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Symbol SMAD4 contributors: mct/pgu - updated : 27-10-2017
HGNC name SMAD family member 4
HGNC id 6770
Corresponding disease
JPHT juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
JPS juvenile polyposis syndrome
MYHRS Myhre syndrome
Location 18q21.2      Physical location : 48.556.582 - 48.611.409
Synonym name
  • SMAD, mothers against DPP homolog 4 (Drosophila)
  • transforming growth factor beta-inducible DNA binding protein carcinoma, locus 4, homeoprotein
  • MAD, mothers against decapentaplegic homolog 4 (Drosophila)
  • deleted in pancreatic cancer 4
  • MAD homolog 4
  • Synonym symbol(s) DPC4, MADH4, JIP
    TYPE functioning gene
    STRUCTURE 54.83 kb     12 Exon(s)
    regulatory sequence Promoter
    Binding site
    text structure
  • four promoters were identified, two of which had significant activity in several cell lines, while two others had minimal activity
  • multiple potentially important transcription factor binding sites for each promoter
  • MAPPING cloned Y linked N status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 8789 60.31 552 - 2007 17724086
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Cardiovascularheartventricle    Homo sapiens
    Respiratorylung   highly
    Urinarykidney   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial Homo sapiens
    Cardiovascularendothelial cell
    cell lineage
    cell lines
    at STAGE
    physiological period fetal
    Text ubiquitous during testis development but becomes cell-specific in the adult
  • dwarfin (DWA)MH1 DNA binding domain, implicated in the interactions with Hox and regulating the transcription activity of Hox proteins
  • a nuclear localization-like signal (NLS-L), non functional
  • a double loop region
  • a linker region and a DWB/MH2 heterodimerization
  • transactivation domain
  • mono polymer heteromer , trimer , complex
    interspecies homolog to Drosophila Mad (mothers against dpp)
    homolog to murine Madh4
    homolog to C.elegans Sma2-3-4
  • Dwarfin (DWA/B)/Smad family
  • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    text ligand induced nuclear translocation, nuclear when complexed with MADH5 or MADH2, cytoplasmic in the abscence of ligand
    basic FUNCTION
  • sequence specific transcriptional activator
  • critical mediator of TGFB and BMP signaling pathways
  • corepressor for estrogen receptor (ER) alpha
  • can repress the SMAD3-enhanced ER alpha (ESR1)transactivation in a dose dependent-manner
  • central intracellular signal transducer for transforming growth factor-beta (TGF-beta) signaling
  • involved in carcinogenesis mainly of the pancreas and colon
  • in colon and pancreatic tumor cells, functioning as a positive transcriptional regulator of all three genes encoding LAMA5
  • having function in the control of an essential basement membrane component
  • having activity in the developing endothelial cells essential for blood vessel remodeling, maturation, and integrity
  • required for the development and maintenance of the lens in addition to the proper development of the cornea, eyelids, and retina
  • may affect lens survival and function by controlling lens differentiation
  • likely functions as a signaling mediator downstream of Activinbeta B in regulating actin stress fiber assembly and eyelid epithelial movement
  • key regulator of prostate cancer progression
  • GATA4 and SMAD4 cooperatively activated the ID2 promoter
  • its endocardial expression is required to promote normal cellularity in the developing endocardial cushion, and SMAD4 is required to promote proliferation during the activation process of the pre-endothelial-to-mesenchymal transformation endocardial cell
  • plays a crucial role in regulating the interplay between TGFB/BMP and WNT signaling to ensure the proper cranial neural crest cell fate decision during organogenesis
  • crucial role in TGFB/bone morphogenetic protein (BMP) signal transduction
  • potentially required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors
  • cooperative regulation of VEGFA signaling by FHL1 and SMAD4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression
  • is essential for initiating the SMC differentiation program during ureter development
  • SMAD4 and STRA8 are essential factors that regulate the female fate of germ cells
  • BSG -induced cell proliferation is associated with SMAD4 signal inhibition
  • CELLULAR PROCESS nucleotide, transcription, regulation
    cell organization/biogenesis
    text suppression of angiogenesis
    signaling signal transduction
  • TGFB, BMP, SMAD pathway
  • TGFB1-SMAD4-FGF6 signaling cascade plays a crucial role in myogenic cell fate determination and lineage progression during tongue myogenesis
  • a component
  • forming a ternary complex with LIP1 and serine-threonine kinase 11 (STK11)
  • interacting with SMAD3 and forming a complex with SNA1
  • transcriptional repressor complex that promotes TGFbeta-mediated epithelial-mesenchymal transition
  • forms a stable complex with the R-SMAD (SMAD3) and the Co-SMAD (SMAD4)
    small molecule
  • binding to MADH1, MADH2, MADH3, MADH5
  • cointeracting with FOXH1 through ASE (asymetric enhancers) of NODAL and LEFTY2
  • interacting with ER alpha (ESR1 gene)
  • interacts with TGFBRAP1
  • SNIP1
  • can interact directly with Hox proteins and suppress their DNA-binding activity
  • interaction between the recombinant homeodomain (HD) of HOXC9 and MH1 domain of SMAD4 (SMAD4 inhibits HOXC9 transcription activity)
  • interacting with USP9X (deubiquitinates mono-ubiquitinated SMAD4)
  • ADP-ribosylation of SMAD proteins by PARP1 is a key step in controlling the strength and duration of SMAD-mediated transcription
  • binding of the N-terminal portion of SMAD4 to the second zinc-finger domain of GATA4 (genetically cooperate in the endocardium during atrioventricular valve formation)
  • TRIM33 is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD4 inhibition
  • NR2F2 interacts with SMAD4 to modulate TGFB1 signalling
  • ZBTB7A is a new partner of SMAD4 and plays a negative role in TGFB1 pathway
  • can regulate cell migration and proliferation by suppressing the expression of SMAD4 in PC (pancreatic cancer), which may provide a novel sight to explore the mechanism and therapeutic strategy for PC
  • EXOC4 regulates CDH2 expression by controlling SMAD3 and SMAD4 expression at the basal transcriptional level, thereby modulating cell migration and adhesion
  • ZFYVE16 binds to SMAD4 and their binding affects the formation of SMAD2/3-SMAD4 complex in TGFB1 signaling
  • TGIF1 is a multifunctional protein that represses TGFB1-activated transcription by interacting with SMAD2-SMAD4 complexes
  • ZNF446 interacts with both SMAD3 and SMAD4 in a TGFB1-dependent fashion, similar to ZNF165
  • cell & other
    activated by activin receptors in the NODAL pathway (ACVR2)
    Phosphorylated by NLK
    Other COPS5 mediates its degradation
    protected by SUMO-1 modification from ubiquitin-dependent degradation and consequently enhancing the growth inhibitory and transcriptional responses of Smad4
    deubiquitination by USP9X is direct
    corresponding disease(s) JPS , JPHT , MYHRS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in cervical cancer
    constitutional germinal mutation      
    in juvenile polyposis with malformative vessels and with a more aggressive digestive phenotype
    tumoral   deletion    
    in juvenile polyposis in biliary and pancreatic cancer, and in juvenile polyposis (mutational hotspot) with gastric polyposis
    tumoral       loss of function
    in pancreas cancer cells lines and in colorectal cancer (in progression)
    constitutional       loss of function
    is a genetically late event that occurs upon transition from premalignant stages to invasive and metastatic growth
    tumoral     --low  
    is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age groups
    constitutional       loss of function
    inactivation in the lens/corneal ectoderm caused disruption in the development of the anterior segment
    constitutional     --over  
    sensitizes hematopoietic stem/progenitor cells to TGFB, resulting in growth arrest and apoptosis
    tumoral     --low  
    of RHOT1 and SMAD4 were significantly associated with lymph node metastasis and shorter survival in pancreatic cancer
    Variant & Polymorphism
    Candidate gene
    Therapy target
  • inhibition of Smad4 SUMOylation impaired spatial learning and memory in rats by downregulating Tpm2, a gene associated with skeletal myopathies