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SMAD3 Gene

protein-coding   GIFtS: 67
GCID: GC15P067358

SMAD Family Member 3

(Previous names: MAD, mothers against decapentaplegic homolog 3 (Drosophila),...)
(Previous symbol: MADH3)
  See SMAD3-related diseases
at  

(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
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Aliases
SMAD Family Member 31 2 3     LDS1C2
MADH31 2 3 5     Mad Homolog JV15-22
Mothers Against DPP Homolog 32 3     Mad Protein Homolog2
JV15-22 3     MAD, Mothers Against Decapentaplegic Homolog 32
hMAD-32 3     mad32
hSMAD32 3     Mothers Against Decapentaplegic Homolog 32
MAD Homolog 32 3     SMA- And MAD-Related Protein 32
LDS32 5     SMAD, Mothers Against DPP Homolog 32
MAD, Mothers Against Decapentaplegic Homolog 3 (Drosophila)1     Mad33
SMAD, Mothers Against DPP Homolog 3 (Drosophila)1     Smad33
HSPC1932     SMAD 33
HsT174362     

External Ids:    HGNC: 67691   Entrez Gene: 40882   Ensembl: ENSG000001669497   OMIM: 6031095   UniProtKB: P840223   

Export aliases for SMAD3 gene to outside databases

Previous GC identifers: GC15P065075 GC15P065145 GC15P044193


(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
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Entrez Gene summary for SMAD3 Gene:
The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the
Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal
transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions as a
transcriptional modulator activated by transforming growth factor-beta and is thought to play a role in the
regulation of carcinogenesis. (provided by RefSeq, Apr 2009)

GeneCards Summary for SMAD3 Gene:
SMAD3 (SMAD family member 3) is a protein-coding gene. Diseases associated with SMAD3 include smad3-related thoracic aortic aneurysms and aortic dissections, and loeys-dietz syndrome type 3. GO annotations related to this gene include sequence-specific DNA binding and sequence-specific DNA binding transcription factor activity. An important paralog of this gene is SMAD2.

UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022
Function: 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

Gene Wiki entry for SMAD3 (Mothers against decapentaplegic homolog 3) Gene


(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
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Regulatory elements:
   Regulatory transcription factor binding sites in the SMAD3 gene promoter:
         Egr-3   C/EBPbeta   Sp1   ATF-2   NF-AT   GATA-1   C/EBPalpha   N-Myc   PPAR-alpha   NF-AT1   
         Other transcription factors

SwitchGear Promoter luciferase reporter plasmids (see all 2): SMAD3 promoter sequence
   Search Chromatin IP Primers for SMAD3

Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat SMAD3


Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 15q22.33   Ensembl cytogenetic band:  15q22.33   HGNC cytogenetic band: 15q21-q22

SMAD3 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
SMAD3 gene location

GeneLoc information about chromosome 15         GeneLoc Exon Structure

GeneLoc location for GC15P067358:  view genomic region     (about GC identifiers)

Start:
67,356,101 bp from pter      End:
67,487,533 bp from pter
Size:
131,433 bases      Orientation:
plus strand

(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, Cloud-Clone Corp., and/or eBioscience,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, Cloud-Clone Corp., and/or eBioscience, Antibodies by EMD Millipore, R&D Systems, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, LSBio, Abcam, Cloud-Clone Corp, and/or others.)
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UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022 (See protein sequence)
Recommended Name: Mothers against decapentaplegic homolog 3  
Size: 425 amino acids; 48081 Da
Subunit: 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) (By similarity). Interacts
with NEDD4L; the interaction requires TGF-beta stimulation (By similarity). 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
Selected PDB 3D structures from and Proteopedia for SMAD3 (see all 7):
1MHD (3D)        1MJS (3D)        1MK2 (3D)        1OZJ (3D)        1U7F (3D)        2LAJ (3D)    
Secondary accessions: A8K4B6 B7Z4Z5 B7Z6M9 B7Z9Q2 F5H383 O09064 O09144 O14510 O35273 Q92940
Q93002 Q9GKR4
Alternative splicing: 4 isoforms:  P84022-1   P84022-2   P84022-3   P84022-4   (No experimental confirmation available)

