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Category   Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21
GIFtS

SMAD4 Gene

protein-coding   GIFtS: 70
GCID: GC18P048494

SMAD Family Member 4

(Previous names: MAD, mothers against decapentaplegic homolog 4 (Drosophila),...)
(Previous symbol: MADH4)
Microbiology & Infectious Diseases Congress
  See 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)
About This Section

Aliases
SMAD Family Member 41 2 3     Deleted In Pancreatic Carcinoma Locus 42
MADH41 2 3 5     Mothers Against Decapentaplegic Homolog 42
DPC42 3 5     Mothers Against Decapentaplegic, Drosophila, Homolog Of, 42
Deletion Target In Pancreatic Carcinoma 42 3     SMAD, Mothers Against DPP Homolog 42
MAD Homolog 42 3     Smad43
JIP2 5     hSMAD43
MAD, Mothers Against Decapentaplegic Homolog 4 (Drosophila)1     Mothers Against DPP Homolog 43
SMAD, Mothers Against DPP Homolog 4 (Drosophila)1     SMAD 43
MYHRS2     

External Ids:    HGNC: 67701   Entrez Gene: 40892   Ensembl: ENSG000001416467   OMIM: 6009935   UniProtKB: Q134853   

Export aliases for SMAD4 gene to outside databases

Previous GC identifers: GC18P046809 GC18P046810 GC18P048556 GC18P045411


(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for SMAD4 Gene:
This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated
and activated by transmembrane serine-threonine receptor kinases in response to TGF-beta signaling. The product
of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then
accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and
recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The Smad proteins are
subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been
shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia
syndrome. (provided by RefSeq, Oct 2009)

GeneCards Summary for SMAD4 Gene: 
SMAD4 (SMAD family member 4) is a protein-coding gene. Diseases associated with SMAD4 include juvenile polyposis syndrome, and myhre syndrome, and among its related super-pathways are BMP signalling and regulation and Cell cycle. 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 SMAD3.

UniProtKB/Swiss-Prot: SMAD4_HUMAN, Q13485
Function: Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming
growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is
required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides
an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric
SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional
activity in response to TGF-beta. May act as a tumor suppressor. 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 SMAD4 (Mothers against decapentaplegic homolog 4) 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 73), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section
RefSeq DNA sequence:
NC_000018.9  NT_010966.14  NC_018929.2  
Regulatory elements:
   SABiosciences Regulatory transcription factor binding sites in the SMAD4 gene promoter:
         AP-1   ATF-2   Nkx2-5   c-Jun   
         Other transcription factors

SwitchGear Promoter luciferase reporter plasmidSMAD4 promoter sequence
   Search SABiosciences Chromatin IP Primers for SMAD4

Epigenetics:
QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat SMAD4


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

Entrez Gene cytogenetic band: 18q21.1   Ensembl cytogenetic band:  18q21.2   HGNC cytogenetic band: 18q21.1

SMAD4 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
SMAD4 gene location

GeneLoc information about chromosome 18         GeneLoc Exon Structure

GeneLoc location for GC18P048494:  view genomic region     (about GC identifiers)

Start:
48,494,410 bp from pter      End:
48,611,415 bp from pter
Size:
117,006 bases      Orientation:
plus strand

(According to UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MAXQB 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, and/or Cloud-Clone Corp.,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Cloud-Clone Corp., Ontologies according to Gene Ontology Consortium 01 Oct 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, LSBio, Abcam, and/or Cloud-Clone Corp.)
About This Section

