O43541 (SMAD6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	496 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	BMP 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 component	cytosol Traceable author statement. Source: Reactome transcription factor complex Inferred from electronic annotation. Source: InterPro
Molecular function	I-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

With	Entry	#Exp.	IntAct	Notes
PRKX	P51817	5	EBI-976374,EBI-4302903
RUNX2	Q13950	3	EBI-976374,EBI-976402
STAMBP	O95630	2	EBI-4324970,EBI-396676

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 496	496	Mothers against decapentaplegic homolog 6		PRO_0000090869
Regions
	Domain	148 – 275	128	MH1
	Domain	331 – 496	166	MH2
	Compositional bias	25 – 33	9	Poly-Gly
	Compositional bias	82 – 85	4	Poly-Arg
	Compositional bias	165 – 168	4	Poly-Leu
	Compositional bias	251 – 254	4	Poly-Ala
	Compositional bias	275 – 278	4	Poly-Pro
Amino acid modifications
	Modified residue	435	1	Phosphoserine; by PRKX; in vitro Ref.17
Natural variations
	Alternative sequence	1 – 261	261	Missing in isoform B.		VSP_006179
	Alternative sequence	262 – 273	12	NPYHF…LCGPE → MSRMGKPIETQK in isoform B.		VSP_006180
	Alternative sequence	318 – 338	21	DASMS…VAYWE → AADAGIGSRGNRGLESSVPC S in isoform D.		VSP_035489
	Alternative sequence	339 – 496	158	Missing in isoform D.		VSP_035490
Experimental info
	Mutagenesis	435	1	S → A: Loss of in vitro phosphorylation by PRKX. Ref.17
	Mutagenesis	471	1	G → S: Loss of interaction with SMAD1 and BMP-receptor.
	Mutagenesis	478 – 496	19	Missing: Loss of interaction with SMAD1.
	Sequence conflict	21	1	D → N in AAB94137. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform A [UniParc]. Last modified October 3, 2006. Version 2. Checksum: A4B928AE2D34EBC2	FASTA	496	53,497
	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
	Isoform B (Smad 6S) [UniParc]. Checksum: 0847C2C84DC0B2A2	FASTA	235	26,236
	10 20 30 40 50 60 MSRMGKPIET QKSPPPPYSR LSPRDEYKPL DLSDSTLSYT ETEATNSLIT APGEFSDASM 70 80 90 100 110 120 SPDATKPSHW CSVAYWEHRT RVGRLYAVYD QAVSIFYDLP QGSGFCLGQL NLEQRSESVR 130 140 150 160 170 180 RTRSKIGFGI LLSKEPDGVW AYNRGEHPIF VNSPTLDAPG GRALVVRKVP PGYSIKVFDF 190 200 210 220 230 ERSGLQHAPE PDAADGPYDP NSVRISFAKG WGPCYSRQFI TSCPCWLEIL LNNPR
	Isoform D [UniParc]. Checksum: C4D02353D7FD76CE	FASTA	338	35,467
	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 TETEATNSLI TAPGEFSAAD AGIGSRGNRG LESSVPCS

References

	« Hide 'large scale' referencesShow '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 , AF041062, AF041063, AF041064 Genomic DNA. Translation: AAF14343.1. AM909653 mRNA. Translation: CAP20377.1. BC012986 mRNA. Translation: AAH12986.1. AF101474 Genomic DNA. Translation: AAF06841.1.
IPI	IPI00012869. IPI00218149. IPI00884203.
RefSeq	NP_001136333.1. NM_001142861.2. NP_005576.3. NM_005585.4.
UniGene	Hs.153863.
3D structure databases
ProteinModelPortal	O43541.
SMR	O43541. Positions 167-271, 323-495.
ModBase	Search...
Protein-protein interaction databases
IntAct	O43541. 4 interactions.
MINT	MINT-1198639.
STRING	O43541.
PTM databases
PhosphoSite	O43541.
Proteomic databases
PRIDE	O43541.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000288840; ENSP00000288840; ENSG00000137834.
GeneID	4091.
KEGG	hsa:4091.
UCSC	uc002aqf.1. human. uc002aqg.1. human.
Organism-specific databases
CTD	4091.
GeneCards	GC15P066994.
H-InvDB	HIX0012368.
HGNC	HGNC:6772. SMAD6.
MIM	602931. gene.
neXtProt	NX_O43541.
PharmGKB	PA30529.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG09283.
GeneTree	ENSGT00600000084353.
HOVERGEN	HBG053021.
InParanoid	O43541.
OMA	VESRGGM.
OrthoDB	EOG4GTKCT.
PhylomeDB	O43541.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling.
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	O43541.
Bgee	O43541.
CleanEx	HS_SMAD6.
Genevestigator	O43541.
GermOnline	ENSG00000137834. Homo sapiens.
Family and domain databases
InterPro	IPR013790. 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]
Gene3D	G3DSA:3.90.520.10. MAD_MH1. 2 hits. G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit.
KO	K04677.
PANTHER	PTHR13703. Dwarfin. 1 hit.
Pfam	PF03165. MH1. 1 hit. PF03166. MH2. 1 hit. [Graphical view]
SMART	SM00523. DWA. 1 hit. SM00524. DWB. 1 hit. [Graphical view]
SUPFAM	SSF56366. MAD_MH1. 1 hit. SSF49879. SMAD_FHA. 1 hit.
PROSITE	PS51075. MH1. 1 hit. PS51076. MH2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	16042.
SOURCE	Search...

Entry information

Entry name

SMAD6_HUMAN

Accession

Primary (citable) accession number: O43541
Secondary accession number(s): A9J6M5 , 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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.