Explore the universe of human proteins at neXtProt for SMAD3: NX_P84022

Explore proteomics data for SMAD3 at MOPED

Post-translational modifications: 

  • 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 G(1)/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 PDPK11
  • Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is
    enhanced by TGF-beta1
  • Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition
    and promotes activation of TGF-beta target genes1
  • Ubiquitination2 at Lys33, Lys81
  • Modification sites at PhosphoSitePlus

  • See SMAD3 Protein Expression from SPIRE MOPED, PaxDB, and MaxQB

    REFSEQ proteins (4 alternative transcripts): 
    NP_001138574.1  NP_001138575.1  NP_001138576.1  NP_005893.1  

    ENSEMBL proteins: 
     ENSP00000453082   ENSP00000332973   ENSP00000453788   ENSP00000455095   ENSP00000437757  
     ENSP00000458060   ENSP00000401133   ENSP00000453684   ENSP00000445348   ENSP00000454165  
     ENSP00000452767   ENSP00000455540  
    Reactome Protein details: P84022

    SMAD3 Human Recombinant Protein Products:

    Browse Purified and Recombinant Proteins at EMD Millipore
    Browse R&D Systems for human recombinant proteins
    Browse recombinant and purified proteins available from Enzo Life Sciences
    OriGene Purified Protein for SMAD3
    OriGene Protein Over-expression Lysate for SMAD3
    OriGene MassSpec for SMAD3
    OriGene Custom Protein Services for SMAD3
    GenScript Custom Purified and Recombinant Proteins Services for SMAD3
    Novus Biologicals SMAD3 Proteins
    Novus Biologicals SMAD3 Lysates
    Browse Sino Biological Recombinant Proteins
    Sino Biological Cell Lysate for SMAD3
    ProSpec Recombinant Protein for SMAD3
    Browse Proteins at Cloud-Clone Corp.

     
    Search eBioscience for Proteins for SMAD3 

    SMAD3 Antibody Products:

    EMD Millipore Mono- and Polyclonal Antibodies for the study of SMAD3
    R&D Systems Antibodies for SMAD3
    Cell Signaling Technology (CST) Antibodies for SMAD3 
    OriGene Antibodies for SMAD3
    OriGene Custom Antibody Services for SMAD3
    Novus Biologicals SMAD3 Antibodies
    Abcam antibodies for SMAD3 (Q99717, P84022)
    Browse Antibodies at Cloud-Clone Corp.
    ThermoFisher Antibody for SMAD3
    LSBio Antibodies in human, mouse, rat for SMAD3

    SMAD3 Assay Products:

    Browse Kits and Assays available from EMD Millipore
    OriGene Custom Assay Services for SMAD3
    R&D Systems ELISAs for SMAD3
    GenScript Custom Assay Services for SMAD3
    Cell Signaling Technology (CST) Sandwich ELISA Kits for SMAD3
    Browse Enzo Life Sciences for kits & assays
    Browse ELISAs at Cloud-Clone Corp.
    Browse CLIAs at Cloud-Clone Corp.
    eBioscience ELISAs for SMAD3:  
                        phospho-SMAD3 (Ser423/425) InstantOne ELISA 96 tests


    (According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
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    HGNC Gene Families:
    SMAD: SMADs

    Selected InterPro protein domains (see all 6):
     IPR013019 MAD_homology_MH1
     IPR008984 SMAD_FHA_domain
     IPR001132 SMAD_dom_Dwarfin-type
     IPR017855 SMAD_dom-like
     IPR013790 Dwarfin

    Graphical View of Domain Structure for InterPro Entry P84022

    ProtoNet protein and cluster: P84022

    1 Blocks protein domain: IPB001132 Dwarfin protein

    UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022
    Domain: The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding
    Domain: The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional
    regulation. Sufficient for nuclear import
    Domain: The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically
    with the MH2 domain
    Similarity: Belongs to the dwarfin/SMAD family
    Similarity: Contains 1 MH1 (MAD homology 1) domain
    Similarity: Contains 1 MH2 (MAD homology 2) domain


    Find genes that share domains with SMAD3           About GenesLikeMe


    (According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, inGenious Targeting Laboratory, genOway,
    transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, Vector BioLabs and/or Addgene, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Flow cytometry from eBioscience, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Molecular Function:

         UniProtKB/Swiss-Prot Summary: SMAD3_HUMAN, P84022
    Function: 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

         Gene Ontology (GO): Selected molecular function terms (see all 26):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000987core promoter proximal region sequence-specific DNA binding IDA18832382
    GO:0000988contributes to protein binding transcription factor activity IDA18832382
    GO:0001102RNA polymerase II activating transcription factor binding IPI17251190
    GO:0003677DNA binding ----
    GO:0003682chromatin binding ----
         
    Find genes that share ontologies with SMAD3           About GenesLikeMe


    Phenotypes:
         Selected MGI mutant phenotypes (inferred from 5 alleles(MGI details for Smad3) (see all 21):
     behavior/neurological  cardiovascular system  cellular  craniofacial  digestive/alimentary 
     embryogenesis  endocrine/exocrine gland  growth/size/body  hematopoietic system  homeostasis/metabolism 
     immune system  integument  limbs/digits/tail  liver/biliary system  mortality/aging 

    Find genes that share phenotypes with SMAD3           About GenesLikeMe

    Animal Models:
         MGI mouse knock-outs for SMAD3: Smad3tm1Xfw Smad3tm1Sche Smad3tm1Cxd

       inGenious Targeting Laboratory: Let us create your new Knockout/Knockin mouse model for SMAD3
       inGenious Targeting Laboratory: Contact us about creating complex and humanized mouse models for SMAD3

       genOway customized KO model: permanent, tissue-specific or time-controlled inactivation for SMAD3
       genOway customized Knockin model: humanization, point mutation, expression monitoring, etc. for SMAD3

    Transcription Factor Targeting: 
    Targeting motifs: HOMER Transcription Factor Regulatory Elements motif viewer 
                                          Consensus sequence:  TWGTCTGV 

    miRNA
    Products:
        
    miRTarBase miRNAs that target SMAD3:
    hsa-mir-17-5p (MIRT050933), hsa-mir-155-5p (MIRT020918), hsa-mir-200a-3p (MIRT007291), hsa-mir-335-5p (MIRT018567), hsa-mir-18a-5p (MIRT007323), hsa-mir-193b-3p (MIRT041360)

    Block miRNA regulation of human, mouse, rat SMAD3 using miScript Target Protectors
    Selected qRT-PCR Assays for microRNAs that regulate SMAD3 (see all 73):
    hsa-miR-323-3p hsa-miR-579 hsa-miR-3194-5p hsa-miR-607 hsa-miR-15a hsa-miR-489 hsa-miR-556-3p hsa-miR-3148
    Browse SwitchGear 3'UTR luciferase reporter plasmids
    Inhib. RNA
    Products:
        
    OriGene RNAi products in human, mouse, rat for SMAD3
    Predesigned siRNA for gene silencing in human, mouse, rat SMAD3

    Gene Editing
    Products:
    DNA2.0 Custom Protein Engineering Service for SMAD3

    Clone
    Products:
         
    OriGene clones in human, mouse for SMAD3 (see all 21)
    OriGene ORF clones in mouse, rat for SMAD3
    OriGene custom cloning services - gene synthesis, subcloning, mutagenesis, variant library, vector shuttling
    GenScript: all cDNA clones in your preferred vector (see all 4): SMAD3 (NM_001145103)
    Sino Biological Human cDNA Clone for SMAD3
    DNA2.0 Custom Codon Optimized Gene Synthesis Service for SMAD3
    Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat SMAD3
    Addgene plasmids for SMAD3 

    Cell Line
    Products:
         
    GenScript Custom overexpressing Cell Line Services for SMAD3
    Browse ESI BIO Cell Lines and PureStem Progenitors for SMAD3 
    In Situ Assay
    Products:
       

     
    Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for SMAD3


    (According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Subcellular locations from UniProtKB/Swiss-Prot
    SMAD3_HUMAN, P84022: 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
    Subcellular locations from COMPARTMENTS: 

    CompartmentConfidence
    nucleus5
    cytosol4
    extracellular3
    cytoskeleton2
    plasma membrane2
    endoplasmic reticulum1
    mitochondrion1
    peroxisome1