UniProtKB/Swiss-Prot: SMAD4_HUMAN, Q13485 (See protein sequence)
Recommended Name: Mothers against decapentaplegic homolog 4  
Size: 552 amino acids; 60439 Da
Subunit: Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on
TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3,
and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary
complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1,
STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation
of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2
leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2
domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). 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 with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with
VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of
SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive
Subcellular location: Cytoplasm. Nucleus. Note=Cytoplasmic in the absence of ligand. Migrates to the nucleus when
complexed with R-SMAD. PDPK1 prevents its nuclear translocation in response to TGF-beta
6 PDB 3D structures from and Proteopedia for SMAD4:
1DD1 (3D)        1G88 (3D)        1MR1 (3D)        1U7F (3D)        1U7V (3D)        1YGS (3D)    
Secondary accessions: A8K405

Explore the universe of human proteins at neXtProt for SMAD4: NX_Q13485

Explore proteomics data for SMAD4 at MOPED 

Post-translational modifications:

  • UniProtKB: Phosphorylated by PDPK1
  • UniProtKB: Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form
    a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade.
    Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling
  • View modification sites using PhosphoSitePlus
  • View neXtProt modification sites for NX_Q13485

  • SMAD4 Protein expression data from MOPED1, PaxDb2 and MAXQB3 :    About this image 

    SMAD4 Protein Expression
    REFSEQ proteins: NP_005350.1  
    ENSEMBL proteins: 
     ENSP00000465878   ENSP00000381452   ENSP00000466934   ENSP00000464772   ENSP00000466941  
     ENSP00000465874   ENSP00000464901   ENSP00000468611   ENSP00000466118   ENSP00000341551  
     ENSP00000409551  
    Reactome Protein details: Q13485
    Human Recombinant Protein Products for SMAD4: 
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    Novus Biologicals SMAD4 Lysate
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    ProSpec Recombinant Protein for SMAD4
    Browse Proteins at Cloud-Clone Corp. 

    Gene Ontology (GO): 5/10 cellular component terms (GO ID links to tree view) (see all 10):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0005622intracellular ----
    GO:0005634nucleus IDA--
    GO:0005654nucleoplasm TAS--
    GO:0005667transcription factor complex IPI12374795
    GO:0005730NOT nucleolus IDA--

    SMAD4 for ontologies           About GeneDecksing



    SMAD4 Antibody Products: 
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    (According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
    About This Section
    HGNC Gene Families: 
    SMAD: SMADs

    5/6 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 Q13485

    ProtoNet protein and cluster: Q13485

    1 Blocks protein domain: IPB001132 Dwarfin protein

    UniProtKB/Swiss-Prot: SMAD4_HUMAN, Q13485
    Domain: The MH1 domain is required for DNA binding
    Domain: The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional
    regulation. Sufficient for nuclear import
    Similarity: Belongs to the dwarfin/SMAD family
    Similarity: Contains 1 MH1 (MAD homology 1) domain
    Similarity: Contains 1 MH2 (MAD homology 2) domain


    SMAD4 for domains           About GeneDecksing


    (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,
    bound targets from SABiosciences, miRNA Gene Targets from miRTarBase, shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Sirion Biotech, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, Vector BioLabs, and Sirion Biotech, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Oct 2013 via Entrez Gene.)
    About This Section

    Molecular Function:

         UniProtKB/Swiss-Prot Summary: SMAD4_HUMAN, Q13485
    Function: Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming
    growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is
    required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides
    an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric
    SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional
    activity in response to TGF-beta. May act as a tumor suppressor. 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): 5/17 molecular function terms (GO ID links to tree view) (see all 17):    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:0001076RNA polymerase II transcription factor binding transcription factor activity IEA--
    GO:0001085RNA polymerase II transcription factor binding IEA--
    GO:0003677contributes to DNA binding IDA9389648
         
    SMAD4 for ontologies           About GeneDecksing


    Phenotypes:
         6 GenomeRNAi human phenotypes for SMAD4:
     Increased S DNA content, incre  Increased mitotic index  Increased sensitivity to pacli  S arrest 
     Synthetic lethal with gemcitab  Upregulation of Wnt/beta-caten 

