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O35182

- SMAD6_MOUSE

UniProt

O35182 - SMAD6_MOUSE

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Protein

Mothers against decapentaplegic homolog 6

Gene

Smad6

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.By similarity1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi206 – 2061ZincBy similarity
Metal bindingi248 – 2481ZincBy similarity
Metal bindingi261 – 2611ZincBy similarity
Metal bindingi266 – 2661ZincBy similarity

GO - Molecular functioni

  1. chromatin binding Source: UniProtKB
  2. metal ion binding Source: UniProtKB-KW
  3. sequence-specific DNA binding transcription factor activity Source: InterPro
  4. transcription regulatory region DNA binding Source: UniProtKB
  5. transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity Source: Ensembl

GO - Biological processi

  1. BMP signaling pathway Source: UniProtKB
  2. cardiac vascular smooth muscle cell development Source: DFLAT
  3. cell-substrate adhesion Source: UniProtKB
  4. coronary vasculature morphogenesis Source: DFLAT
  5. fat cell differentiation Source: UniProtKB
  6. immune response Source: Ensembl
  7. negative regulation of apoptotic process Source: Ensembl
  8. negative regulation of BMP signaling pathway Source: Ensembl
  9. negative regulation of cell proliferation Source: Ensembl
  10. negative regulation of pathway-restricted SMAD protein phosphorylation Source: Ensembl
  11. negative regulation of SMAD protein complex assembly Source: Ensembl
  12. negative regulation of transforming growth factor beta receptor signaling pathway Source: Ensembl
  13. negative regulation of vasodilation Source: DFLAT
  14. positive regulation of vasoconstriction Source: DFLAT
  15. response to estrogen Source: Ensembl
  16. response to laminar fluid shear stress Source: Ensembl
  17. transcription, DNA-templated Source: UniProtKB-KW
  18. transforming growth factor beta receptor signaling pathway Source: InterPro
  19. ureteric bud development Source: UniProtKB
  20. zygotic specification of dorsal/ventral axis Source: Ensembl
Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_220505. Signaling by BMP.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Smad6
Synonyms:Madh6, Madh7, Msmad6
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 9

Organism-specific databases

MGIiMGI:1336883. Smad6.

Subcellular locationi

Nucleus By similarity

GO - Cellular componenti

  1. nucleus Source: UniProtKB
  2. protein complex Source: MGI
  3. transcription factor complex Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi74 – 741R → A: Strongly decreased methylation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 495495Mothers against decapentaplegic homolog 6PRO_0000090870Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei74 – 741Dimethylated arginine; alternate1 Publication
Modified residuei74 – 741Omega-N-methylarginine; alternate1 Publication
Modified residuei81 – 811Dimethylated arginine; alternate1 Publication
Modified residuei81 – 811Omega-N-methylarginine; alternate1 Publication
Cross-linki174 – 174Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei436 – 4361Phosphoserine; by PRKX; in vitroPROSITE-ProRule annotation

Post-translational modificationi

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.By similarity1 Publication
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.1 Publication

Keywords - PTMi

Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiO35182.
PRIDEiO35182.

PTM databases

PhosphoSiteiO35182.

Expressioni

Tissue specificityi

Ubiquitous in various organs, with higher levels in lung.

Inductioni

By TGF-beta and BMP4.1 Publication

Gene expression databases

BgeeiO35182.
CleanExiMM_SMAD6.
ExpressionAtlasiO35182. baseline and differential.
GenevestigatoriO35182.

Interactioni

Subunit structurei

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.By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Axin1O356252EBI-4321242,EBI-2365912
Bmpr1bP368982EBI-4321242,EBI-7107883
Prmt1Q9JIF03EBI-4321242,EBI-519055
UBE2OQ9C0C94EBI-4321242,EBI-2339946From a different organism.

Protein-protein interaction databases

BioGridi201279. 11 interactions.
IntActiO35182. 189 interactions.
MINTiMINT-1899791.

Structurei

3D structure databases

ProteinModelPortaliO35182.
SMRiO35182. Positions 193-270, 329-492.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini149 – 276128MH1PROSITE-ProRule annotationAdd
BLAST
Domaini332 – 495164MH2PROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi25 – 317Poly-Gly
Compositional biasi81 – 844Poly-Arg
Compositional biasi166 – 1694Poly-Leu
Compositional biasi276 – 2794Poly-Pro