    Gene Ontology (GO): Selected cellular component terms (see all 11):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0005622intracellular ----
    GO:0005634nucleus IDA12446380
    GO:0005637nuclear inner membrane IDA15647271
    GO:0005654nucleoplasm TAS--
    GO:0005667transcription factor complex IDA--

    Find genes that share ontologies with SMAD3           About GenesLikeMe


    (SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
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    SuperPaths for SMAD3 About   (see all 53)  
    See pathways by source

    SuperPathSelected contained pathways About (see all per SuperPath)
    1Cell cycle
    Cell cycle0.59
    Cell cycle0.59
    2Wnt signaling pathway (KEGG)
    Wnt signaling pathway0.40
    Wnt Signaling Pathway NetPath0.37
    3Loss of Function of SMAD2/3 in Cancer
    Transcriptional activity of SMAD2/SMAD3-SMAD4 heterotrimer0.72
    TGFBR2 Kinase Domain Mutants in Cancer0.60
    SMAD2/SMAD3-SMAD4 heterotrimer regulates transcription0.72
    Signaling by TGF-beta Receptor Complex0.60
    Loss of Function of SMAD2/3 in Cancer0.60
    TGFBR1 KD Mutants in Cancer0.60
    TGFBR2 MSI Frameshift Mutants in Cancer0.60
    SMAD2/3 MH2 Domain Mutants in Cancer0.60
    4TGF-beta receptor signaling activates SMADs
    Downregulation of TGF-beta receptor signaling0.82
    TGF-beta receptor signaling activates SMADs0.82
    5Chronic myeloid leukemia
    Chronic myeloid leukemia0.42
    Pancreatic cancer0.42


    Find genes that share SuperPaths with SMAD3           About GenesLikeMe

    Pathways by source                                                                                                                                                                 See SuperPaths
    Show all pathways

    3 R&D Systems Pathways for SMAD3
        Notch Signaling Pathways
    Th17 Differentiation
    TGF-beta Signaling Pathways

    Selected Downloadable PowerPoint Slides of GeneGlobe Pathway Central Maps for SMAD3 (see all 14)
        PKA Signaling
    Androgen Signaling
    Molecular Mechanisms of Cancer
    Glucocorticoid Receptor Signaling
    JAK-STAT Pathway

    1 Cell Signaling Technology (CST) Pathway for SMAD3
        TGF-beta/Smad Signaling

    Selected GeneGo (Thomson Reuters) Pathways for SMAD3 (see all 11)
        Transcription Androgen Receptor nuclear signaling
    Signal transduction Activin A signaling regulation
    Signal transduction PKA signaling
    Transcription Role of VDR in regulation of genes involved in osteoporosis
    Development Role of Activin A in cell differentiation and proliferation

    Selected BioSystems Pathways for SMAD3 (see all 22)
        Cell cycle
    TGF Beta Signaling Pathway
    Senescence and Autophagy
    EGFR1 Signaling Pathway
    Adipogenesis


    Selected Reactome Pathways for SMAD3 (see all 10)
        TGF-beta receptor signaling activates SMADs
    SMAD2/3 MH2 Domain Mutants in Cancer
    SMAD4 MH2 Domain Mutants in Cancer
    Signaling by Activin
    Downregulation of SMAD2/3:SMAD4 transcriptional activity


    Selected Kegg Pathways  (Kegg details for SMAD3) (see all 15):
        FoxO signaling pathway
    Cell cycle
    Endocytosis
    Wnt signaling pathway
    TGF-beta signaling pathway

        Pathway & Disease-focused RT2 Profiler PCR Arrays including SMAD3 (see all 8): 
              Osteogenesis in human mouse rat
              Fibrosis in human mouse rat
              TGFB/BMP Signaling Pathway in human mouse rat
              Stem Cell Signaling in human mouse rat
              JAK / STAT Signaling Pathway in human mouse rat

    Interactions:

        GeneGlobe Interaction Network for SMAD3

    STRING Interaction Network Preview (showing 5 interactants - click image to see 25)

    Selected Interacting proteins for SMAD3 (P840221, 2, 3 ENSP000003329734) via UniProtKB, MINT, STRING, and/or I2D (see all 452)
    InteractantInteraction Details
    GeneCardExternal ID(s)
    ENSG00000237724P081073, ENSP000004063594I2D: score=1 STRING: ENSP00000406359
    ENSG00000212866P081073I2D: score=1 
    ENSG00000215328P081073I2D: score=1 
    ENSG00000224501P081073I2D: score=1 
    ENSG00000231555P081073I2D: score=1 
    About this table

