
WP1161: TGF-beta Receptor Signaling Pathway
WP1449: Regulation of toll-like receptor signaling pathway
WP341: Nodal signaling pathway
WP560: TGF Beta Signaling Pathway
WP1834: Interactions of the immunoglobulin superfamily (IgSF) member proteins
WP926: TGF-beta Receptor Signaling Pathway
WP211: BMP signaling pathway
WP113: TGF Beta Signaling Pathway
WP1425: BMP signalling and regulation
WP339: ESC Pluripotency Pathways
WP505: TGF Beta Signaling Pathway
WP1578: BMP signalling and regulation
WP1799: Costimulation by the CD28 family
WP812: TGF Beta Signaling Pathway
WP2039: CDKN1A-EGF-CREB
WP1048: TGF Beta Signaling Pathway
WP1164: TGF Beta Signaling Pathway
WP1485: Interactions between CFTR and other ion channels

Related Genes :
[SMAD6 MADH6] Mothers against decapentaplegic homolog 6 (MAD homolog 6) (Mothers against DPP homolog 6) (SMAD family member 6) (SMAD 6) (Smad6) (hSMAD6)
[Smad1 Madh1 Madr1] Mothers against decapentaplegic homolog 1 (MAD homolog 1) (Mothers against DPP homolog 1) (Dwarfin-A) (Dwf-A) (Mothers-against-DPP-related 1) (Mad-related protein 1) (mMad1) (SMAD family member 1) (SMAD 1) (Smad1)
[Smad3 Madh3] Mothers against decapentaplegic homolog 3 (MAD homolog 3) (Mad3) (Mothers against DPP homolog 3) (mMad3) (SMAD family member 3) (SMAD 3) (Smad3)
[Smad4 Dpc4 Madh4] Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (Deletion target in pancreatic carcinoma 4 homolog) (SMAD family member 4) (SMAD 4) (Smad4)
[SMAD1 BSP1 MADH1 MADR1] Mothers against decapentaplegic homolog 1 (MAD homolog 1) (Mothers against DPP homolog 1) (JV4-1) (Mad-related protein 1) (SMAD family member 1) (SMAD 1) (Smad1) (hSMAD1) (Transforming growth factor-beta-signaling protein 1) (BSP-1)
[SMAD7 MADH7 MADH8] 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) (hSMAD7)
[SMAD4 DPC4 MADH4] Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (Deletion target in pancreatic carcinoma 4) (SMAD family member 4) (SMAD 4) (Smad4) (hSMAD4)
[Smad7 Madh7 Madh8] 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)
[SMAD3 MADH3] Mothers against decapentaplegic homolog 3 (MAD homolog 3) (Mad3) (Mothers against DPP homolog 3) (hMAD-3) (JV15-2) (SMAD family member 3) (SMAD 3) (Smad3) (hSMAD3)
[SMAD2 MADH2 MADR2] Mothers against decapentaplegic homolog 2 (MAD homolog 2) (Mothers against DPP homolog 2) (JV18-1) (Mad-related protein 2) (hMAD-2) (SMAD family member 2) (SMAD 2) (Smad2) (hSMAD2)
[SMAD4 MADH4] Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (SMAD family member 4) (SMAD 4) (Smad4)
[SMAD3 MADH3] Mothers against decapentaplegic homolog 3 (MAD homolog 3) (Mad3) (Mothers against DPP homolog 3) (SMAD family member 3) (SMAD 3) (Smad3)
[Smad3 Madh3] Mothers against decapentaplegic homolog 3 (MAD homolog 3) (Mad3) (Mothers against DPP homolog 3) (SMAD family member 3) (SMAD 3) (Smad3)
[Smad4 Madh4] Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (SMAD family member 4) (SMAD 4) (Smad4)
[Smad7 Madh7] Mothers against decapentaplegic homolog 7 (MAD homolog 7) (Mothers against DPP homolog 7) (SMAD family member 7) (SMAD 7) (Smad7)
[Smad1 Mad1 Madh1] Mothers against decapentaplegic homolog 1 (MAD homolog 1) (Mothers against DPP homolog 1) (SMAD family member 1) (SMAD 1) (Smad1)
[SMAD1] Mothers against decapentaplegic homolog 1 (MAD homolog 1) (Mothers against DPP homolog 1) (SMAD family member 1) (SMAD 1) (Smad1)
[Smox Dmel\CG2262 DSMAD2 DSmad2 dSMAD2 dSmad2 dsmad2 l(1)G0348 Sad sad Smad SMAD2 Smad2 smad2 SMOX SmoX smox ted tmp CG2262 Dmel_CG2262] Mothers against decapentaplegic homolog (MAD homolog) (Mothers against DPP homolog) (SMAD family member)
[SMAD4] Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (SMAD family member 4) (SMAD 4) (Smad4)
[Peli1] E3 ubiquitin-protein ligase pellino homolog 1 (Pellino-1) (EC 2.3.2.27) (RING-type E3 ubiquitin transferase pellino homolog 1)
[ZFYVE9 MADHIP SARA SMADIP] Zinc finger FYVE domain-containing protein 9 (Mothers against decapentaplegic homolog-interacting protein) (Madh-interacting protein) (Novel serine protease) (NSP) (Receptor activation anchor) (hSARA) (Smad anchor for receptor activation)
[Mad CG12399] Protein mothers against dpp
[Cdc42] Cell division control protein 42 homolog (EC 3.6.5.2) (G25K GTP-binding protein)
[Wrn] Werner syndrome ATP-dependent helicase homolog (EC 3.6.4.12) (Exonuclease WRN) (EC 3.1.-.-)
[Slc27a3 Acsvl3 Fatp3] Solute carrier family 27 member 3 (EC 6.2.1.-) (Arachidonate--CoA ligase) (EC 6.2.1.15) (Long-chain fatty acid transport protein 3) (FATP-3) (Fatty acid transport protein 3) (Very long-chain acyl-CoA synthetase homolog 3) (VLCS-3)
[Pard6b Par6b] Partitioning defective 6 homolog beta (PAR-6 beta) (PAR-6B)
[Cers6 Lass6] Ceramide synthase 6 (CerS6) (EC 2.3.1.-) (LAG1 longevity assurance homolog 6)
[Upf1 Rent1] Regulator of nonsense transcripts 1 (EC 3.6.4.-) (ATP-dependent helicase RENT1) (Nonsense mRNA reducing factor 1) (NORF1) (Up-frameshift suppressor 1 homolog) (mUpf1)
[Tomt Comt2] Transmembrane O-methyltransferase homolog (mTOMT) (EC 2.1.1.6) (Catechol O-methyltransferase 2) (Protein LRTOMT2)
[Dnaja3 Tid1] DnaJ homolog subfamily A member 3, mitochondrial (DnaJ protein Tid-1) (mTid-1) (Tumorous imaginal discs protein Tid56 homolog)

Bibliography :