         15/19 MGI mutant phenotypes (inferred from 17 alleles(MGI details for Smad4) (see all 19):
     behavior/neurological  cardiovascular system  cellular  digestive/alimentary  embryogenesis 
     endocrine/exocrine gland  growth/size  hematopoietic system  homeostasis/metabolism  immune system 
     integument  liver/biliary system  mortality/aging  muscle  nervous system 

    SMAD4 for phenotypes           About GeneDecksing

    Animal Models:
         MGI mouse knock-outs for SMAD4: Smad4tm1.1Rob Smad4tm1.1Rdp Smad4tm2.1Rob Smad4tm2.2Cxd Smad4tm1Cxd Smad4tm1Mak
                                                         Smad4tm2Cxd Smad4tm1Mmt

       inGenious Targeting Laboratory - Custom generated mouse model solutions for SMAD4 
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    miRNA
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    miRTarBase miRNAs that target SMAD4:
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    QIAGEN Custom miScript Target Protector blocks miRNA-binding site of human, mouse, rat SMAD4
    8/195 QIAGEN miScript miRNA Assays for microRNAs that regulate SMAD4 (see all 195):
    hsa-miR-411* hsa-miR-106a hsa-miR-146a hsa-miR-605 hsa-miR-519a hsa-miR-3921 hsa-miR-298 hsa-miR-130b
    SwitchGear 3'UTR luciferase reporter plasmidSMAD4 3' UTR sequence
    Inhib. RNA
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    (Pathways according to EMD Millipore, 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 SABiosciences, 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 Oct 2013 via Entrez Gene).
    About This Section

    SuperPaths for SMAD4 About   (see all 49)                                                                                              See pathways by source

    SuperPathContained pathways About
    1Signaling by BMP
    Signaling by BMP0.35
    BMP receptor signaling0.31
    BMP signalling and regulation0.35
    2Cell cycle
    Cell cycle0.59
    Cell cycle0.59
    3Wnt signaling pathway
    Wnt signaling pathway0.40
    Wnt Signaling Pathway NetPath0.37
    4Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
    Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer0.63
    Signaling by TGF-beta Receptor Complex0.61
    SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription0.63
    Downregulation of SMAD2/3:SMAD4 transcriptional activity0.56
    5Signaling by NODAL
    Signaling by NODAL0.56
    Signaling by Activin0.36

    Pathways by source                                                                                                                                                                 See SuperPaths
    Show all pathways

    5/8 EMD Millipore Pathways for SMAD4 (see all 8)
        Development Role of Activin A in cell differentiation and proliferation
    Selected targets of Oct-3/4
    Cell cycle Regulation of G1/S transition (part 1)
    Signal transduction JNK pathway
    Signal transduction Activin A signaling regulation

    2 R&D Systems Pathways for SMAD4
        Th17 Differentiation
    TGF-beta Signaling Pathways


    1 Cell Signaling Technology (CST) Pathway for SMAD4
        TGF-beta/Smad Signaling

    5/7 GeneGo (Thomson Reuters) Pathways for SMAD4 (see all 7)
        Signal transduction Activin A signaling regulation
    Signal transduction PKA signaling
    Cell cycle Regulation of G1/S transition (part 1)
    Development Role of Activin A in cell differentiation and proliferation
    Cytokine production by Th17 cells in CF (Mouse model)

    5/24 BioSystems Pathways for SMAD4 (see all 24)
        TGF Beta Signaling Pathway
    Senescence and Autophagy
    Cell cycle
    Heart Development
    DNA damage response (only ATM dependent)


    5/12        Reactome Pathways for SMAD4 (see all 12)
        Developmental Biology
    TGF-beta receptor signaling activates SMADs
    Generic Transcription Pathway
    Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
    Signaling by Activin


    5/11         Kegg Pathways  (Kegg details for SMAD4) (see all 11):
        Cell cycle
    Wnt signaling pathway
    TGF-beta signaling pathway
    Hippo signaling pathway
    Adherens junction


    SMAD4 for pathways           About GeneDecksing

    Interactions:

        SABiosciences Gene Network CentralTM Interacting Genes and Proteins Network for SMAD4

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

    5/412 Interacting proteins for SMAD4 (Q134851, 2, 3 ENSP000003415514) via UniProtKB, MINT, STRING, and/or I2D (see all 412)
    InteractantInteraction Details
    GeneCardExternal ID(s)
    SMAD2Q157961, 2, 3, ENSP000002621604EBI-347263,EBI-1040141 MINT-6799119 MINT-15900 MINT-61945 I2D: score=10 STRING: ENSP00000262160
    TRIM33Q9UPN91, 2, 3, ENSP000003512504EBI-347263,EBI-2214398 MINT-8200333 MINT-8200350 I2D: score=4 STRING: ENSP00000351250
    UBE2IP632791, 2, 3, ENSP000003248974EBI-347263,EBI-80168 MINT-61950 I2D: score=7 STRING: ENSP00000324897
    SKIP127551, 2, 3, ENSP000003677974EBI-347263,EBI-347281 MINT-61954 I2D: score=6 STRING: ENSP00000367797
    SMAD1Q157972, 3, ENSP000003057694MINT-62001 MINT-4298076 I2D: score=7 STRING: ENSP00000305769
    About this table

    Gene Ontology (GO): 5/58 biological process terms (GO ID links to tree view) (see all 58):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000122negative regulation of transcription from RNA polymerase II promoter TAS--
    GO:0001658branching involved in ureteric bud morphogenesis IEA--
    GO:0001666response to hypoxia IMP12411310
    GO:0001701in utero embryonic development IEA--
    GO:0001702gastrulation with mouth forming second IEA--

    SMAD4 for ontologies           About GeneDecksing



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB, with drugs/clinical trials/news search links to CenterWatch)
    About This Section

    SMAD4 for compounds           About GeneDecksing

    Browse Small Molecules at EMD Millipore
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    Browse Tocris compounds for SMAD4

    10/30 Novoseek inferred chemical compound relationships for SMAD4 gene (see all 30)    About this table
    Compound   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    tgf beta1 66.2 23 11784716 (4), 11196469 (2), 12935295 (2), 17469181 (2) (see all 10)
    threonine 43.3 4 9312063 (1), 14656470 (1), 11889196 (1), 15702493 (1)
    serine 38 5 9312063 (1), 14656470 (1), 11889196 (1), 12759229 (1) (see all 5)
    crcs 34.8 2 18471510 (2)
    leptomycin b 30.2 5 11074002 (2), 18519565 (1)
    propoxur 24.3 1 12010891 (1)
    pd 98,059 21.8 1 11371552 (1)
    doxazosin 9.66 3 12771931 (2), 16007219 (1)
    paraffin 6.79 8 11866987 (2), 12479060 (2), 11075857 (1), 12010891 (1)
    mg 132 6.25 3 17200344 (2), 11818334 (1)

    Search CenterWatch for drugs/clinical trials and news about SMAD4

    (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,
    Conferences by KenesGroup, exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
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    About This Section

    REFSEQ mRNAs for SMAD4 gene: 
    NM_005359.5  

    Unigene Cluster for SMAD4:

    SMAD family member 4
    Hs.75862  [show with all ESTs]
    Unigene Representative Sequence: NM_005359
    17 Ensembl transcripts including schematic representations, and UCSC links where relevant:
    ENST00000588860 ENST00000398417(uc002lfb.4) ENST00000589076 ENST00000590061
    ENST00000591914 ENST00000592911 ENST00000589941 ENST00000588745 ENST00000592186
    ENST00000589706 ENST00000585448 ENST00000591126 ENST00000590499 ENST00000593223
    ENST00000586253 ENST00000342988(uc010xdp.2) ENST00000452201(uc010xdo.1)

    Congresses - knowledge worth sharing:  
    European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 10 - 13 May 2014

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    Additional mRNA sequence: 

    AK290770.1 AL832789.1 BC002379.2 BX647129.1 U44378.1 

    17 DOTS entries:

    DT.317208  DT.121090072  DT.105413  DT.100691422  DT.40284956  DT.100001068  DT.97802720  DT.121090073 
    DT.92438228  DT.92438229  DT.95078262  DT.100818887  DT.121087023  DT.40264776  DT.75168357  DT.91684967 
    DT.95370406 

    24/272 AceView cDNA sequences (see all 272):

    CF529222 BC014624 AI985283 AA233569 BI492620 AI016049 BM790026 AI669235 
    AU117884 AA954421 CD365218 CD678304 BF842398 F10678 AA456439 CB217085 
    AA815191 BM992533 AI627672 H93306 AW087656 CB155810 NM_018696 AU119862 

    GeneLoc Exon Structure

    5/10 Alternative Splicing Database (ASD) splice patterns (SP) for SMAD4 (see all 10)    About this scheme

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


    ECgene alternative splicing isoforms for SMAD4

    (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™, plus additional links to Genevestigator, and/or SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from SABiosciences, Primers from OriGene, SABiosciences, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
    About This Section

    SMAD4 expression in normal human tissues (normalized intensities)      SMAD4 embryonic expression: see
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS <intensity>2/3
    CGAP TAG: TATGTTATGA
    SMAD4 Expression
    About this image


    SMAD4 expression in embryonic tissues and stem cells    About this table
    Data from LifeMap, the Embryonic Development and Stem Cells Database 
     5/10 selected tissues (see all 10) fully expand
     
     Neural Crest (Gastrulation Derivatives)    fully expand to see all 2 entries
             Neural Crest Outflow Tract Cells Outflow Tract
     
     Primitive Streak (Early Embryo)    fully expand to see all 2 entries
             Primitive Streak Cells Primitive Streak
     
     Smooth Muscle (Muscoskeletal System)
             Mural Cells Splanchnic Mesoderm
     
     Peripheral Nervous System (Nervous System)
             spinal/ganglion/dorsal root ganglion   
     
     Head Mesenchyme (Muscoskeletal System)
             Cardiac Neural Crest Cells Branchial Arch 3,4,6

    See SMAD4 Protein Expression from SPIRE MOPED and PaxDB
    Genevestigator expression for SMAD4

    SOURCE GeneReport for Unigene cluster: Hs.75862
        SABiosciences Expression via Pathway-Focused PCR Arrays including SMAD4 (see all 13): 
              Osteogenesis in human mouse rat
              Oncogenes & Tumor Suppressor Genes in human mouse rat
              Fibrosis in human mouse rat
              TGFB/BMP Signaling Pathway in human mouse rat
              Stem Cell Signaling in human mouse rat

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    Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for SMAD4

    (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)
    About This Section

    This gene was present in the common ancestor of animals.

    Orthologs for SMAD4 gene from 6/16 species (see all 16)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    mouse
    (Mus musculus)
    Mammalia Smad41 , 5 MAD homolog 4 (Drosophila)5
    SMAD family member 41
    91.53(n)1
    98.55(a)1
      18 (49.51 cM)5
    171281  NM_008540.21  NP_032566.21 
     736390095 
    lizard
    (Anolis carolinensis)
    Reptilia SMAD46
    Uncharacterized protein
    96(a)
    1 ↔ 1
    GL343471.1(494708-519318)
    African clawed frog
    (Xenopus laevis)
    Amphibia Xl.8852 Xenopus laevis mRNA for Xsmad4a, complete cds 78.03(n)    AB022721.1 
    zebrafish
    (Danio rerio)
    Actinopterygii madh42 MAD homolog 4 (Drosophila) 77.62(n)   30640  AF229175.1 
    fruit fly
    (Drosophila melanogaster)
    Insecta Med1 Medea 61.24(n)
    70.6(a)
      43725  NM_170559.2  NP_733438.1 
    worm
    (Caenorhabditis elegans)
    Secernentea sma-36
    sma-46
    (see all 6)
    Dwarfin sma-4
    (see all 6)
    34(a)
    33(a)
    (see all 6)
    many ↔ many
    many ↔ many
    (see all 6)
    III(6860963-6863969)
    III(5816203-5820203)