    Gene Ontology (GO): Selected biological process terms (see all 79):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000122negative regulation of transcription from RNA polymerase II promoter TAS--
    GO:0001501skeletal system development ----
    GO:0001649osteoblast differentiation ----
    GO:0001657ureteric bud development IEA--
    GO:0001666response to hypoxia IMP12411310

    Find genes that share ontologies with SMAD3           About GenesLikeMe



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
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    Browse Small Molecules at EMD Millipore
       Browse drugs & compounds from Enzo Life Sciences
      Browse compounds at ApexBio 

    Browse Tocris compounds for SMAD3

    Selected Novoseek inferred chemical compound relationships for SMAD3 gene (see all 40)    About this table
    Compound   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    tgf beta1 78.1 31 17095240 (3), 19214138 (2), 18353785 (2), 17270292 (2) (see all 17)
    wp631 75.2 1 16705627 (1)
    threonine 50.9 8 15104092 (1), 15210694 (1), 17270292 (1), 11106403 (1) (see all 7)
    serine 47.6 29 14610066 (3), 9380693 (2), 12759229 (2), 15247277 (2) (see all 15)
    rpa 2 44.4 2 15691381 (1), 15153434 (1)
    antide 42.7 2 14678567 (1)
    sb 203580 42.6 3 12270924 (1), 16924420 (1), 17003485 (1)
    pd 98,059 38.7 6 17003485 (2), 16156666 (1), 17197157 (1), 17002919 (1)
    mithramycin 26.8 2 11114293 (1)
    procollagen 23.3 1 17889631 (1)



    Find genes that share compounds with SMAD3           About GenesLikeMe



    (Secondary structures according to fRNAdb,
    GenBank/EMBL/DDBJ Accessions according to
    Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
    RefSeq according to Entrez Gene,
    DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
    exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
    siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
    Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, and/or Addgene, Primers from OriGene, and/or QIAGEN, Flow cytometry from eBioscience )
    About This Section

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    REFSEQ mRNAs for SMAD3 gene (4 alternative transcripts): 
    NM_001145102.1  NM_001145103.1  NM_001145104.1  NM_005902.3  

    15 Ensembl transcripts including schematic representations, and UCSC links where relevant:
    ENST00000559460 ENST00000327367(uc002aqj.3 uc010ujr.2 uc010ujs.2 uc010ujt.2)
    ENST00000559937 ENST00000559092 ENST00000560175 ENST00000540846 ENST00000558894
    ENST00000439724 ENST00000558739 ENST00000537194 ENST00000558428 ENST00000558827
    ENST00000560402 ENST00000560424 ENST00000558763
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    hsa-miR-323-3p hsa-miR-579 hsa-miR-3194-5p hsa-miR-607 hsa-miR-15a hsa-miR-489 hsa-miR-556-3p hsa-miR-3148
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    Selected AceView cDNA sequences (see all 267):

    AA984951 BM551682 AI453146 CB160752 AA970972 AA385619 CK906150 AI918940 
    BF002854 BU740565 BF059171 BE670685 AW139059 CB118637 AI638244 BC050743 
    AW183043 BQ212091 AI990600 BU607581 BQ879956 BQ917888 BM973576 CF541118 

    GeneLoc Exon Structure

    Selected Alternative Splicing Database (ASD) splice patterns (SP) for SMAD3 (see all 11)    About this scheme

    ExUns: 1 ^ 2 ^ 3 ^ 4 ^ 5 ^ 6 ^ 7a · 7b ^ 8a · 8b ^ 9 ^ 10a · 10b ^ 11a · 11b · 11c ^ 12 ^ 13a · 13b ^ 14a · 14b ^ 15a · 15b ^ 16 ^ 17
    SP1:        -     -     -     -     -                             -     -                       -                       -     -                           
    SP2:                                                                    -                       -                       -     -                           
    SP3:                                                                                            -                       -     -                           
    SP4:              -     -     -     -                             -     -                                                                                 
    SP5:                          -     -                             -     -                                                                                 


    ECgene alternative splicing isoforms for SMAD3

    (RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
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    SMAD3 expression in normal human tissues (normalized intensities)
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS <intensity>2/3
    CGAP TAG: AGGGTCTCCA
    SMAD3 Expression
    About this image


    SMAD3 expression in embryonic tissues and stem cells    About this table
    Data from LifeMap, the Embryonic Development and Stem Cells Database
     selected tissues (see all 9) fully expand
     
     Trophoblast (Extraembryonic Tissues)    fully expand to see all 2 entries
             Trophoblast Cells Trophoblast
     
     Adipose (Muscoskeletal System)    fully expand to see all 2 entries
             Brown-like Adipocyte Cells Visceral White Adipose
     
     Smooth Muscle (Muscoskeletal System)
             Contractile smooth muscle-like cells
     
     Epithelial Cells
             Mature Retinal Pigmented Epithelium Cells Retinal Pigmented Epithelium
     
     Thymus (Hematopoietic System)
             T Helper Cells Thymus
    SMAD3 Protein expression data from MOPED1, PaxDb2 and MaxQB3    About this image

    SMAD3 Protein Expression
        Pathway & Disease-focused RT2 Profiler PCR Arrays including SMAD3 (see all 8): 
              Osteogenesis in human mouse rat
              Fibrosis in human mouse rat
              TGFB/BMP Signaling Pathway in human mouse rat
              Stem Cell Signaling in human mouse rat
              JAK / STAT Signaling Pathway in human mouse rat

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    (Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
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    This gene was present in the common ancestor of animals.

    Orthologs for SMAD3 gene from Selected species (see all 17)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    mouse
    (Mus musculus)
    Mammalia Smad31 , 5 MAD homolog 3 (Drosophila)5
    SMAD family member 31
    93.02(n)1
    100(a)1
      9 (34.22 cM)5
    171271  NM_016769.41  NP_058049.31 
     636467675 
    chicken
    (Gallus gallus)
    Aves SMAD31 SMAD family member 3 86.75(n)
    99.06(a)
      395132  NM_204475.1  NP_989806.1 
    lizard
    (Anolis carolinensis)
    Reptilia --
    --
    84(a)
    many ↔ many
    2(1145535-1200543)
    African clawed frog
    (Xenopus laevis)
    Amphibia madh3-A2 MAD, mothers against decapentaplegic homolog 3 83.56(n)    AJ311059.1 
    zebrafish
    (Danio rerio)
    Actinopterygii madh3b2 MAD, mothers against decapentaplegic homolog 3b (Drosophila) 81.3(n)   326283  AY134490.1 
    fruit fly
    (Drosophila melanogaster)
    Insecta Smox1 Smad on X 67.22(n)
    70.55(a)
      31738  NM_078524.3  NP_511079.1 
    worm
    (Caenorhabditis elegans)
    Secernentea sma-26
    Protein SMA-2 (sma-2) mRNA, complete cds
    50(a)
    1 → many
    III(8749771-8757069) WBGene00004856


    ENSEMBL Gene Tree for SMAD3 (if available)
    TreeFam Gene Tree for SMAD3 (if available)

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
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    Paralogs for SMAD3 gene
    SMAD22  SMAD12  SMAD62  SMAD52  SMAD42  SMAD92  SMAD72  
    9 SIMAP similar genes for SMAD3 using alignment to 9 protein entries:     SMAD3_HUMAN (see all proteins):
    DKFZp686J10186    SMAD2    SMAD1    SMAD5    SMAD9    MADH5
    SMAD4    DKFZp781O1323    SMAD7

    Find genes that share paralogs with SMAD3           About GenesLikeMe


    1 Pseudogenes.org Pseudogene for SMAD3
    PGOHUM00000262253


    (SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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    Selected SNPs for SMAD3 (see all 2728)    About this table                                 

