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O43541 (SMAD6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 113. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mothers against decapentaplegic homolog 6

Short name=MAD homolog 6
Short name=Mothers against DPP homolog 6
Alternative name(s):
SMAD family member 6
Short name=SMAD 6
Short name=Smad6
Short name=hSMAD6
Gene names
Name:SMAD6
Synonyms:MADH6
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length496 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit selectively BMP (bone morphogenetic proteins) signaling by competing with the co-SMAD SMAD4 for receptor-activated SMAD1. SMAD6 is an inhibitory SMAD (I-SMAD) or antagonistic SMAD. Binds to regulatory elements in target promoter regions. Ref.13 Ref.17

Subunit structure

Interacts with NEDD4L By similarity. Interacts with WWP1 By similarity. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, SMAD1, HOXC8 and HOXC9. Interacts with STAMBP and PRKX. Ref.12 Ref.14 Ref.15 Ref.16 Ref.17

Subcellular location

Nucleus Ref.17.

Tissue specificity

Ubiquitous in various organs, with higher levels in lung. Isoform B is up-regulated in diseased heart tissue.

Post-translational modification

Phosphorylated by BMP type 1 receptor kinase and by PRKX. Ref.17

Ubiquitinated by WWP1 By similarity.

Sequence similarities

Belongs to the dwarfin/SMAD family.

Contains 1 MH1 (MAD homology 1) domain.

Contains 1 MH2 (MAD homology 2) domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological processBMP signaling pathway

Traceable author statement. Source: Reactome

cell-substrate adhesion

Inferred from mutant phenotype Ref.17. Source: UniProtKB

immune response

Inferred from mutant phenotype. Source: BHF-UCL

negative regulation of BMP signaling pathway

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of SMAD protein complex assembly

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of apoptotic process

Inferred from mutant phenotype. Source: BHF-UCL

negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from mutant phenotype. Source: BHF-UCL

negative regulation of pathway-restricted SMAD protein phosphorylation

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of transforming growth factor beta receptor signaling pathway

Inferred from mutant phenotype. Source: BHF-UCL

positive regulation of S phase of mitotic cell cycle

Inferred from mutant phenotype. Source: BHF-UCL

response to laminar fluid shear stress

Inferred from expression pattern. Source: BHF-UCL

transcription, DNA-dependent

Inferred from electronic annotation. Source: UniProtKB-KW

transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

zygotic specification of dorsal/ventral axis

Inferred from mutant phenotype Ref.2. Source: BHF-UCL

   Cellular componentcytosol

Traceable author statement. Source: Reactome

transcription factor complex

Inferred from electronic annotation. Source: InterPro

   Molecular functionI-SMAD binding

Inferred from physical interaction. Source: BHF-UCL

R-SMAD binding

Inferred from physical interaction Ref.2. Source: BHF-UCL

chromatin binding

Inferred from direct assay Ref.17. Source: UniProtKB

co-SMAD binding

Inferred from physical interaction. Source: BHF-UCL

protein binding

Inferred from physical interaction Ref.14Ref.17. Source: IntAct

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: InterPro

transcription regulatory region DNA binding

Inferred from direct assay Ref.17. Source: UniProtKB

transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity

Inferred from direct assay. Source: BHF-UCL

type I activin receptor binding

Inferred from direct assay Ref.2. Source: BHF-UCL

type I transforming growth factor beta receptor binding

Inferred from direct assay Ref.2. Source: BHF-UCL

ubiquitin protein ligase binding

Inferred from physical interaction. Source: BHF-UCL

Complete GO annotation...

Binary interactions

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform A (identifier: O43541-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform B (identifier: O43541-2)

Also known as: Smad 6S;

The sequence of this isoform differs from the canonical sequence as follows:
     1-261: Missing.
     262-273: NPYHFSRLCGPE → MSRMGKPIETQK
Isoform D (identifier: O43541-4)

The sequence of this isoform differs from the canonical sequence as follows:
     318-338: DASMSPDATKPSHWCSVAYWE → AADAGIGSRGNRGLESSVPCS
     339-496: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 496496Mothers against decapentaplegic homolog 6
PRO_0000090869

Regions

Domain148 – 275128MH1
Domain331 – 496166MH2
Compositional bias25 – 339Poly-Gly
Compositional bias82 – 854Poly-Arg
Compositional bias165 – 1684Poly-Leu
Compositional bias251 – 2544Poly-Ala
Compositional bias275 – 2784Poly-Pro

