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    SMAD4 SMAD family member 4 [ Homo sapiens (human) ]

    Gene ID: 4089, updated on 26-Jul-2021

    Summary

    Official Symbol
    SMAD4provided by HGNC
    Official Full Name
    SMAD family member 4provided by HGNC
    Primary source
    HGNC:HGNC:6770
    See related
    Ensembl:ENSG00000141646 MIM:600993
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    JIP; DPC4; MADH4; MYHRS
    Summary
    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 transforming growth factor (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 protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasng blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. 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, Aug 2017]
    Expression
    Ubiquitous expression in thyroid (RPKM 12.0), endometrium (RPKM 10.8) and 25 other tissues See more
    Orthologs
    NEW
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    Genomic context

    See SMAD4 in Genome Data Viewer
    Location:
    18q21.2
    Exon count:
    12
    Annotation release Status Assembly Chr Location
    109.20210514 current GRCh38.p13 (GCF_000001405.39) 18 NC_000018.10 (51030213..51085042)
    105.20201022 previous assembly GRCh37.p13 (GCF_000001405.25) 18 NC_000018.9 (48556583..48611412)

    Chromosome 18 - NC_000018.10Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC107985152 Neighboring gene elaC ribonuclease Z 1 Neighboring gene Sharpr-MPRA regulatory region 5267 Neighboring gene uncharacterized LOC105372117 Neighboring gene serine and arginine rich splicing factor 10 pseudogene 1 Neighboring gene uncharacterized LOC105372118 Neighboring gene mex-3 RNA binding family member C

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    Phenotypes

    Associated conditions

    Description Tests
    A genome-wide association study of host genetic determinants of the antibody response to Anthrax Vaccine Adsorbed.
    GeneReviews: Not available
    Carcinoma of pancreas
    MedGen: C0235974 OMIM: 260350 GeneReviews: Not available
    Compare labs
    Generalized juvenile polyposis/juvenile polyposis coli
    MedGen: C1868081 OMIM: 174900 GeneReviews: Juvenile Polyposis Syndrome
    Compare labs
    Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Compare labs
    Myhre syndrome
    MedGen: C0796081 OMIM: 139210 GeneReviews: Myhre Syndrome
    Compare labs

    Copy number response

    Description
    Copy number response
    Triplosensitivity

    No evidence available (Last evaluated 2020-12-16)

    ClinGen Genome Curation Page
    Haploinsufficency

    Sufficient evidence for dosage pathogenicity (Last evaluated 2020-12-16)

    ClinGen Genome Curation PagePubMed

    HIV-1 interactions

    Protein interactions

    Protein Gene Interaction Pubs
    Tat tat HIV-1 Tat-treated pulmonary arterial smooth muscle cells downregulate levels of phosphorylated SMAD2/3 proteins and SMAD2/3-SMAD4 protein complex, which are repressed by cocaine exposure PubMed
    tat HIV-1 Tat-treated pulmonary arterial smooth muscle cells modulate levels of phosphorylated SMAD1/5/8 proteins and SMAD1/5/8-SMAD4 protein complex, which are repressed by cocaine exposure PubMed
    tat HIV-1 Tat proteins from different clades modulate differently Pur-alpha and SMAD4 to bind the JCV non-coding control region and affect differently on SMAD4 localization to the nucleus PubMed
    tat HIV-1 Tat enhances binding of SMAD2, -3 and -4 and their binding partner Fast1 to the JCV DNA control region (CR) to stimulate JCV gene transcription in living cells PubMed
    tat Smad-4 inhibits Smad-3 and HIV-1 Tat-induced transcription from the HIV-1 LTR promoter and the MCP promoter through a direct association with amino acids 1-40 of Tat PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Potential readthrough

    Included gene: ELAC1

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    contributes_to DNA binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables DNA-binding transcription activator activity, RNA polymerase II-specific IDA
    Inferred from Direct Assay
    more info
    PubMed 
    contributes_to DNA-binding transcription factor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables DNA-binding transcription factor activity, RNA polymerase II-specific IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    enables DNA-binding transcription factor activity, RNA polymerase II-specific ISA
    Inferred from Sequence Alignment
    more info
     
    enables I-SMAD binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    enables I-SMAD binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables R-SMAD binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables RNA polymerase II cis-regulatory region sequence-specific DNA binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    enables RNA polymerase II cis-regulatory region sequence-specific DNA binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables RNA polymerase II-specific DNA-binding transcription factor binding IEA
    Inferred from Electronic Annotation
    more info
     
    enables chromatin binding IEA
    Inferred from Electronic Annotation
    more info
     
    enables collagen binding IEA
    Inferred from Electronic Annotation
    more info
     
