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FLASH GENE
Symbol SMAD3 contributors: mct/ - updated : 06-04-2011
HGNC name SMAD family member 3
HGNC id 6769
Corresponding disease
LDS3 Loeys-Dietz syndrome, type 3
TAAD5 thoracic aortic aneurysm with aortic dissection 5
Location 15q22.33      Physical location : 67.358.194 - 67.487.532
Synonym name
  • MAD, mothers against decapentaplegic homolog 3 (Drosophila)
  • SMAD, mothers against DPP homolog 3 (Drosophila)
  • SMA- and MAD-related protein 3
  • mad homolog JV15-2
  • Synonym symbol(s) MADR3, JV15.2, MADH3, HsT17436, DKFZp586N0721, DKFZp686J10186, HSPC193, MGC60396, mad3
    DNA
    TYPE functioning gene
    STRUCTURE 129.34 kb     9 Exon(s)
    regulatory sequence Promoter
    text structure
  • CACGTG E-boxes in its promoter
  • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 6256 48 425 - 2009 19289081
    isoform 1
    - splicing 1148 - - higher in colon compared to stomach or thymus 2004 14980711
  • also called SMAD3 delta3
  • lacks exon 3 resulting in a truncated linker region
  • having transcriptional and possessing functional transactivating properties
  • 9 - 5997 36 320 - 2009 19289081
    isoform 2
    9 - 5808 43.1 381 - 2009 19289081
    isoform 3
    7 - 5441 25.6 230 - 2009 19289081
    isoform 4
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveliver    
     salivary gland   highly
    Endocrinepancreas    
     thyroid   highly
    Nervousbrain    
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • Dwarfin (DWA)/MH1 DNA binding domain including a nuclear localization-like signal (NLS-L)
  • a double loop region, followed by a linker region
  • a DWB/MH2 heterodimerization and transactivation domain
  • secondary structure beta hairpin
    mono polymer complex
    HOMOLOGY
    interspecies homolog to Drosophila Mad (mothers against dpp) gene JV15-1
    Homologene
    FAMILY
  • Dwarfin (DWA/B)/Smad family
  • CATEGORY transcription factor , tumor suppressor , receptor nuclear
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • ligand induced nuclear translocation
  • upon TGFB stimulation, SMAD3 is activated and translocated to nucleus where it binds to NKX2.5, which blocks NKX2.5 binding to the MYOCD promoter and thus inhibits the mRNA expression of MYOCD
  • basic FUNCTION
  • critical mediator of the TGFB signaling pathway
  • sequence specific transcriptional activator, physically bound with AP1 family members : JUNB, JUNC and JUND and interacting with response elements to mediate transcriptional activation of target genes
  • involved in TGFB dependent regulation of steroidogenesis and in T-cell response to TGFB
  • primary transducer of male gonadal tumorigenesis, and potentially overlaps with SMAD2 function in the ovary
  • playing a key role in the regulation of Cdc25A ubiquitination by SCFbeta-TrCP
  • key intracellular signal transducer for TGF-beta signaling, and its transcriptional activity is controlled through reversible phosphorylation and nucleocytoplasmic shuttling
  • plays an essential role in development and maintenance of self-tolerance
  • involved in the increase of cell invasion ability induced by TGF-beta in cancer cells, in cooperation with S100A4
  • regulates RHOA activation and cytoskeletal reorganization by controlling NET1 in TGF-beta1-induced retinal pigment epithelial cells
  • a new role as a modulator of RHOA activation in the regulation of TGF-beta1-induced epithelial-mesenchymal transitions
  • its expression in the normal colon is considered to contribute to the formation of a “proliferative zone” at the bottom of colonic crypts
  • crucial role of SMAD3 reduction in tumor progression in colonic epithelium as well as in restitution of colonic epithelial cell crypts
  • blocks NKX2.5 Binding to the MYOCD promoter and inhibits NKX2.5-mediated MYOCD promoter activation in a dose-dependent manner
  • implication of SMAD3-mediated inhibition of MYOCD in the initiation phase of smooth muscle cells differentiation
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    TGFB
    a component
  • forming a heterodimer with itself and SMAD4
  • key component of the transforming growth factor-beta (TGF-beta) pathway , complexing with SNAI1
  • INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • binding to AP1 members : JUNB, JUNC, JUND
  • androgen receptor coregulator in prostate cancer cells
  • binding activin receptor in associating with DOK1, triggered by activin stimulations and leading to apoptosis
  • SARA, TGIF, RUNX3, SMURF2, SKIL
  • interacting with XPO4 (XPO4 binds a conserved peptide sequence in the MH2 domain of SMAD3 in a Ran-dependent manner and is sufficient for carrying the nuclear export of SMAD3 in cooperation with RAN)
  • interacting with ERBB2IP1 via its MH2 domain
  • in the nucleus, binds to the TERT gene promoter directly and inhibits TERT gene transcription activity, acting as a repressor of the TERT gene
  • interaction between SMAD3 and the CDC42 guanine nucleotide exchange factor, and Zizimin1, in response to TGF-beta1
  • PP2R1A physically interacted with SMAD3 that occurred only in hypoxia (SMAD3-associated PP2R1A activity was found under hypoxic conditions)
  • can phsycially and functionally interact with S100A4 in a Ca2+dependent manner
  • physically interacts with DEDD (through its interaction with SMAD3, DEDD is a novel negative regulator of the TGF-B1 signaling pathway)
  • ADP-ribosylation of SMAD proteins by PARP1 is a key step in controlling the strength and duration of SMAD-mediated transcription
  • interacts with NKX2.5 (SMAD3-NKX2.5 interaction may lead to the blockade of MYOCD in the initiation phase of TGFB-induced smooth muscle cell differentiation)
  • TRIB3 triggering the degradation of SMAD ubiquitin regulatory factor 2 (SMURF2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3
  • PPP5C modulates SMAD3 function in the TGFB pathway
  • FOXO3 and SMAD3, converge to coordinately and directly regulate transcription of TRIM63
  • cell & other
    REGULATION
    activated by in response to transforming growth factor-beta (TGF-beta)
    inhibited by inactivated by MEN1 (disruption of DNA binding)
    Other regulated by CDK4 and CDK2 for antiproliferative function
    ASSOCIATED DISORDERS
    corresponding disease(s) LDS3 , TAAD5
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral        
    in acute T-cell lymphoblastic leukemia and in gastric carcinoma in the early stage
    constitutional     --low  
    accelerates not only cutaneous wound healing and keratinocyte proliferation but also colonic epithelial cell proliferation
    Susceptibility to osteoarthritis
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Smad3 -/- mice showed an increased number of proliferating epithelial cells with activation of the Wnt/beta-catenin pathway in the colonic crypts