    Genomic DataTranscription Related DataAllele Frequencies
    SNP IDValidClinical
    significance
    Chr 15 posSequence#AA
    Chg
    TypeMore#Allele
    freq
    PopTotal
    sample
    More
    ----------
    VAR_0364744
    A colorectal cancer sample4--see VAR_0364742 P L mis40--------
    VAR_0670484
    Loeys-Dietz syndrome 3 (LDS3)4--see VAR_0670482 R K mis40--------
    VAR_0655784
    Loeys-Dietz syndrome 3 (LDS3)4--see VAR_0655782 T I mis40--------
    VAR_0670474
    Loeys-Dietz syndrome 3 (LDS3)4--see VAR_0670472 E K mis40--------
    VAR_0670514
    Loeys-Dietz syndrome 3 (LDS3)4--see VAR_0670512 A V mis40--------
    VAR_0655794
    Loeys-Dietz syndrome 3 (LDS3)4--see VAR_0655792 R W mis40--------
    rs343076011,2
    C,F--47413021(+) GATCGG/TAGACT 1 -- us2k17Minor allele frequency- T:0.26NA WA EA 366
    rs1862931521,2
    --47413026(+) GAGACG/TGAGGC 1 -- us2k10--------
    rs1178026941,2
    C,F--47413177(+) GCAGGC/TGGACT 1 -- us2k11Minor allele frequency- T:0.08EA 120
    rs1121431031,2
    F--47413182(+) CGGACG/TACCCG 1 -- us2k11Minor allele frequency- T:0.50CSA 2

    HapMap Linkage Disequilibrium report for SMAD3 (67356101 - 67487533 bp)

    Structural Variations
         Database of Genomic Variants (DGV) 9 variations for SMAD3:    About this table    
    Variant IDTypeSubtypePubMed ID
    esv1476959CNV Deletion17803354
    esv1009806CNV Deletion20482838
    dgv457e199CNV Deletion23128226
    esv2749799CNV Deletion23290073
    nsv507785CNV Insertion20534489
    nsv457187CNV Loss19166990
    nsv512399CNV Loss21212237
    nsv94737CNV Loss16902084
    nsv904327CNV Loss21882294

    Human Gene Mutation Database (HGMD): SMAD3
    Locus Specific Mutation Databases (LSDB): SMAD3

    Site Specific Mutation Identification with PCR Assays
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    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Novoseek, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
    About This Section

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    OMIM gene information: 603109   
    OMIM disorders: 613795  
    UniProtKB/Swiss-Prot: SMAD3_HUMAN, P84022
  • 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. 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

  • 14 diseases for SMAD3:    
    About MalaCards
    smad3-related thoracic aortic aneurysms and aortic dissections    loeys-dietz syndrome type 3    smad3-related loeys-dietz syndrome    anisakiasis
    familial thoracic aortic aneurysm and dissection    thoracic aortic aneurysms and aortic dissections    thoracic aortic aneurysm    loeys-dietz syndrome
    renal fibrosis    aortic aneurysm, familial thoracic 4    nephrogenic systemic fibrosis    cleidocranial dysplasia
    aortic aneurysm    colorectal cancer

    3 diseases from the University of Copenhagen DISEASES database for SMAD3:
    Ureteral obstruction     Cancer     Pulmonary fibrosis

    Find genes that share disorders with SMAD3           About GenesLikeMe

    Selected Novoseek inferred disease relationships for SMAD3 gene (see all 47)    About this table

    Disease   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    keloid 55 10 17889631 (4), 11496185 (3), 17144456 (2), 16676428 (1)
    renal fibrosis 47.9 1 18032789 (1)
    liver fibrosis 45 1 15099469 (1)
    sclerosis systemic 42.7 1 20430497 (1)
    leukemogenesis 37.8 6 15295048 (3), 10611754 (1)
    cancer 37.8 27 16474430 (2), 20070253 (2), 17881189 (2), 15904468 (1) (see all 19)
    tumors 35.7 73 12161532 (6), 20037158 (3), 17908958 (3), 18095113 (2) (see all 28)
    pancreatic cancer 34 1 16714330 (1)
    pulmonary fibrosis 33.6 4 17303001 (3), 15590184 (1)
    scars hypertrophic 31.1 6 11955370 (5)

    Genetic Association Database (GAD): SMAD3
    Human Genome Epidemiology (HuGE) Navigator: SMAD3 (33 documents)