Amino acid modifications

Modified residue4351Phosphoserine; by PRKX; in vitro Ref.17

Natural variations

Alternative sequence1 – 261261Missing in isoform B.
VSP_006179
Alternative sequence262 – 27312NPYHF…LCGPE → MSRMGKPIETQK in isoform B.
VSP_006180
Alternative sequence318 – 33821DASMS…VAYWE → AADAGIGSRGNRGLESSVPC S in isoform D.
VSP_035489
Alternative sequence339 – 496158Missing in isoform D.
VSP_035490

Experimental info

Mutagenesis4351S → A: Loss of in vitro phosphorylation by PRKX. Ref.17
Mutagenesis4711G → S: Loss of interaction with SMAD1 and BMP-receptor.
Mutagenesis478 – 49619Missing: Loss of interaction with SMAD1.
Sequence conflict211D → N in AAB94137. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform A [UniParc].

Last modified October 3, 2006. Version 2.
Checksum: A4B928AE2D34EBC2

FASTA49653,497
        10         20         30         40         50         60 
MFRSKRSGLV RRLWRSRVVP DREEGGSGGG GGGDEDGSLG SRAEPAPRAR EGGGCGRSEV 

        70         80         90        100        110        120 
RPVAPRRPRD AVGQRGAQGA GRRRRAGGPP RPMSEPGAGA GSSLLDVAEP GGPGWLPESD 

       130        140        150        160        170        180 
CETVTCCLFS ERDAAGAPRD ASDPLAGAAL EPAGGGRSRE ARSRLLLLEQ ELKTVTYSLL 

       190        200        210        220        230        240 
KRLKERSLDT LLEAVESRGG VPGGCVLVPR ADLRLGGQPA PPQLLLGRLF RWPDLQHAVE 

       250        260        270        280        290        300 
LKPLCGCHSF AAAADGPTVC CNPYHFSRLC GPESPPPPYS RLSPRDEYKP LDLSDSTLSY 

       310        320        330        340        350        360 
TETEATNSLI TAPGEFSDAS MSPDATKPSH WCSVAYWEHR TRVGRLYAVY DQAVSIFYDL 

       370        380        390        400        410        420 
PQGSGFCLGQ LNLEQRSESV RRTRSKIGFG ILLSKEPDGV WAYNRGEHPI FVNSPTLDAP 

       430        440        450        460        470        480 
GGRALVVRKV PPGYSIKVFD FERSGLQHAP EPDAADGPYD PNSVRISFAK GWGPCYSRQF 

       490 
ITSCPCWLEI LLNNPR 

« Hide

Isoform B (Smad 6S) [UniParc].

Checksum: 0847C2C84DC0B2A2
Show »

FASTA23526,236
Isoform D [UniParc].

Checksum: C4D02353D7FD76CE
Show »

