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O35182 (SMAD6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·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):
Mad homolog 7
SMAD family member 6
Short name=SMAD 6
Short name=Smad6
Gene names
Name:Smad6
Synonyms:Madh6, Madh7, Msmad6
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length495 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Binds to regulatory elements in target promoter regions By similarity. May block the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding By similarity. 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. Ref.6

Subunit structure

Interacts with NEDD4L. Interacts with WWP1. Interacts with STAMBP and PRKX By similarity. Interacts with RNF111 and AXIN1. Interacts with TGF-beta type I receptor superfamily members, including ACVR1B, BMPR1B and TGFBR1. In response to BMP2 treatment, interacts with SMAD1; this interaction may inhibit SMAD1-binding to SMAD4. Interacts with HOXC8 and HOXC9 By similarity. 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. Ref.3 Ref.4 Ref.5 Ref.6

Subcellular location

Nucleus By similarity.

Tissue specificity

Ubiquitous in various organs, with higher levels in lung.

Induction

By TGF-beta and BMP4. Ref.6

Post-translational modification

Monoubiquitinated at Lys-174 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 By similarity. Ubiquitinated by WWP1. Ref.4

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.

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
   LigandDNA-binding
Metal-binding
Zinc
   PTMIsopeptide bond
Methylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcardiac vascular smooth muscle cell development

Traceable author statement PubMed 20299672. Source: DFLAT

cell-substrate adhesion

Inferred from sequence or structural similarity. Source: UniProtKB

coronary vasculature morphogenesis

Traceable author statement PubMed 20299672. Source: DFLAT

immune response

Inferred from electronic annotation. Source: Ensembl

negative regulation of BMP signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of SMAD protein complex assembly

Inferred from electronic annotation. Source: Ensembl

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of pathway-restricted SMAD protein phosphorylation

Inferred from electronic annotation. Source: Ensembl

negative regulation of transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of vasodilation

Traceable author statement PubMed 20299672. Source: DFLAT

positive regulation of vasoconstriction

Traceable author statement PubMed 20299672. Source: DFLAT

response to estrogen

Inferred from electronic annotation. Source: Ensembl

response to laminar fluid shear stress

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

ureteric bud development

Inferred from expression pattern PubMed 14656760. Source: UniProtKB

zygotic specification of dorsal/ventral axis

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentnucleus

Inferred from sequence or structural similarity. Source: UniProtKB

protein complex

Inferred from sequence orthology PubMed 23610558. Source: MGI

transcription factor complex

Inferred from electronic annotation. Source: InterPro

   Molecular_functionchromatin binding

Inferred from sequence or structural similarity. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 16601693PubMed 17118358PubMed 23455153. Source: IntAct

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: InterPro

transcription regulatory region DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 495495Mothers against decapentaplegic homolog 6
PRO_0000090870

Regions

Domain149 – 276128MH1
Domain332 – 495164MH2
Compositional bias25 – 317Poly-Gly
Compositional bias81 – 844Poly-Arg
Compositional bias166 – 1694Poly-Leu
Compositional bias276 – 2794Poly-Pro

Sites

Metal binding2061Zinc By similarity
Metal binding2481Zinc By similarity
Metal binding2611Zinc By similarity
Metal binding2661Zinc By similarity

Amino acid modifications

Modified residue741Dimethylated arginine; alternate Ref.7
Modified residue741Omega-N-methylarginine; alternate Ref.7
Modified residue811Dimethylated arginine; alternate Ref.7
Modified residue811Omega-N-methylarginine; alternate Ref.7
Modified residue4361Phosphoserine; by PRKX; in vitro By similarity
Cross-link174Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Mutagenesis741R → A: Strongly decreased methylation. Ref.7
Sequence conflict176 – 1772VT → AQ in BAB23460. Ref.2

Sequences

Sequence LengthMass (Da)Tools
O35182 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: D9282D42B120C507

FASTA49553,714
        10         20         30         40         50         60 
MFRSKRSGLV RRLWRSRVVP DREEGSGGGG GVDEDGSLGS RAEPAPRARE GGGCSRSEVR 

        70         80         90        100        110        120 
SVAPRRPRDA VGPRGAAIAG RRRRTGGLPR PVSESGAGAG GSPLDVAEPG GPGWLPESDC 