    Export disorders for SMAD3 gene to outside databases

    (in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
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    PubMed articles for SMAD3 gene, integrated from 10 sources (see all 862):
    (articles sorted by number of sources associating them with SMAD3)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. Mad-related genes in the human. (PubMed id 8673135)1, 2, 3 Riggins G.J.... Vogelstein B.V. (Nat. Genet. 1996)
    2. Receptor-associated Mad homologues synergize as effectors of the TGF- beta response. (PubMed id 8774881)1, 2, 3 Zhang Y.... Derynck R. (Nature 1996)
    3. The mechanism of nuclear export of Smad3 involves exportin 4 and Ran. (PubMed id 16449645)1, 2, 9 Kurisaki A.... Moustakas A. (Mol. Cell. Biol. 2006)
    4. Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. (PubMed id 16156666)1, 2, 9 Matsuura I.... Liu F. (Biochemistry 2005)
    5. Potentiation of Smad-mediated transcriptional activation by the RNA- binding protein RBPMS. (PubMed id 17099224)1, 2, 9 Sun Y.... Ye Q. (Nucleic Acids Res. 2006)
    6. Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling. (PubMed id 18794808)1, 2, 9 Guo X.... Wang X.-F. (Oncogene 2008)
    7. Novel function of androgen receptor-associated protein 55/Hic-5 as a negative regulator of Smad3 signaling. (PubMed id 15561701)1, 2, 9 Wang H.... Danielpour D. (J. Biol. Chem. 2005)
    8. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. (PubMed id 12154125)1, 2, 9 Qin B.Y.... Lin K. (Genes Dev. 2002)
    9. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta- induced transcription. (PubMed id 9732876)1, 2, 9 Zhang Y.... Derynck R. (Nature 1998)
    10. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. (PubMed id 9311995)1, 2, 9 Nakao A.... ten Dijke P. (EMBO J. 1997)

    (in PubMed, OMIM, and NCBI Bookshelf)
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     ANDOR
    Aliases
    Disorders
    Free Text  

      Query String
    PubMed
    OMIM
    NCBI Bookshelf
      (Note: In FireFox, select the above section and copy using Ctrl-C)

    (According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
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    Entrez Gene: 4088 HGNC: 6769 AceView: SMAD3 Ensembl:ENSG00000166949 euGenes: HUgn4088
    ECgene: SMAD3 Kegg: 4088 H-InvDB: SMAD3

    (According to HUGE)
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      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
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    NameDescription
    PharmGKB entry for SMAD3 Pharmacogenomics, SNPs, Pathways
    ATLAS Chromosomes in Cancer entry for SMAD3 Genetics and Cytogenetics in Oncology and Haematology

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
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    Patent Information for SMAD3 gene:
    Search GeneIP for patents involving SMAD3

    GeneCards and IP:
    Japan Patent Office Licenses GeneCards     European Patent Office Licenses GeneCards     Improving the IP Search



    (Antibodies, recombinant proteins, and assays from EMD Millipore, R&D Systems, OriGene, QIAGEN, GenScript, Cell Signaling Technology, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Cloud-Clone Corp., Thermo Fisher Scientific, LSBio, eBioscience, and/or others, Gene Editing from DNA2.0. Clones from OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Addgene, Cell lines from GenScript, and ESI BIO, Flow cytometery from eBioscience, PCR Arrays from QIAGEN, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, Enzo Life Sciences, and/or ApexBio, In Situ Hybridization Assays from
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     Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat SMAD3
     inGenious Targeting Laboratory: Let us create your new Knockout/Knockin mouse model for SMAD3
     inGenious Targeting Laboratory: Contact us about creating complex and humanized mouse models for SMAD3
     LSBio Antibodies in human, mouse, rat for SMAD3
    Customized transgenic rodents for:
     Humanization
     Biomarker expression
     Off-target effect monitoring
     Translational medicine
     Tissue-specific gene expresssion
     Time-controlled gene expresssion
     Browse compounds at ApexBio
     Addgene plasmids for SMAD3
      Search eBioscience for proteins for SMAD3
     eBioscience elisas for SMAD3 (phospho-SMAD3 (Ser423/425) InstantOne ELISA 96 tests)
      eBioscience FlowRNA Probe Sets
           
    GeneCards Homepage - Last full update: 7 May 2014 - Incrementals: 9 May 2014 , 2 Jun 2014 , 26 Jun 2014 , 30 Jun 2014 , 21 Aug 2014 , 8 Sep 2014

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