FASTA33835,467

References

« Hide 'large scale' references
[1]"Mad-related genes in the human."
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.
Nat. Genet. 13:347-349(1996) [PubMed: 8673135] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
[2]"Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor."
Hata A., Lagna G., Massague J., Hemmati-Brivanlou A.
Genes Dev. 12:186-197(1998) [PubMed: 9436979] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), MUTAGENESIS.
Tissue: T-cell.
[3]"Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members."
Afrakhte M., Moren A., Jossan S., Itoh S., Sampath K., Westermark B., Heldin C.H., Heldin N.E., ten Dijke P.
Biochem. Biophys. Res. Commun. 249:505-511(1998) [PubMed: 9712726] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
Tissue: Placenta.
[4]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
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM A).
[5]"Identification of a new SMAD6 variant in human."
Konrad L., Scheiber J.A., Brandt H., Eickelberg O., Hofmann R.
Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM D).
Tissue: Prostatic carcinoma.
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
Tissue: Uterus.
[7]"Determination of the genomic structure of human Smad3, Smad6 and Smad7 and the cloning of the human Smad3 promoter."
Hagiwara K., Freeman A.A.H., McMenamin M.G., Bennett W.P., Yang K., Takenoshita S., Harris C.C.
Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases
Cited for: PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM B).
[8]"TGF-beta signal transduction."
Massague J.
Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract]
Cited for: REVIEW.
[9]"Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells."
Verschueren K., Huylebroeck D.
Cytokine Growth Factor Rev. 10:187-199(1999) [PubMed: 10647776] [Abstract]
Cited for: REVIEW.
[10]"The Smad pathway."
Wrana J.L., Attisano L.
Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract]
Cited for: REVIEW.
[11]"TGF-beta signaling by Smad proteins."
Miyazono K.
Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract]
Cited for: REVIEW.
[12]"Smad6 as a transcriptional corepressor."
Bai S., Shi X., Yang X., Cao X.
J. Biol. Chem. 275:8267-8270(2000) [PubMed: 10722652] [Abstract]
Cited for: INTERACTION WITH HOXC8.
[13]"Human truncated Smad 6 (Smad 6s) inhibits the BMP pathway in Xenopus laevis."
Krishnan P., King M.W., Neff A.W., Sandusky G.E., Bierman K.L., Grinnell B., Smith R.C.
Dev. Growth Differ. 43:115-132(2001) [PubMed: 11284962] [Abstract]
Cited for: FUNCTION (ISOFORM B).
[14]"Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads."
Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S.
EMBO J. 20:4132-4142(2001) [PubMed: 11483516] [Abstract]
Cited for: INTERACTION WITH STAMBP.
[15]"Arkadia amplifies TGF-beta superfamily signaling through degradation of Smad7."
Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A., Ebina M., Nukiwa T., Miyazawa K., Imamura T., Miyazono K.
EMBO J. 22:6458-6470(2003) [PubMed: 14657019] [Abstract]
Cited for: INTERACTION WITH RNF111.
[16]"Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia."
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.
EMBO J. 25:1646-1658(2006) [PubMed: 16601693] [Abstract]
Cited for: INTERACTION WITH AXIN1.
[17]"Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation."
Glesne D., Huberman E.
Oncogene 25:4086-4098(2006) [PubMed: 16491121] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PRKX, MUTAGENESIS OF SER-435, PHOSPHORYLATION AT SER-435.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U59914 mRNA. Translation: AAC50792.1.
AF035528 mRNA. Translation: AAB94137.1.
AF043640 mRNA. Translation: AAC00497.1.
AF037469 mRNA. Translation: AAC82331.1.
AF041065 expand/collapse EMBL AC list , AF041062, AF041063, AF041064 Genomic DNA. Translation: AAF14343.1.
AM909653 mRNA. Translation: CAP20377.1.
BC012986 mRNA. Translation: AAH12986.1.
AF101474 Genomic DNA. Translation: AAF06841.1.
IPIIPI00012869.
IPI00218149.
IPI00884203.
RefSeqNP_001136333.1. NM_001142861.2.
NP_005576.3. NM_005585.4.
UniGeneHs.153863.

3D structure databases

ProteinModelPortalO43541.
SMRO43541. Positions 167-271, 323-495.
ModBaseSearch...

Protein-protein interaction databases

IntActO43541. 4 interactions.
MINTMINT-1198639.
STRINGO43541.

PTM databases

PhosphoSiteO43541.

Proteomic databases

PRIDEO43541.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000288840; ENSP00000288840; ENSG00000137834.
GeneID4091.
KEGGhsa:4091.
UCSCuc002aqf.1. human.
uc002aqg.1. human.

Organism-specific databases

CTD4091.
GeneCardsGC15P066994.
H-InvDBHIX0012368.
HGNCHGNC:6772. SMAD6.
MIM602931. gene.
neXtProtNX_O43541.
PharmGKBPA30529.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG09283.
GeneTreeENSGT00600000084353.
HOVERGENHBG053021.
InParanoidO43541.
OMAVESRGGM.
OrthoDBEOG4GTKCT.
PhylomeDBO43541.

Enzyme and pathway databases

Pathway_Interaction_DBbmppathway. BMP receptor signaling.
ReactomeREACT_111102. Signal Transduction.

Gene expression databases

ArrayExpressO43541.
BgeeO43541.
CleanExHS_SMAD6.
GenevestigatorO43541.
GermOnlineENSG00000137834. Homo sapiens.

Family and domain databases

InterProIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
Gene3DG3DSA:3.90.520.10. MAD_MH1. 2 hits.
G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit.
KOK04677.
PANTHERPTHR13703. Dwarfin. 1 hit.
PfamPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMSSF56366. MAD_MH1. 1 hit.
SSF49879. SMAD_FHA. 1 hit.
PROSITEPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio16042.
SOURCESearch...

Entry information

Entry nameSMAD6_HUMAN
AccessionPrimary (citable) accession number: O43541
Secondary accession number(s): A9J6M5 expand/collapse secondary AC list , O43654, Q15799, Q7Z7L4, Q96E31, Q9UKZ3
Entry history
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: October 3, 2006
Last modified: January 25, 2012
This is version 113 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families