    enables identical protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
     
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables protein homodimerization activity IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    contributes_to sequence-specific DNA binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables sulfate binding IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    enables transcription cis-regulatory region binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables transcription coactivator binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    Process Evidence Code Pubs
    involved_in BMP signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in BMP signaling pathway IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in BMP signaling pathway ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in SMAD protein complex assembly IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in SMAD protein signal transduction IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in SMAD protein signal transduction IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in anatomical structure morphogenesis IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in atrioventricular canal development ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in atrioventricular valve formation ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in axon guidance IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in brainstem development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in branching involved in ureteric bud morphogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in cardiac conduction system development NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in cell differentiation IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in cell population proliferation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in cellular iron ion homeostasis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in cellular response to BMP stimulus NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in developmental growth IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in embryonic digit morphogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in endocardial cell differentiation ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in endothelial cell activation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in epithelial to mesenchymal transition involved in endocardial cushion formation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in female gonad morphogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in formation of anatomical boundary IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in gastrulation with mouth forming second IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in in utero embryonic development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in interleukin-6-mediated signaling pathway ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in intracellular signal transduction IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in left ventricular cardiac muscle tissue morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in mesendoderm development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in metanephric mesenchyme morphogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of ERK1 and ERK2 cascade ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of cardiac muscle hypertrophy ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of cardiac myofibril assembly ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of cell death IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of cell growth IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in negative regulation of cell population proliferation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in negative regulation of transcription by RNA polymerase II ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in negative regulation of transcription, DNA-templated IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in nephrogenic mesenchyme morphogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in neural crest cell differentiation IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in neuron fate commitment IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in outflow tract septum morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in ovarian follicle development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in positive regulation of BMP signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in positive regulation of SMAD protein signal transduction ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of cell proliferation involved in heart valve morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of epithelial to mesenchymal transition ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of follicle-stimulating hormone secretion IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in positive regulation of histone H3-K4 methylation ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of histone H3-K9 acetylation ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of luteinizing hormone secretion IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in positive regulation of pathway-restricted SMAD protein phosphorylation ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of pri-miRNA transcription by RNA polymerase II IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in positive regulation of transcription by RNA polymerase II IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of transcription by RNA polymerase II ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in positive regulation of transcription, DNA-templated IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of transforming growth factor beta receptor signaling pathway IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in regulation of binding IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in regulation of hair follicle development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in regulation of transcription by RNA polymerase II IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in regulation of transforming growth factor beta receptor signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in regulation of transforming growth factor beta2 production IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in response to hypoxia IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in response to transforming growth factor beta IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in sebaceous gland development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in secondary palate development ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in seminiferous tubule development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in single fertilization IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in somite rostral/caudal axis specification IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in spermatogenesis IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in transforming growth factor beta receptor signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    involved_in transforming growth factor beta receptor signaling pathway IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in transforming growth factor beta receptor signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in transforming growth factor beta receptor signaling pathway ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    involved_in uterus development IEA
    Inferred from Electronic Annotation
    more info
     
    involved_in ventricular septum morphogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    Component Evidence Code Pubs
    part_of SMAD protein complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    part_of SMAD protein complex IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    part_of activin responsive factor complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in centrosome IDA
    Inferred from Direct Assay
    more info
     
    located_in chromatin IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in chromatin ISA
    Inferred from Sequence Alignment
    more info
     
    located_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
     
    located_in cytosol TAS
    Traceable Author Statement
    more info
     
    part_of heteromeric SMAD protein complex IBA
    Inferred from Biological aspect of Ancestor
    more info
    PubMed 
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
     
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
     
    located_in nucleus IDA
    Inferred from Direct Assay
    more info
    PubMed 
    part_of transcription regulator complex IDA
    Inferred from Direct Assay
    more info
    PubMed 
    part_of transcription regulator complex IPI
    Inferred from Physical Interaction
    more info
    PubMed 

    General protein information

    Preferred Names
    mothers against decapentaplegic homolog 4
    Names
    MAD homolog 4
    SMAD, mothers against DPP homolog 4
    deleted in pancreatic carcinoma locus 4
    deletion target in pancreatic carcinoma 4
    mothers against decapentaplegic, Drosophila, homolog of, 4

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_013013.2 RefSeqGene

      Range
      67174..122003
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_318

    mRNA and Protein(s)

    1. NM_005359.6NP_005350.1  mothers against decapentaplegic homolog 4

      See identical proteins and their annotated locations for NP_005350.1

      Status: REVIEWED

      Source sequence(s)
      AC091551, AU120224, BC002379, BM701399
      Consensus CDS
      CCDS11950.1
      UniProtKB/Swiss-Prot
      Q13485
      UniProtKB/TrEMBL
      A0A024R274
      Related
      ENSP00000341551.3, ENST00000342988.8
      Conserved Domains (2) summary
      cd10492
      Location:14138
      MH1_SMAD_4; N-terminal Mad Homology 1 (MH1) domain in SMAD4
      cd10498
      Location:320541
      MH2_SMAD_4; C-terminal Mad Homology 2 (MH2) domain in SMAD4

    RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20210514

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p13 Primary Assembly

    Genomic

    1. NC_000018.10 Reference GRCh38.p13 Primary Assembly

      Range
      51030213..51085042
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
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