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated
Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiNOG309572.
GeneTreeiENSGT00760000119091.
HOGENOMiHOG000060106.
HOVERGENiHBG053021.
InParanoidiO35182.
KOiK04677.
OMAiWRSRLIP.
OrthoDBiEOG7GN2PK.
PhylomeDBiO35182.
TreeFamiTF314923.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 2 hits.
InterProiIPR013790. 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]
PANTHERiPTHR13703. PTHR13703. 1 hit.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O35182-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MFRSKRSGLV RRLWRSRVVP DREEGSGGGG GVDEDGSLGS RAEPAPRARE
60 70 80 90 100
GGGCSRSEVR SVAPRRPRDA VGPRGAAIAG RRRRTGGLPR PVSESGAGAG
110 120 130 140 150
GSPLDVAEPG GPGWLPESDC ETVTCCLFSE RDAAGAPRDS GDPQARQSPE
160 170 180 190 200
PEEGGGPRSR EARSRLLLLE QELKTVTYSL LKRLKERSLD TLLEAVESRG
210 220 230 240 250
GVPGGCVLVP RADLRLGGQP APPQLLLGRL FRWPDLQHAV ELKPLCGCHS
260 270 280 290 300
FTAAADGPTV CCNPYHFSRL CGPESPPPPY SRLSPPDQYK PLDLSDSTLS
310 320 330 340 350
YTETEATNSL ITAPGEFSDA SMSPDATKPS HWCSVAYWEH RTRVGRLYAV
360 370 380 390 400
YDQAVSIFYD LPQGSGFCLG QLNLEQRSES VRRTRSKIGF GILLSKEPDG
410 420 430 440 450
VWAYNRGEHP IFVNSPTLDA PGGRALVVRK VPPGYSIKVF DFERSGLLQH
460 470 480 490
ADAAHGPYDP HSVRISFAKG WGPCYSRQFI TSCPCWLEIL LNNHR
Length:495
Mass (Da):53,714
Last modified:January 1, 1998 - v1
Checksum:iD9282D42B120C507
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti176 – 1772VT → AQ in BAB23460. (PubMed:16141072)Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF010133 mRNA. Translation: AAB81351.1.
AK004671 mRNA. Translation: BAB23460.1.
CCDSiCCDS23273.1.
RefSeqiNP_032568.3. NM_008542.3.
XP_006510885.1. XM_006510822.1.
UniGeneiMm.325757.

Genome annotation databases

EnsembliENSMUST00000041029; ENSMUSP00000036285; ENSMUSG00000036867.
GeneIDi17130.
KEGGimmu:17130.
UCSCiuc009qbk.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF010133 mRNA. Translation: AAB81351.1 .
AK004671 mRNA. Translation: BAB23460.1 .
CCDSi CCDS23273.1.
RefSeqi NP_032568.3. NM_008542.3.
XP_006510885.1. XM_006510822.1.
UniGenei Mm.325757.

3D structure databases

ProteinModelPortali O35182.
SMRi O35182. Positions 193-270, 329-492.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 201279. 11 interactions.
IntActi O35182. 189 interactions.
MINTi MINT-1899791.

PTM databases

PhosphoSitei O35182.

Proteomic databases

PaxDbi O35182.
PRIDEi O35182.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000041029 ; ENSMUSP00000036285 ; ENSMUSG00000036867 .
GeneIDi 17130.
KEGGi mmu:17130.
UCSCi uc009qbk.2. mouse.

Organism-specific databases

CTDi 4091.
MGIi MGI:1336883. Smad6.

Phylogenomic databases

eggNOGi NOG309572.
GeneTreei ENSGT00760000119091.
HOGENOMi HOG000060106.
HOVERGENi HBG053021.
InParanoidi O35182.
KOi K04677.
OMAi WRSRLIP.
OrthoDBi EOG7GN2PK.
PhylomeDBi O35182.
TreeFami TF314923.

Enzyme and pathway databases

Reactomei REACT_220505. Signaling by BMP.

Miscellaneous databases

NextBioi 291324.
PROi O35182.
SOURCEi Search...

Gene expression databases

Bgeei O35182.
CleanExi MM_SMAD6.
ExpressionAtlasi O35182. baseline and differential.
Genevestigatori O35182.

Family and domain databases

Gene3Di 2.60.200.10. 1 hit.
3.90.520.10. 2 hits.
InterProi 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 ]
PANTHERi PTHR13703. PTHR13703. 1 hit.
Pfami PF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view ]
SMARTi SM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view ]
SUPFAMi SSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEi PS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. 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.
    , 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. Cited for: METHYLATION AT ARG-74 AND ARG-81, MUTAGENESIS OF ARG-74.

Entry informationi

Entry nameiSMAD6_MOUSE
AccessioniPrimary (citable) accession number: O35182
Secondary accession number(s): Q9CW62
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: January 1, 1998
Last modified: October 29, 2014
This is version 128 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3