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

Gene ID: 4089, updated on 26-Sep-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
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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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