SMAD9_HUMAN
ID SMAD9_HUMAN Reviewed; 467 AA.
AC O15198; A2A2Y6; O14989; Q5TBA1;
DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 217.
DE RecName: Full=Mothers against decapentaplegic homolog 9;
DE Short=MAD homolog 9;
DE Short=Mothers against DPP homolog 9;
DE AltName: Full=Madh6;
DE AltName: Full=SMAD family member 9;
DE Short=SMAD 9;
DE Short=Smad9;
GN Name=SMAD9; Synonyms=MADH6, MADH9, SMAD8 {ECO:0000303|PubMed:25755279};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
RC TISSUE=Fetal brain;
RX PubMed=9205116; DOI=10.1006/geno.1997.4753;
RA Watanabe T.K., Suzuki M., Omori Y., Hishigaki H., Horie M., Kanemoto N.,
RA Fujiwara T., Nakamura Y., Takahashi E.;
RT "Cloning and characterization of a novel member of the human Mad gene
RT family (MADH6).";
RL Genomics 42:446-451(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND B).
RC TISSUE=Brain, and Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP REVIEW.
RX PubMed=9759503; DOI=10.1146/annurev.biochem.67.1.753;
RA Massague J.;
RT "TGF-beta signal transduction.";
RL Annu. Rev. Biochem. 67:753-791(1998).
RN [6]
RP REVIEW.
RX PubMed=10647776; DOI=10.1016/s1359-6101(99)00012-x;
RA Verschueren K., Huylebroeck D.;
RT "Remarkable versatility of Smad proteins in the nucleus of transforming
RT growth factor-beta activated cells.";
RL Cytokine Growth Factor Rev. 10:187-199(1999).
RN [7]
RP REVIEW.
RX PubMed=10708948; DOI=10.1016/s1359-6101(99)00024-6;
RA Wrana J.L., Attisano L.;
RT "The Smad pathway.";
RL Cytokine Growth Factor Rev. 11:5-13(2000).
RN [8]
RP REVIEW.
RX PubMed=10708949; DOI=10.1016/s1359-6101(99)00025-8;
RA Miyazono K.;
RT "TGF-beta signaling by Smad proteins.";
RL Cytokine Growth Factor Rev. 11:15-22(2000).
RN [9]
RP INTERACTION WITH RANBP3L.
RX PubMed=25755279; DOI=10.1128/mcb.00121-15;
RA Chen F., Lin X., Xu P., Zhang Z., Chen Y., Wang C., Han J., Zhao B.,
RA Xiao M., Feng X.H.;
RT "Nuclear export of Smads by RanBP3L regulates bone morphogenetic protein
RT signaling and mesenchymal stem cell differentiation.";
RL Mol. Cell. Biol. 35:1700-1711(2015).
RN [10]
RP VARIANT PPH2 GLU-43, AND CHARACTERIZATION OF VARIANT PPH2 GLU-43.
RX PubMed=21898662; DOI=10.1002/humu.21605;
RA Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M.,
RA Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M., Gibbs J.S.,
RA Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B., Coulet F., Soubrier F.,
RA Humbert M., Morrell N.W., Trembath R.C., Machado R.D.;
RT "Molecular genetic characterization of SMAD signaling molecules in
RT pulmonary arterial hypertension.";
RL Hum. Mutat. 32:1385-1389(2011).
CC -!- FUNCTION: Transcriptional modulator activated by BMP (bone
CC morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-
CC regulated SMAD (R-SMAD).
CC -!- SUBUNIT: Interaction with the co-SMAD SMAD4. Interacts with PEBP2-alpha
CC subunit. Interacts with RANBP3L (PubMed:25755279).
CC {ECO:0000269|PubMed:25755279}.
CC -!- INTERACTION:
CC O15198; O60341: KDM1A; NbExp=2; IntAct=EBI-748763, EBI-710124;
CC O15198; Q96LA8: PRMT6; NbExp=2; IntAct=EBI-748763, EBI-912440;
CC O15198; Q13485: SMAD4; NbExp=4; IntAct=EBI-748763, EBI-347263;
CC O15198-2; P28799: GRN; NbExp=3; IntAct=EBI-12273450, EBI-747754;
CC O15198-2; Q9Y2U8: LEMD3; NbExp=4; IntAct=EBI-12273450, EBI-2561428;
CC O15198-2; Q13485: SMAD4; NbExp=3; IntAct=EBI-12273450, EBI-347263;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Note=In the cytoplasm in the absence of ligand. Migration to the
CC nucleus when complexed with SMAD4 (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=A;
CC IsoId=O15198-1; Sequence=Displayed;
CC Name=B;
CC IsoId=O15198-2; Sequence=VSP_006182;
CC -!- TISSUE SPECIFICITY: Expressed in heart, brain, placenta, lung, skeletal
CC muscle, prostate, testis, ovary and small intestine. Also expressed in
CC fetal brain, lung and kidney.
CC -!- PTM: Phosphorylated on serine by BMP (bone morphogenetic proteins) type
CC 1 receptor kinase.
CC -!- DISEASE: Pulmonary hypertension, primary, 2 (PPH2) [MIM:615342]: A rare
CC disorder characterized by plexiform lesions of proliferating
CC endothelial cells in pulmonary arterioles. The lesions lead to elevated
CC pulmonary arterial pression, right ventricular failure, and death. The
CC disease can occur from infancy throughout life and it has a mean age at
CC onset of 36 years. Penetrance is reduced. Although familial pulmonary
CC hypertension is rare, cases secondary to known etiologies are more
CC common and include those associated with the appetite-suppressant
CC drugs. {ECO:0000269|PubMed:21898662}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; D83760; BAA21128.1; -; mRNA.
DR EMBL; D83761; BAA21129.1; -; mRNA.
DR EMBL; AL138706; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471075; EAX08571.1; -; Genomic_DNA.
DR EMBL; CH471075; EAX08572.1; -; Genomic_DNA.
DR EMBL; BC011559; AAH11559.1; -; mRNA.
DR EMBL; BC104760; AAI04761.1; -; mRNA.
DR EMBL; BC104762; AAI04763.1; -; mRNA.
DR EMBL; BC143240; AAI43241.1; -; mRNA.
DR CCDS; CCDS45032.1; -. [O15198-1]
DR CCDS; CCDS9360.1; -. [O15198-2]
DR RefSeq; NP_001120689.1; NM_001127217.2. [O15198-1]
DR RefSeq; NP_005896.1; NM_005905.5. [O15198-2]
DR PDB; 6FZT; X-ray; 2.46 A; A/B=1-140.
DR PDBsum; 6FZT; -.
DR AlphaFoldDB; O15198; -.
DR SASBDB; O15198; -.
DR SMR; O15198; -.
DR BioGRID; 110268; 124.
DR CORUM; O15198; -.
DR IntAct; O15198; 105.
DR MINT; O15198; -.
DR STRING; 9606.ENSP00000369154; -.
DR iPTMnet; O15198; -.
DR PhosphoSitePlus; O15198; -.
DR BioMuta; SMAD9; -.
DR EPD; O15198; -.
DR jPOST; O15198; -.
DR MassIVE; O15198; -.
DR MaxQB; O15198; -.
DR PaxDb; O15198; -.
DR PeptideAtlas; O15198; -.
DR PRIDE; O15198; -.
DR ProteomicsDB; 48505; -. [O15198-1]
DR ProteomicsDB; 48506; -. [O15198-2]
DR Antibodypedia; 3969; 348 antibodies from 39 providers.
DR DNASU; 4093; -.
DR Ensembl; ENST00000350148.10; ENSP00000239885.6; ENSG00000120693.14. [O15198-2]
DR Ensembl; ENST00000379826.5; ENSP00000369154.4; ENSG00000120693.14. [O15198-1]
DR GeneID; 4093; -.
DR KEGG; hsa:4093; -.
DR MANE-Select; ENST00000379826.5; ENSP00000369154.4; NM_001127217.3; NP_001120689.1.
DR UCSC; uc001uvw.3; human. [O15198-1]
DR CTD; 4093; -.
DR DisGeNET; 4093; -.
DR GeneCards; SMAD9; -.
DR GeneReviews; SMAD9; -.
DR HGNC; HGNC:6774; SMAD9.
DR HPA; ENSG00000120693; Tissue enhanced (thyroid).
DR MalaCards; SMAD9; -.
DR MIM; 603295; gene.
DR MIM; 615342; phenotype.
DR neXtProt; NX_O15198; -.
DR OpenTargets; ENSG00000120693; -.
DR Orphanet; 275777; Heritable pulmonary arterial hypertension.
DR PharmGKB; PA30531; -.
DR VEuPathDB; HostDB:ENSG00000120693; -.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000163092; -.
DR HOGENOM; CLU_026736_0_2_1; -.
DR InParanoid; O15198; -.
DR OMA; YHATETP; -.
DR OrthoDB; 608001at2759; -.
DR PhylomeDB; O15198; -.
DR TreeFam; TF314923; -.
DR PathwayCommons; O15198; -.
DR Reactome; R-HSA-201451; Signaling by BMP.
DR SignaLink; O15198; -.
DR SIGNOR; O15198; -.
DR BioGRID-ORCS; 4093; 12 hits in 1097 CRISPR screens.
DR ChiTaRS; SMAD9; human.
DR GeneWiki; Mothers_against_decapentaplegic_homolog_9; -.
DR GenomeRNAi; 4093; -.
DR Pharos; O15198; Tbio.
DR PRO; PR:O15198; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; O15198; protein.
DR Bgee; ENSG00000120693; Expressed in corpus epididymis and 177 other tissues.
DR ExpressionAtlas; O15198; baseline and differential.
DR Genevisible; O15198; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; ISS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; ISS:BHF-UCL.
DR GO; GO:0071141; C:SMAD protein complex; NAS:BHF-UCL.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0070411; F:I-SMAD binding; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0030509; P:BMP signaling pathway; ISS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0071773; P:cellular response to BMP stimulus; NAS:BHF-UCL.
DR GO; GO:1901522; P:positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus; TAS:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISS:BHF-UCL.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IBA:GO_Central.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR001132; SMAD_dom_Dwarfin-type.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036578; SMAD_MH1_sf.
DR PANTHER; PTHR13703; PTHR13703; 1.
DR Pfam; PF03165; MH1; 1.
DR Pfam; PF03166; MH2; 1.
DR SMART; SM00523; DWA; 1.
DR SMART; SM00524; DWB; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 1.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant;
KW DNA-binding; Metal-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Zinc.
FT CHAIN 1..467
FT /note="Mothers against decapentaplegic homolog 9"
FT /id="PRO_0000090875"
FT DOMAIN 16..140
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 273..467
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 174..246
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 192..221
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 68
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 113
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 125
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 130
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT VAR_SEQ 224..260
FT /note="Missing (in isoform B)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9205116"
FT /id="VSP_006182"
FT VARIANT 43
FT /note="K -> E (in PPH2; affects SMAD-mediated signaling;
FT dbSNP:rs397514715)"
FT /evidence="ECO:0000269|PubMed:21898662"
FT /id="VAR_066871"
FT STRAND 10..12
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 16..22
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 29..45
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 51..60
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 70..72
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 79..81
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 84..86
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 88..96
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 107..109
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 122..125
FT /evidence="ECO:0007829|PDB:6FZT"
FT HELIX 128..130
FT /evidence="ECO:0007829|PDB:6FZT"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:6FZT"
SQ SEQUENCE 467 AA; 52493 MW; CFC8F982945BC6DD CRC64;
MHSTTPISSL FSFTSPAVKR LLGWKQGDEE EKWAEKAVDS LVKKLKKKKG AMDELERALS
CPGQPSKCVT IPRSLDGRLQ VSHRKGLPHV IYCRVWRWPD LQSHHELKPL ECCEFPFGSK
QKEVCINPYH YRRVETPVLP PVLVPRHSEY NPQLSLLAKF RSASLHSEPL MPHNATYPDS
FQQPPCSALP PSPSHAFSQS PCTASYPHSP GSPSEPESPY QHSVDTPPLP YHATEASETQ
SGQPVDATAD RHVVLSIPNG DFRPVCYEEP QHWCSVAYYE LNNRVGETFQ ASSRSVLIDG
FTDPSNNRNR FCLGLLSNVN RNSTIENTRR HIGKGVHLYY VGGEVYAECV SDSSIFVQSR
NCNYQHGFHP ATVCKIPSGC SLKVFNNQLF AQLLAQSVHH GFEVVYELTK MCTIRMSFVK
GWGAEYHRQD VTSTPCWIEI HLHGPLQWLD KVLTQMGSPH NPISSVS