    ENSEMBL Gene Tree for SMAD4 (if available)
    TreeFam Gene Tree for SMAD4 (if available)

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
    About This Section
    Paralogs for SMAD4 gene
    SMAD32  SMAD22  SMAD12  SMAD62  SMAD52  SMAD92  SMAD72  
    5 SIMAP similar genes for SMAD4 using alignment to 11 protein entries:     SMAD4_HUMAN (see all proteins):
    SMAD1    DKFZp686J10186    SMAD5    SMAD3    SMAD7

    SMAD4 for paralogs           About GeneDecksing



    (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) and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers from QIAGEN, Cancer Mutation PCR Arrays and Assays and Copy Number PCR Arrays from SABiosciences)
    About This Section

    10/1095 SNPs in SMAD4 are shown (see all 1095)    About this table     
    Genomic DataTranscription Related DataAllele Frequencies
    SNP IDValidClinical
    significance
    Chr 18 posSequence#AA
    Chg
    TypeMore#Allele
    freq
    PopTotal
    sample
    More
    ----------
    VAR_0364774
    A colorectal cancer sample4--see VAR_0364772 R H mis40--------
    VAR_0195734
    Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT)4--see VAR_0195732 G D mis40--------
    VAR_0364754
    A colorectal cancer sample4--see VAR_0364752 P S mis40--------
    VAR_0364764
    A colorectal cancer sample4--see VAR_0364762 D N mis40--------
    VAR_0113804
    Pancreatic carcinoma4--see VAR_0113802 D H mis40--------
    rs1219125811,2,4
    CJuvenile polyposis syndrome (JPS)4 pathogenic148592085(+) TTGATA/GGATAC 2 R G mis10--------
    rs803389631,2,4
    CJuvenile polyposis syndrome (JPS)4 pathogenic148592112(+) GAGATA/C/G/
            
    GCTTT
    4 S R G C mis10--------
    rs1459886181,2
    C,Fnon-pathogenic148575354(+) TATGCG/ATTTGA 2 /A syn12Minor allele frequency- A:0.00NA EU 5873
    rs9485891,2
    C,F,Hnon-pathogenic148586378(-) TCTAAT/CGCTAA 1 -- int116Minor allele frequency- C:0.04NS EA NA 1784
    rs3777673341,2
    Cpathogenic148584713(+) GGGGG-/GCAGCC 2 S Q fra10--------

    HapMap Linkage Disequilibrium report for SMAD4 (48494410 - 48611415 bp)

    Structural Variations
         Database of Genomic Variants (DGV) 1 variation for SMAD4:    About this table     
    Variant IDTypeSubtypePubMed ID
    nsv909645CNV Gain21882294


    Human Gene Mutation Database (HGMD): SMAD4

    Locus Specific Mutation Databases (LSDB): SMAD4
    1 SABiosciences Cancer Mutation PCR Assay for SMAD4:
    Cosmic IdAA Change
    14057p.Q245*
    2 SABiosciences Cancer Mutation PCR Arrays containing SMAD4:
    Pancreatic Cancer
    Cancer Comprehensive Panel 384HT
    1 SABiosciences qBiomarker Copy Number PCR Array containing SMAD4:
    Oncogenes & Tumor Suppressor Genes 384HC
    SeqTarget long-range PCR primers for resequencing SMAD4
    DNA2.0 Custom Variant and Variant Library Synthesis for SMAD4

    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Conferences by KenesGroup, Novoseek, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
    About This Section
    OMIM gene information: 600993   
    OMIM disorders: 174900  175050  
    UniProtKB/Swiss-Prot: SMAD4_HUMAN, Q13485
  • Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both
    the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including
    the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Note=The gene represented in this
    entry may be involved in disease pathogenesis
  • Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous
    polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are
    typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core.
    Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without
    associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased
    risk of colon and other gastrointestinal cancers. Note=The disease is caused by mutations affecting the gene
    represented in this entry
  • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome
    phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT)
    [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and
    non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused
    by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or
    ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although
    there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of
    this association is unknown. Note=The disease is caused by mutations affecting the gene represented in this entry
  • 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
  • Primary pulmonary hypertension (PPH1) [MIM:178600]: A rare disorder characterized by plexiform lesions of
    proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial
    pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a
    mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known
    etiologies are more common and include those associated with the appetite-suppressant drugs. Note=The disease may
    be caused by mutations affecting the gene represented in this entry
  • Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency,
    mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility,
    cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia,
    prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs,
    iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital
    heart disease, may also occur. Note=The disease is caused by mutations affecting the gene represented in this
    entry

  • 20/110 diseases for SMAD4 (see all 110):    About MalaCards
    juvenile polyposis syndrome    myhre syndrome    smad4-related hereditary hemorrhagic telangiectasia    smad4-related juvenile polyposis
    juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome    pancreatitis    hereditary hemorrhagic telangiectasia    bmpr1a-related juvenile polyposis
    pancreatic cancer    mutyh-associated polyposis    bile duct adenoma    pancreatic ductal adenocarcinoma
    biliary tract cancer    pancreatoblastoma    small intestine adenocarcinoma    pancreatic endocrine carcinoma
    acinar cell carcinoma    clear cell adenocarcinoma    bannayan-riley-ruvalcaba syndrome    ruvalcaba syndrome

    5 diseases from the University of Copenhagen DISEASES database for SMAD4:
    Pancreatic cancer     Carcinoma     Hereditary hemorrhagic telangiectasia     Colorectal cancer
    Adenoma

    SMAD4 for disorders           About GeneDecksing

    10/94 Novoseek inferred disease relationships for SMAD4 gene (see all 94)    About this table

    Disease   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    juvenile polyposis syndrome 88 12 19014666 (2), 16152648 (1), 17873119 (1), 15378062 (1) (see all 8)
    pancreatic cancer 81 126 11323508 (3), 12479060 (3), 11783110 (3), 15592526 (3) (see all 65)
    polyps juvenile 80.8 9 19266212 (5), 15447767 (1), 19014666 (1)
    pancreatic carcinoma 77.5 95 18985820 (6), 9098646 (5), 12352188 (4), 11866987 (3) (see all 37)
    polyposis 77.4 50 10797267 (3), 15031030 (3), 18355998 (3), 12821112 (2) (see all 32)
    allelic loss 70.3 33 17088901 (2), 17659731 (2), 19443408 (2), 11337365 (2) (see all 18)
    adenocarcinoma 68 148 11751510 (6), 11431719 (5), 17587453 (5), 17854080 (5) (see all 58)
    pancreatic tumor 67.3 7 16135802 (2), 10415855 (1), 9644295 (1), 11553622 (1) (see all 6)
    tumors 65.6 415 15814640 (6), 12352188 (6), 15014009 (5), 10331746 (4) (see all 99)
    colorectal cancer 61.6 78 11172591 (4), 8898652 (4), 11481457 (4), 16144935 (3) (see all 39)

    GeneTests: SMAD4
    GeneReviews: SMAD4
    Genetic Association Database (GAD): SMAD4
    Human Genome Epidemiology (HuGE) Navigator: SMAD4 (37 documents)

    Export disorders for SMAD4 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)
    About This Section

    PubMed articles for SMAD4 gene, integrated from 9 sources (see all 983):
    (articles sorted by number of sources associating them with SMAD4)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. (PubMed id 12417513)1, 2, 4, 9 Sayed M.G.... Howe J.R. (2002)
    2. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. (PubMed id 8553070)1, 2, 3 Hahn S.A.... Kern S.E. (1996)
    3. Receptor-associated Mad homologues synergize as effectors of the TGF- beta response. (PubMed id 8774881)1, 2, 3 Zhang Y.... Derynck R. (1996)
    4. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. (PubMed id 15235019)1, 4, 9 Howe J.R....Lynch H.T. (2004)
    5. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. (PubMed id 9811934)1, 2, 9 Houlston R.... Tomlinson I. (1998)
    6. Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation. (PubMed id 11818334)1, 2, 9 Wan M.... Cao X. (2002)
    7. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. (PubMed id 18823382)1, 4, 9 Calva-Cerqueira D....Howe J. (2008)
    8. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). (PubMed id 15031030)1, 2, 9 Gallione C.J.... Marchuk D.A. (2004)
    9. Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma. (PubMed id 9098646)1, 2, 9 Moskaluk C.A....Kern S.E. (1997)
    10. Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. (PubMed id 9389648)1, 2, 9 Liu F.... Massague J. (1997)

    (in PubMed, OMIM, and NCBI Bookshelf)
    About This Section
     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)
    About This Section
    Entrez Gene: 4089 HGNC: 6770 AceView: SMAD4andELAC1 Ensembl:ENSG00000141646 euGenes: HUgn4089
    ECgene: SMAD4 Kegg: 4089 H-InvDB: SMAD4

    (According to HUGE)
    About This Section
      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL,
    Wikipedia and/or GeneReviews via UniProtKB/Swiss-Prot)
    About This Section
    NameDescription
    PharmGKB entry for SMAD4 Pharmacogenomics, SNPs, Pathways
    ATLAS Chromosomes in Cancer entry for SMAD4 Genetics and Cytogenetics in Oncology and Haematology
    GeneReviewshttp://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SMAD4

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
    About This Section
    Patent Information for SMAD4 gene:
    Search GeneIP for patents involving SMAD4

    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, SABiosciences, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Cloud-Clone Corp., Thermo Fisher Scientific, LSBio, Gene Editing from DNA2.0 and Sirion Biotech, Clones from EMD Millipore, OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Sirion Biotech, Cell lines from GenScript, and LifeMap BioReagents, PCR Arrays from SABiosciences, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, and/or Enzo Life Sciences, In Situ Hybridization Assays from
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    About This Section

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     Recombinant Protein for SMAD4




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     Browse Antibodies at Cloud-Clone Corp.
     Browse ELISAs at Cloud-Clone Corp.
     Browse CLIAs at Cloud-Clone Corp.
     Search LifeMap BioReagents cell lines for SMAD4
     Gene Synthesis
     Protein Engineering
     Variant Library Synthesis
     Codon Optimization
     Protein Production and Purification
     Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for SMAD4
     SwitchGear 3'UTR luciferase reporter plasmids for SMAD4
     SwitchGear Promoter luciferase reporter plasmids for SMAD4
     ThermoFisher Antibody for SMAD4
     Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat SMAD4
     inGenious Targeting Laboratory - Custom generated mouse model solutions for SMAD4
     inGenious Targeting Laboratory - Custom generated inducible mouse model solutions for SMAD4
    Customized:
     lentivirus for stable overexpression of SMAD4
     lentivirus expression plasmids for stable overexpression of SMAD4
     adenovirus for overexpression of SMAD4
     Search LSBio for Antibodies for SMAD4
    Customized transgenic rodents for:
     Humanization
     Biomarker expression
     Off-target effect monitoring
     Translational medicine
     Tissue-specific gene expresssion
     Time-controlled gene expresssion
           
    GeneCards Homepage - Last full update: 23 Oct 2013 - Incrementals: 3 Nov 2013 , 7 Nov 2013 , 23 Jan 2014

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    (GIFtS: 73)
    transforming growth factor, beta 1
    GIFtS Group
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