       130        140        150        160        170        180 
ETVTCCLFSE RDAAGAPRDS GDPQARQSPE PEEGGGPRSR EARSRLLLLE QELKTVTYSL 

       190        200        210        220        230        240 
LKRLKERSLD TLLEAVESRG GVPGGCVLVP RADLRLGGQP APPQLLLGRL FRWPDLQHAV 

       250        260        270        280        290        300 
ELKPLCGCHS FTAAADGPTV CCNPYHFSRL CGPESPPPPY SRLSPPDQYK PLDLSDSTLS 

       310        320        330        340        350        360 
YTETEATNSL ITAPGEFSDA SMSPDATKPS HWCSVAYWEH RTRVGRLYAV YDQAVSIFYD 

       370        380        390        400        410        420 
LPQGSGFCLG QLNLEQRSES VRRTRSKIGF GILLSKEPDG VWAYNRGEHP IFVNSPTLDA 

       430        440        450        460        470        480 
PGGRALVVRK VPPGYSIKVF DFERSGLLQH ADAAHGPYDP HSVRISFAKG WGPCYSRQFI 

       490 
TSCPCWLEIL LNNHR 

« Hide

References

« Hide 'large scale' references
[1]"Smad6 inhibits signalling by the TGF-beta superfamily."
Imamura T., Takase M., Nishihara A., Oeda E., Hanai J., Kawabata M., Miyazono K.
Nature 389:622-626(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Lung.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 174-495.
Strain: C57BL/6J.
Tissue: Lung.
[3]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RNF111.
[4]"Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1)."
Komuro A., Imamura T., Saitoh M., Yoshida Y., Yamori T., Miyazono K., Miyazawa K.
Oncogene 23:6914-6923(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH WWP1, UBIQUITINATION.
[5]"NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor."
Kuratomi G., Komuro A., Goto K., Shinozaki M., Miyazawa K., Miyazono K., Imamura T.
Biochem. J. 386:461-470(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NEDD4L.
[6]"Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1."
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.
Nat. Immunol. 7:1057-1065(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PELI1, INDUCTION.
[7]"Arginine Methylation Initiates BMP-Induced Smad Signaling."
Xu J., Wang A.H., Oses-Prieto J., Makhijani K., Katsuno Y., Pei M., Yan L., Zheng Y.G., Burlingame A., Bruckner K., Derynck R.
Mol. Cell 51:5-19(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: METHYLATION AT ARG-74 AND ARG-81, MUTAGENESIS OF ARG-74.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF010133 mRNA. Translation: AAB81351.1.
AK004671 mRNA. Translation: BAB23460.1.
CCDSCCDS23273.1.
RefSeqNP_032568.3. NM_008542.3.
XP_006510885.1. XM_006510822.1.
UniGeneMm.325757.

3D structure databases

ProteinModelPortalO35182.
SMRO35182. Positions 193-270, 329-492.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid201279. 11 interactions.
IntActO35182. 189 interactions.
MINTMINT-1899791.

PTM databases

PhosphoSiteO35182.

Proteomic databases

PaxDbO35182.
PRIDEO35182.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000041029; ENSMUSP00000036285; ENSMUSG00000036867.
GeneID17130.
KEGGmmu:17130.
UCSCuc009qbk.2. mouse.

Organism-specific databases

CTD4091.
MGIMGI:1336883. Smad6.

Phylogenomic databases

eggNOGNOG309572.
GeneTreeENSGT00600000084353.
HOGENOMHOG000060106.
HOVERGENHBG053021.
InParanoidO35182.
KOK04677.
OMAWRSRLIP.
OrthoDBEOG7GN2PK.
PhylomeDBO35182.
TreeFamTF314923.

Gene expression databases

ArrayExpressO35182.
BgeeO35182.
CleanExMM_SMAD6.
GenevestigatorO35182.

Family and domain databases

Gene3D2.60.200.10. 1 hit.
3.90.520.10. 2 hits.
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]
PANTHERPTHR13703. PTHR13703. 1 hit.
PfamPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio291324.
PROO35182.
SOURCESearch...

Entry information

Entry nameSMAD6_MOUSE
AccessionPrimary (citable) accession number: O35182
Secondary accession number(s): Q9CW62
Entry history
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: January 1, 1998
Last modified: July 9, 2014
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot