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P84022

- SMAD3_HUMAN

UniProt

P84022 - SMAD3_HUMAN

Protein

Mothers against decapentaplegic homolog 3

Gene

SMAD3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 133 (01 Oct 2014)
      Sequence version 1 (05 Jul 2004)
      Previous versions | rss
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    Functioni

    Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.11 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei40 – 401Required for trimerization
    Sitei41 – 411Required for interaction with DNA and JUN and for functional cooperation with JUN
    Metal bindingi64 – 641Zinc
    Metal bindingi109 – 1091Zinc
    Metal bindingi121 – 1211Zinc
    Metal bindingi126 – 1261Zinc

    GO - Molecular functioni

    1. beta-catenin binding Source: BHF-UCL
    2. bHLH transcription factor binding Source: BHF-UCL
    3. chromatin DNA binding Source: Ensembl
    4. core promoter proximal region sequence-specific DNA binding Source: UniProtKB
    5. co-SMAD binding Source: BHF-UCL
    6. double-stranded DNA binding Source: Ensembl
    7. enhancer binding Source: BHF-UCL
    8. phosphatase binding Source: UniProtKB
    9. protein binding Source: UniProtKB
    10. protein homodimerization activity Source: BHF-UCL
    11. protein kinase binding Source: UniProtKB
    12. RNA polymerase II activating transcription factor binding Source: BHF-UCL
    13. R-SMAD binding Source: BHF-UCL
    14. sequence-specific DNA binding Source: BHF-UCL
    15. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    16. transcription factor binding Source: BHF-UCL
    17. transcription regulatory region DNA binding Source: BHF-UCL
    18. transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity Source: BHF-UCL
    19. transforming growth factor beta receptor binding Source: BHF-UCL
    20. ubiquitin binding Source: UniProtKB
    21. ubiquitin protein ligase binding Source: BHF-UCL
    22. zinc ion binding Source: UniProtKB

    GO - Biological processi

    1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: BHF-UCL
    2. activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: Ensembl
    3. activin receptor signaling pathway Source: BHF-UCL
    4. cell-cell junction organization Source: BHF-UCL
    5. cell cycle arrest Source: BHF-UCL
    6. developmental growth Source: Ensembl
    7. embryonic cranial skeleton morphogenesis Source: Ensembl
    8. embryonic foregut morphogenesis Source: Ensembl
    9. embryonic pattern specification Source: Ensembl
    10. endoderm development Source: Ensembl
    11. evasion or tolerance of host defenses by virus Source: BHF-UCL
    12. extrinsic apoptotic signaling pathway Source: BHF-UCL
    13. gene expression Source: Reactome
    14. heart looping Source: Ensembl
    15. immune response Source: BHF-UCL
    16. immune system development Source: Ensembl
    17. intracellular signal transduction Source: GOC
    18. in utero embryonic development Source: Ensembl
    19. lens fiber cell differentiation Source: Ensembl
    20. liver development Source: Ensembl
    21. mesoderm formation Source: Ensembl
    22. negative regulation of apoptotic process Source: Ensembl
    23. negative regulation of cell growth Source: BHF-UCL
    24. negative regulation of inflammatory response Source: Ensembl
    25. negative regulation of mitotic cell cycle Source: BHF-UCL
    26. negative regulation of osteoblast differentiation Source: Ensembl
    27. negative regulation of osteoblast proliferation Source: Ensembl
    28. negative regulation of protein catabolic process Source: BHF-UCL
    29. negative regulation of protein phosphorylation Source: BHF-UCL
    30. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    31. negative regulation of transforming growth factor beta receptor signaling pathway Source: Reactome
    32. negative regulation of wound healing Source: Ensembl
    33. nodal signaling pathway Source: BHF-UCL
    34. osteoblast development Source: Ensembl
    35. paraxial mesoderm morphogenesis Source: Ensembl
    36. pericardium development Source: Ensembl
    37. positive regulation of alkaline phosphatase activity Source: Ensembl
    38. positive regulation of bone mineralization Source: Ensembl
    39. positive regulation of canonical Wnt signaling pathway Source: BHF-UCL
    40. positive regulation of catenin import into nucleus Source: BHF-UCL
    41. positive regulation of cell migration Source: Ensembl
    42. positive regulation of chondrocyte differentiation Source: Ensembl
    43. positive regulation of epithelial to mesenchymal transition Source: BHF-UCL
    44. positive regulation of focal adhesion assembly Source: Ensembl
    45. positive regulation of gene expression involved in extracellular matrix organization Source: BHF-UCL
    46. positive regulation of interleukin-1 beta production Source: Ensembl
    47. positive regulation of positive chemotaxis Source: Ensembl
    48. positive regulation of stress fiber assembly Source: Ensembl
    49. positive regulation of transcription, DNA-templated Source: BHF-UCL
    50. positive regulation of transcription factor import into nucleus Source: BHF-UCL
    51. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    52. positive regulation of transforming growth factor beta3 production Source: Ensembl
    53. primary miRNA processing Source: BHF-UCL
    54. protein stabilization Source: BHF-UCL
    55. regulation of binding Source: Ensembl
    56. regulation of epithelial cell proliferation Source: Ensembl
    57. regulation of immune response Source: Ensembl
    58. regulation of striated muscle tissue development Source: Ensembl
    59. regulation of transforming growth factor beta2 production Source: BHF-UCL
    60. regulation of transforming growth factor beta receptor signaling pathway Source: BHF-UCL
    61. response to hypoxia Source: BHF-UCL
    62. signal transduction involved in regulation of gene expression Source: Ensembl
    63. SMAD protein complex assembly Source: BHF-UCL
    64. somitogenesis Source: Ensembl
    65. T cell activation Source: Ensembl
    66. thyroid gland development Source: Ensembl
    67. transcription, DNA-templated Source: Reactome
    68. transcription initiation from RNA polymerase II promoter Source: Reactome
    69. transdifferentiation Source: Ensembl
    70. transforming growth factor beta receptor signaling pathway Source: UniProtKB
    71. transport Source: BHF-UCL
    72. ureteric bud development Source: Ensembl
    73. wound healing Source: BHF-UCL

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_111057. Signaling by NODAL.
    REACT_120727. Downregulation of TGF-beta receptor signaling.
    REACT_120734. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_120850. TGF-beta receptor signaling activates SMADs.
    REACT_121111. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_150238. Signaling by Activin.
    REACT_169103. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_169107. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_169165. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_169263. TGFBR1 KD Mutants in Cancer.
    SignaLinkiP84022.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mothers against decapentaplegic homolog 3
    Short name:
    MAD homolog 3
    Short name:
    Mad3
    Short name:
    Mothers against DPP homolog 3
    Short name:
    hMAD-3
    Alternative name(s):
    JV15-2
    SMAD family member 3
    Short name:
    SMAD 3
    Short name:
    Smad3
    Short name:
    hSMAD3
    Gene namesi
    Name:SMAD3
    Synonyms:MADH3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 15

    Organism-specific databases

    HGNCiHGNC:6769. SMAD3.

    Subcellular locationi

    Cytoplasm. Nucleus
    Note: Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4. Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1. Co-localizes with LEMD3 at the nucleus inner membrane. MAPK-mediated phosphorylation appears to have no effect on nuclear import. PDPK1 prevents its nuclear translocation in response to TGF-beta.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. cytosol Source: Reactome
    3. nuclear chromatin Source: BHF-UCL
    4. nuclear inner membrane Source: UniProtKB
    5. nucleoplasm Source: Reactome
    6. nucleus Source: UniProtKB
    7. plasma membrane Source: Ensembl
    8. receptor complex Source: BHF-UCL
    9. SMAD2-SMAD3 protein complex Source: BHF-UCL
    10. SMAD protein complex Source: UniProtKB
    11. transcription factor complex Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
    Note: The disease may be caused by mutations affecting the gene represented in this entry.
    Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]: An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.1 Publication
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti112 – 1121A → V in LDS3. 1 Publication
    VAR_067051
    Natural varianti239 – 2391E → K in LDS3. 1 Publication
    VAR_067047
    Natural varianti261 – 2611T → I in LDS3. 1 Publication
    VAR_065578
    Natural varianti279 – 2791R → K in LDS3. 1 Publication
    VAR_067048
    Natural varianti287 – 2871R → W in LDS3. 1 Publication
    VAR_065579

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi8 – 81T → V: Reduced phosphorylation, increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-179 and A-213. 1 Publication
    Mutagenesisi33 – 331K → R: Slightly decreased monoubiquitination. 1 Publication
    Mutagenesisi40 – 401K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-41; A-43 and A-44. 1 Publication
    Mutagenesisi41 – 411K → A: Greatly reduced interaction with DNA and JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-44 and A-43. 1 Publication
    Mutagenesisi43 – 431K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with DNA and JUN; when associated with A-40; A-41 and A-44. 1 Publication
    Mutagenesisi44 – 441K → A: Little effect on interaction with DNA or JUN. Abolishes interaction with JUN; when associated with A-40; A-41 and A-43. 1 Publication
    Mutagenesisi53 – 531K → R: Slightly decreased monoubiquitination. 1 Publication
    Mutagenesisi74 – 741R → D: Reduced interaction with JUN. Loss of transcriptional activity and cooperation with JUN. 1 Publication
    Mutagenesisi81 – 811K → R: Decreased monoubiquitination. 1 Publication
    Mutagenesisi179 – 1791T → V: Reduced phosphorylation, increased transcriptional and increased antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and A-213. 3 Publications
    Mutagenesisi204 – 2041S → A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208. 3 Publications
    Mutagenesisi208 – 2081S → A: Increased transcriptional activity. Further increased transcriptional activity; when associated with S-208. 3 Publications
    Mutagenesisi213 – 2131S → A: Reduced phosphorylation. Increased transcriptional and antiproliferative activities. Further increase in transcriptional and antiproliferative activities; when associated with V-8 and V-179. 1 Publication
    Mutagenesisi333 – 3331K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-341; R-378 and R-409. 1 Publication
    Mutagenesisi341 – 3411K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-378 and R-409. 1 Publication
    Mutagenesisi378 – 3781K → Q: Increased transcriptional activity. No further increase in transcriptional activity with EP300. 1 Publication
    Mutagenesisi378 – 3781K → R: Greatly reduced acetylation and 85% reduction in transcriptional activity. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-409. 1 Publication
    Mutagenesisi409 – 4091K → R: No effect on acetylation. Completely abolishes acetylation and 97% reduction in transcriptional activity; when associated with R-333; R-341 and R-378. 1 Publication
    Mutagenesisi418 – 4181S → A: Increased constitutive activity. 1 Publication
    Mutagenesisi418 – 4181S → D: Decreased activity. 1 Publication
    Mutagenesisi422 – 4254SSVS → AAVA: Does not abolish protein nuclear export. Abolishes almost completely acetylation.
    Mutagenesisi422 – 4254SSVS → EEVE: Forms heterotrimers.
    Mutagenesisi422 – 4254SSVS → RRVR: Diminishes cargo protein export.

    Keywords - Diseasei

    Aortic aneurysm, Disease mutation

    Organism-specific databases

    MIMi114500. phenotype.
    613795. phenotype.
    Orphaneti284984. Aneurysm - osteoarthritis syndrome.
    91387. Familial thoracic aortic aneurysm and aortic dissection.
    PharmGKBiPA30526.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed2 Publications
    Chaini2 – 425424Mothers against decapentaplegic homolog 3PRO_0000090856Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserine2 Publications
    Modified residuei8 – 81Phosphothreonine; by CDK2 and CDK41 Publication
    Cross-linki33 – 33Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Cross-linki81 – 81Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Modified residuei179 – 1791Phosphothreonine; by CDK2, CDK4 and MAPK3 Publications
    Modified residuei204 – 2041Phosphoserine; by GSK3 and MAPK3 PublicationsPROSITE-ProRule annotation
    Modified residuei208 – 2081Phosphoserine; by MAPK3 PublicationsPROSITE-ProRule annotation
    Modified residuei213 – 2131Phosphoserine; by CDK2 and CDK41 PublicationPROSITE-ProRule annotation
    Modified residuei378 – 3781N6-acetyllysine1 Publication
    Modified residuei416 – 4161Phosphoserine1 PublicationPROSITE-ProRule annotation
    Modified residuei418 – 4181Phosphoserine; by CK11 PublicationPROSITE-ProRule annotation
    Modified residuei422 – 4221Phosphoserine; by TGFBR1PROSITE-ProRule annotation
    Modified residuei423 – 4231Phosphoserine; by TGFBR1PROSITE-ProRule annotation
    Modified residuei425 – 4251Phosphoserine; by TGFBR1PROSITE-ProRule annotation

    Post-translational modificationi

    Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G1/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.11 Publications
    Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.3 Publications
    Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes.1 Publication

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP84022.
    PaxDbiP84022.
    PRIDEiP84022.

    PTM databases

    PhosphoSiteiP84022.

    Expressioni

    Gene expression databases

    ArrayExpressiP84022.
    BgeeiP84022.
    CleanExiHS_SMAD3.
    GenevestigatoriP84022.

    Organism-specific databases

    HPAiCAB008094.

    Interactioni

    Subunit structurei

    Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, HGS, WWP1 and SNW1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts (via the MH2 domain) with ZFYVE9. Interacts with HDAC1, VDR, TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and TGFB1I1. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via the MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1.39 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    CHRDQ9H2X02EBI-347161,EBI-947551
    DAB2P980823EBI-347161,EBI-1171238
    DOCK9Q9BZ293EBI-347161,EBI-2695893
    EPAS1Q998142EBI-347161,EBI-447470
    MTMR4Q9NYA44EBI-347161,EBI-1052346
    MYD88Q998363EBI-347161,EBI-447677
    PCK2Q168222EBI-347161,EBI-2825219
    PPP1R12CQ9BZL42EBI-347161,EBI-721802
    RNF31Q96EP02EBI-347161,EBI-948111
    SETD2Q9BYW22EBI-347161,EBI-945869
    SKIP127552EBI-347161,EBI-347281
    SMAD2Q157962EBI-347161,EBI-1040141
    SMAD4Q1348517EBI-347161,EBI-347263
    SMURF2Q9HAU47EBI-347161,EBI-396727
    SNW1Q135735EBI-347161,EBI-632715
    SQSTM1Q135013EBI-347161,EBI-307104
    TSC22D4Q9Y3Q82EBI-347161,EBI-739485
    USP7Q930092EBI-347161,EBI-302474
    WWP2O003084EBI-347161,EBI-743923
    ZC3H12AQ5D1E82EBI-347161,EBI-747793
    ZFYVE9O954052EBI-347161,EBI-296817

    Protein-protein interaction databases

    BioGridi110263. 317 interactions.
    DIPiDIP-29720N.
    IntActiP84022. 158 interactions.
    MINTiMINT-193987.

    Structurei

    Secondary structure

    1
    425
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi10 – 167
    Helixi25 – 4420
    Helixi48 – 5710
    Beta strandi60 – 623
    Beta strandi66 – 683
    Beta strandi75 – 773
    Beta strandi80 – 823
    Helixi84 – 929
    Helixi100 – 1023
    Beta strandi103 – 1053
    Helixi113 – 1153
    Beta strandi118 – 1214
    Helixi124 – 1263
    Beta strandi127 – 1293
    Beta strandi221 – 2255
    Beta strandi231 – 2399
    Beta strandi242 – 2509
    Beta strandi252 – 2587
    Beta strandi268 – 2703
    Helixi271 – 2733
    Helixi281 – 29010
    Beta strandi294 – 2996
    Beta strandi302 – 3076
    Beta strandi309 – 3113
    Beta strandi313 – 3164
    Helixi318 – 3214
    Helixi323 – 3253
    Beta strandi332 – 3343
    Beta strandi339 – 3435
    Helixi345 – 35814
    Helixi360 – 3645
    Helixi365 – 3706
    Beta strandi371 – 3777
    Beta strandi384 – 3863
    Helixi389 – 3913
    Beta strandi392 – 4009
    Helixi401 – 41313

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1MHDX-ray2.80A/B1-132[»]
    1MJSX-ray1.91A229-425[»]
    1MK2X-ray2.74A220-425[»]
    1OZJX-ray2.40A/B1-144[»]
    1U7FX-ray2.60A/C228-425[»]
    2LAJNMR-B202-211[»]
    2LB2NMR-B178-189[»]
    ProteinModelPortaliP84022.
    SMRiP84022. Positions 7-132, 228-425.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP84022.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini10 – 136127MH1PROSITE-ProRule annotationAdd
    BLAST
    Domaini232 – 425194MH2PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni137 – 23195LinkerAdd
    BLAST
    Regioni271 – 32454Sufficient for interaction with XPO4Add
    BLAST

    Domaini

    The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.
    The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.
    The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.

    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

    eggNOGiNOG320700.
    HOGENOMiHOG000286018.
    HOVERGENiHBG053353.
    InParanoidiP84022.
    KOiK04500.
    OMAiAVELCEY.
    PhylomeDBiP84022.
    TreeFamiTF314923.

    Family and domain databases

    Gene3Di2.60.200.10. 1 hit.
    3.90.520.10. 1 hit.
    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]

    Sequences (4)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P84022-1) [UniParc]FASTAAdd to Basket

    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.

    « Hide

    MSSILPFTPP IVKRLLGWKK GEQNGQEEKW CEKAVKSLVK KLKKTGQLDE    50
    LEKAITTQNV NTKCITIPRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH 100
    HELRAMELCE FAFNMKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEIPAEF 150
    PPLDDYSHSI PENTNFPAGI EPQSNIPETP PPGYLSEDGE TSDHQMNHSM 200
    DAGSPNLSPN PMSPAHNNLD LQPVTYCEPA FWCSISYYEL NQRVGETFHA 250
    SQPSMTVDGF TDPSNSERFC LGLLSNVNRN AAVELTRRHI GRGVRLYYIG 300
    GEVFAECLSD SAIFVQSPNC NQRYGWHPAT VCKIPPGCNL KIFNNQEFAA 350
    LLAQSVNQGF EAVYQLTRMC TIRMSFVKGW GAEYRRQTVT STPCWIELHL 400
    NGPLQWLDKV LTQMGSPSIR CSSVS 425
    Length:425
    Mass (Da):48,081
    Last modified:July 5, 2004 - v1
    Checksum:i46DF5E8B371321AC
    GO
    Isoform 2 (identifier: P84022-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-68: MSSILPFTPP...NVNTKCITIP → MSCLHPRQTWKGAALVHRKAWWMG

    Note: No experimental confirmation available.

    Show »
    Length:381
    Mass (Da):43,237
    Checksum:iD436B607B2677761
    GO
    Isoform 3 (identifier: P84022-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-105: Missing.

    Show »
    Length:320
    Mass (Da):35,895
    Checksum:iCB3D9B2D53AAC9E9
    GO
    Isoform 4 (identifier: P84022-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-195: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:230
    Mass (Da):25,722
    Checksum:iAFC64318B5EC08D1
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti178 – 1781E → EVGTWAAQAGL in BAA22032. (PubMed:9464505)Curated
    Sequence conflicti360 – 3601F → L in BAH13315. (PubMed:14702039)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti112 – 1121A → V in LDS3. 1 Publication
    VAR_067051
    Natural varianti170 – 1701I → V.
    Corresponds to variant rs35874463 [ dbSNP | Ensembl ].
    VAR_052021
    Natural varianti239 – 2391E → K in LDS3. 1 Publication
    VAR_067047
    Natural varianti261 – 2611T → I in LDS3. 1 Publication
    VAR_065578
    Natural varianti279 – 2791R → K in LDS3. 1 Publication
    VAR_067048
    Natural varianti287 – 2871R → W in LDS3. 1 Publication
    VAR_065579
    Natural varianti393 – 3931P → L in a colorectal cancer sample; somatic mutation. 1 Publication
    VAR_036474

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 195195Missing in isoform 4. 1 PublicationVSP_045348Add
    BLAST
    Alternative sequencei1 – 105105Missing in isoform 3. 1 PublicationVSP_043793Add
    BLAST
    Alternative sequencei1 – 6868MSSIL…CITIP → MSCLHPRQTWKGAALVHRKA WWMG in isoform 2. 1 PublicationVSP_042900Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U68019 mRNA. Translation: AAB80960.1.
    U76622 mRNA. Translation: AAB18967.1.
    AB004930 Genomic DNA. Translation: BAA22032.1.
    AF025300
    , AF025293, AF025294, AF025295, AF025296, AF025297, AF025298, AF025299 Genomic DNA. Translation: AAL68976.1.
    AK290881 mRNA. Translation: BAF83570.1.
    AK298139 mRNA. Translation: BAH12731.1.
    AK300614 mRNA. Translation: BAH13315.1.
    AK316017 mRNA. Translation: BAH14388.1.
    AC012568 Genomic DNA. No translation available.
    AC087482 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77788.1.
    BC050743 mRNA. Translation: AAH50743.1.
    CCDSiCCDS10222.1. [P84022-1]
    CCDS45288.1. [P84022-2]
    CCDS53950.1. [P84022-3]
    CCDS53951.1. [P84022-4]
    PIRiS71798.
    RefSeqiNP_001138574.1. NM_001145102.1. [P84022-3]
    NP_001138575.1. NM_001145103.1. [P84022-2]
    NP_001138576.1. NM_001145104.1. [P84022-4]
    NP_005893.1. NM_005902.3. [P84022-1]
    UniGeneiHs.727986.
    Hs.742270.

    Genome annotation databases

    EnsembliENST00000327367; ENSP00000332973; ENSG00000166949. [P84022-1]
    ENST00000439724; ENSP00000401133; ENSG00000166949. [P84022-2]
    ENST00000537194; ENSP00000445348; ENSG00000166949. [P84022-4]
    ENST00000540846; ENSP00000437757; ENSG00000166949. [P84022-3]
    GeneIDi4088.
    KEGGihsa:4088.
    UCSCiuc002aqj.3. human. [P84022-1]
    uc010ujs.2. human. [P84022-2]

    Polymorphism databases

    DMDMi51338669.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U68019 mRNA. Translation: AAB80960.1 .
    U76622 mRNA. Translation: AAB18967.1 .
    AB004930 Genomic DNA. Translation: BAA22032.1 .
    AF025300
    , AF025293 , AF025294 , AF025295 , AF025296 , AF025297 , AF025298 , AF025299 Genomic DNA. Translation: AAL68976.1 .
    AK290881 mRNA. Translation: BAF83570.1 .
    AK298139 mRNA. Translation: BAH12731.1 .
    AK300614 mRNA. Translation: BAH13315.1 .
    AK316017 mRNA. Translation: BAH14388.1 .
    AC012568 Genomic DNA. No translation available.
    AC087482 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77788.1 .
    BC050743 mRNA. Translation: AAH50743.1 .
    CCDSi CCDS10222.1. [P84022-1 ]
    CCDS45288.1. [P84022-2 ]
    CCDS53950.1. [P84022-3 ]
    CCDS53951.1. [P84022-4 ]
    PIRi S71798.
    RefSeqi NP_001138574.1. NM_001145102.1. [P84022-3 ]
    NP_001138575.1. NM_001145103.1. [P84022-2 ]
    NP_001138576.1. NM_001145104.1. [P84022-4 ]
    NP_005893.1. NM_005902.3. [P84022-1 ]
    UniGenei Hs.727986.
    Hs.742270.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1MHD X-ray 2.80 A/B 1-132 [» ]
    1MJS X-ray 1.91 A 229-425 [» ]
    1MK2 X-ray 2.74 A 220-425 [» ]
    1OZJ X-ray 2.40 A/B 1-144 [» ]
    1U7F X-ray 2.60 A/C 228-425 [» ]
    2LAJ NMR - B 202-211 [» ]
    2LB2 NMR - B 178-189 [» ]
    ProteinModelPortali P84022.
    SMRi P84022. Positions 7-132, 228-425.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 110263. 317 interactions.
    DIPi DIP-29720N.
    IntActi P84022. 158 interactions.
    MINTi MINT-193987.

    Chemistry

    BindingDBi P84022.
    ChEMBLi CHEMBL1293258.

    PTM databases

    PhosphoSitei P84022.

    Polymorphism databases

    DMDMi 51338669.

    Proteomic databases

    MaxQBi P84022.
    PaxDbi P84022.
    PRIDEi P84022.

    Protocols and materials databases

    DNASUi 4088.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000327367 ; ENSP00000332973 ; ENSG00000166949 . [P84022-1 ]
    ENST00000439724 ; ENSP00000401133 ; ENSG00000166949 . [P84022-2 ]
    ENST00000537194 ; ENSP00000445348 ; ENSG00000166949 . [P84022-4 ]
    ENST00000540846 ; ENSP00000437757 ; ENSG00000166949 . [P84022-3 ]
    GeneIDi 4088.
    KEGGi hsa:4088.
    UCSCi uc002aqj.3. human. [P84022-1 ]
    uc010ujs.2. human. [P84022-2 ]

    Organism-specific databases

    CTDi 4088.
    GeneCardsi GC15P067358.
    GeneReviewsi SMAD3.
    HGNCi HGNC:6769. SMAD3.
    HPAi CAB008094.
    MIMi 114500. phenotype.
    603109. gene.
    613795. phenotype.
    neXtProti NX_P84022.
    Orphaneti 284984. Aneurysm - osteoarthritis syndrome.
    91387. Familial thoracic aortic aneurysm and aortic dissection.
    PharmGKBi PA30526.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG320700.
    HOGENOMi HOG000286018.
    HOVERGENi HBG053353.
    InParanoidi P84022.
    KOi K04500.
    OMAi AVELCEY.
    PhylomeDBi P84022.
    TreeFami TF314923.

    Enzyme and pathway databases

    Reactomei REACT_111057. Signaling by NODAL.
    REACT_120727. Downregulation of TGF-beta receptor signaling.
    REACT_120734. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_120850. TGF-beta receptor signaling activates SMADs.
    REACT_121111. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_150238. Signaling by Activin.
    REACT_169103. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_169107. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_169165. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_169263. TGFBR1 KD Mutants in Cancer.
    SignaLinki P84022.

    Miscellaneous databases

    ChiTaRSi SMAD3. human.
    EvolutionaryTracei P84022.
    GeneWikii Mothers_against_decapentaplegic_homolog_3.
    GenomeRNAii 4088.
    NextBioi 16026.
    PROi P84022.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P84022.
    Bgeei P84022.
    CleanExi HS_SMAD3.
    Genevestigatori P84022.

    Family and domain databases

    Gene3Di 2.60.200.10. 1 hit.
    3.90.520.10. 1 hit.
    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

    1. "Receptor-associated Mad homologues synergize as effectors of the TGF-beta response."
      Zhang Y., Feng X.-H., Wu R.-Y., Derynck R.
      Nature 383:168-172(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PHOSPHORYLATION.
      Tissue: Placenta.
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    3. "Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers."
      Arai T., Akiyama Y., Okabe S., Ando M., Endo M., Yuasa Y.
      Cancer Lett. 122:157-163(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Tissue: Colon carcinoma.
    4. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    5. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2; 3 AND 4).
      Tissue: Brain.
    6. "Analysis of the DNA sequence and duplication history of human chromosome 15."
      Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A.
      , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
      Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. "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] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Pancreas.
    9. Cited for: INTERACTION WITH TGFBR1.
    10. "SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor."
      Tsukazaki T., Chiang T.A., Davison A.F., Attisano L., Wrana J.L.
      Cell 95:779-791(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ZFYVE9.
    11. "Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors."
      Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K.
      EMBO J. 17:4056-4065(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT.
    12. "TGF-beta-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein."
      Shen X., Hu P.P., Liberati N.T., Datto M.B., Frederick J.P., Wang X.F.
      Mol. Biol. Cell 9:3309-3319(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION, INTERACTION WITH EP300.
    13. "The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3."
      Kurokawa M., Mitani K., Irie K., Matsuyama T., Takahashi T., Chiba S., Yazaki Y., Matsumoto K., Hirai H.
      Nature 394:92-96(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MECOM.
    14. "Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription."
      Zhang Y., Feng X.H., Derynck R.
      Nature 394:909-913(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, INTERACTION WITH JUN AND FOS, DNA-BINDING, FUNCTION.
    15. "Roles of pathway-specific and inhibitory Smads in activin receptor signaling."
      Lebrun J.J., Takabe K., Chen Y., Vale W.
      Mol. Endocrinol. 13:15-23(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ACVR1B, FUNCTION.
    16. "Structural and functional characterization of the transforming growth factor-beta -induced Smad3/c-Jun transcriptional cooperativity."
      Qing J., Zhang Y., Derynck R.
      J. Biol. Chem. 275:38802-38812(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH JUN IN THE SMAD3/SMAD4/JUN/FOS COMPLEX, DNA-BINDING, FUNCTION, MUTAGENESIS OF LYS-40; LYS-41; LYS-43; LYS-44 AND ARG-74.
    17. "The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway."
      Hocevar B.A., Smine A., Xu X.X., Howe P.H.
      EMBO J. 20:2789-2801(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH DAB2.
    18. "Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription."
      Leong G.M., Subramaniam N., Figueroa J., Flanagan J.L., Hayman M.J., Eisman J.A., Kouzmenko A.P.
      J. Biol. Chem. 276:18243-18248(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SNW1.
    19. "TGIF2 interacts with histone deacetylase 1 and represses transcription."
      Melhuish T.A., Gallo C.M., Wotton D.
      J. Biol. Chem. 276:32109-32114(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH TGIF2.
    20. "The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization."
      Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K.
      Nat. Struct. Biol. 8:248-253(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT, PHOSPHORYLATION, MUTAGENESIS OF 422-SER--SER-425.
    21. "Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling."
      Kaji H., Canaff L., Lebrun J.J., Goltzman D., Hendy G.N.
      Proc. Natl. Acad. Sci. U.S.A. 98:3837-3842(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MEN1.
    22. Cited for: INTERACTION WITH DACH1.
    23. "Cyclin-dependent kinases regulate the antiproliferative function of Smads."
      Matsuura I., Denissova N.G., Wang G., He D., Long J., Liu F.
      Nature 430:226-231(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-8; THR-179; SER-204; SER-208 AND SER-213, FUNCTION, MUTAGENESIS OF THR-8; THR-179; SER-204; SER-208 AND SER-213.
    24. "The Smad3 linker region contains a transcriptional activation domain."
      Wang G., Long J., Matsuura I., He D., Liu F.
      Biochem. J. 386:29-34(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: TRANSCRIPTIONAL ACTIVATION DOMAIN, FUNCTION, PHOSPHORYLATION, SUBUNIT, INTERACTION WITH EP300.
    25. "Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3."
      Matsuura I., Wang G., He D., Liu F.
      Biochemistry 44:12546-12553(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-179; SER-204 AND SER-208, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF THR-179; SER-204 AND SER-208.
    26. "MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling."
      Lin F., Morrison J.M., Wu W., Worman H.J.
      Hum. Mol. Genet. 14:437-445(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, INTERACTION WITH LEMD3.
    27. "Novel function of androgen receptor-associated protein 55/Hic-5 as a negative regulator of Smad3 signaling."
      Wang H., Song K., Sponseller T.L., Danielpour D.
      J. Biol. Chem. 280:5154-5162(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH TGFB1I1.
    28. "The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines."
      Pan D., Estevez-Salmeron L.D., Stroschein S.L., Zhu X., He J., Zhou S., Luo K.
      J. Biol. Chem. 280:15992-16001(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH LEMD3.
    29. "Nuclear targeting of transforming growth factor-beta-activated Smad complexes."
      Chen H.B., Rud J.G., Lin K., Xu L.
      J. Biol. Chem. 280:21329-21336(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBUNIT, SUBCELLULAR LOCATION.
    30. "Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues."
      Arndt S., Poser I., Schubert T., Moser M., Bosserhoff A.-K.
      Lab. Invest. 85:1330-1341(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SKOR2.
    31. "Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP."
      Nitta E., Izutsu K., Yamaguchi Y., Imai Y., Ogawa S., Chiba S., Kurokawa M., Hirai H.
      Oncogene 24:6165-6173(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MECOM.
    32. Cited for: INTERACTION WITH PPM1A, DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION.
    33. "Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway."
      He W., Dorn D.C., Erdjument-Bromage H., Tempst P., Moore M.A., Massague J.
      Cell 125:929-941(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN A COMPLEX WITH SMAD2 AND TRIM33, INTERACTION WITH SMAD2 AND TRIM33.
    34. "The mechanism of nuclear export of Smad3 involves exportin 4 and Ran."
      Kurisaki A., Kurisaki K., Kowanetz M., Sugino H., Yoneda Y., Heldin C.-H., Moustakas A.
      Mol. Cell. Biol. 26:1318-1332(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION IN A COMPLEX WITH RAN AND XPO4, INTERACTION WITH XPO4, MUTAGENESIS OF 422-SER--SER-425.
    35. "Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS."
      Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., Song H., Ye Q.
      Nucleic Acids Res. 34:6314-6326(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RBPMS.
    36. "3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins."
      Seong H.A., Jung H., Kim K.T., Ha H.
      J. Biol. Chem. 282:12272-12289(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, INTERACTION WITH PDPK1.
    37. "Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling."
      Arndt S., Poser I., Moser M., Bosserhoff A.-K.
      Mol. Cell. Neurosci. 34:603-611(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH SKOR1.
    38. "Smad3 is acetylated by p300/CBP to regulate its transactivation activity."
      Inoue Y., Itoh Y., Abe K., Okamoto T., Daitoku H., Fukamizu A., Onozaki K., Hayashi H.
      Oncogene 26:500-508(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION AT LYS-378, FUNCTION, MUTAGENESIS OF LYS-333; LYS-341; LYS-378; LYS-409 AND 422-SER--SER-425.
    39. "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal."
      Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L.
      Nat. Cell Biol. 10:837-848(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH WWTR1.
    40. "Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling."
      Guo X., Waddell D.S., Wang W., Wang Z., Liberati N.T., Yong S., Liu X., Wang X.-F.
      Oncogene 27:7235-7247(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CSNK1G2, UBIQUITINATION, PHOSPHORYLATION AT SER-418 BY CSNK1G2/CK1, MUTAGENESIS OF SER-418.
    41. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-416, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    42. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
      Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
      Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
    43. "Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling."
      Dai F., Lin X., Chang C., Feng X.H.
      Dev. Cell 16:345-357(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RANBP3, SUBCELLULAR LOCATION, FUNCTION.
    44. Cited for: INTERACTION WITH PRDM16; SKI AND HDAC1.
    45. "Transforming growth factor-{beta}-inducible phosphorylation of Smad3."
      Wang G., Matsuura I., He D., Liu F.
      J. Biol. Chem. 284:9663-9673(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-179; SER-204 AND SER-208, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF THR-179; SER-204 AND SER-208.
    46. "TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling."
      Watanabe Y., Itoh S., Goto T., Ohnishi E., Inamitsu M., Itoh F., Satoh K., Wiercinska E., Yang W., Shi L., Tanaka A., Nakano N., Mommaas A.M., Shibuya H., Ten Dijke P., Kato M.
      Mol. Cell 37:123-134(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PMEPA1.
    47. Cited for: INTERACTION WITH IL1F7.
    48. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    49. Cited for: UBIQUITINATION, DEUBIQUITINATION BY USP15, DNA-BINDING, INTERACTION WITH USP15, UBIQUITINATION AT LYS-33 AND LYS-81, MUTAGENESIS OF LYS-33; LYS-53 AND LYS-81.
    50. "Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-? pathway."
      Bruce D.L., Macartney T., Yong W., Shou W., Sapkota G.P.
      Cell. Signal. 24:1999-2006(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PPP5C, SUBCELLULAR LOCATION.
    51. Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    52. Cited for: INTERACTION WITH LDLRAD4.
    53. "Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling."
      Shi Y., Wang Y.-F., Jayaraman L., Yang H., Massague J., Pavletich N.P.
      Cell 94:585-594(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-144.
    54. "Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control."
      Qin B.Y., Lam S.S., Correia J.J., Lin K.
      Genes Dev. 16:1950-1963(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF 220-425 IN COMPLEX WITH ZFYVE9.
    55. "Features of a Smad3 MH1-DNA complex. Roles of water and zinc in DNA binding."
      Chai J., Wu J.W., Yan N., Massague J., Pavletich N.P., Shi Y.
      J. Biol. Chem. 278:20327-20331(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1-144 IN COMPLEX WITH DNA, ZINC.
    56. "Structural basis of heteromeric smad protein assembly in TGF-beta signaling."
      Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J., De Caestecker M., Lin K.
      Mol. Cell 15:813-823(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 228-424 IN COMPLEX WITH SMAD4, SUBUNIT.
    57. Cited for: VARIANT [LARGE SCALE ANALYSIS] LEU-393.
    58. "Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms."
      Regalado E.S., Guo D.C., Villamizar C., Avidan N., Gilchrist D., McGillivray B., Clarke L., Bernier F., Santos-Cortez R.L., Leal S.M., Bertoli-Avella A.M., Shendure J., Rieder M.J., Nickerson D.A., Milewicz D.M.
      Circ. Res. 109:680-686(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS LDS3 VAL-112; LYS-239 AND LYS-279.
    59. Cited for: VARIANTS LDS3 ILE-261 AND TRP-287.

    Entry informationi

    Entry nameiSMAD3_HUMAN
    AccessioniPrimary (citable) accession number: P84022
    Secondary accession number(s): A8K4B6
    , B7Z4Z5, B7Z6M9, B7Z9Q2, F5H383, O09064, O09144, O14510, O35273, Q92940, Q93002, Q9GKR4
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 5, 2004
    Last sequence update: July 5, 2004
    Last modified: October 1, 2014
    This is version 133 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 15
      Human chromosome 15: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3