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SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

Identity

Other namesMADH4
DPC4
JIP
HGNC (Hugo) SMAD4
LocusID (NCBI) 4089
Location 18q21.2
Location_base_pair Starts at 48556583 and ends at 48611411 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

DNA/RNA

Description The gene encompasses 49.5 kb of DNA; 13 exons.
Transcription 3220 nucleotides mRNA.

Protein

Description 552 amino acids; 60.4 kDa protein. Smad4 belongs to the Darfwin family of proteins which harbours two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively. Smad4 in the basal state is found mostly as a homo-oligomer, most likely a trimer.
Expression Ubiquitous.
Function Smad4 is an intracellular mediator of TGF-beta family and activin type 1 receptor. Smad4 mediate TGF-beta signaling to regulate cell growth and differentiation. TGF-beta stimulation leads to phosphorylation and activation of Smad2 and Smad3, which form complexes with Smad4 that accumulate in the nucleus and regulate transcription of target genes. By interacting with DNA-binding proteins, Smad complexes then positively or negatively regulate the transcription of target genes.
Homology With the other members of the Darfwin/Smad family.

Implicated in

Entity Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Disease Juvenile polyposis and hereditary hemorrhagic telangiectasia syndrome is an autosomal dominant disorder with distinct clinical features. One form corresponding to a predisposition to gastrointestinal polyps and cancer may be associated with mutations in Smad4 gene.
Oncogenesis Polyps are formed by inactivation of the Smad4 gene through germline mutations and loss of the unaffected wild-type allele.
  
Entity Pancreatic carcinoma
Disease 90% of pancreatic carcinomas show allelic loss at 18q. A consensus region of homozygous deletion at 18q21.1 was found in one third of pancreatic carcinomas and intragenic mutations were found in another 20% of this tumor type.
Prognosis Smad4 expression may be a molecular prognostic marker for pancreatic carcinoma. A lower patient survival may be associated with loss of Smad4 expression.
Oncogenesis Smad4 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription. Most of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2) which interfere with the homo-oligomer formation of Smad4 protein and hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-beta signaling.
  

To be noted

Mutation of Smad4 is seen also in approximately 15% of colorectal carcinomas and occasionally (less than 10%) in the rest of human cancers such as breast, ovarian, hepatocellular or head and neck squamous cell carcinomas.

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors ProstateOverviewID5041

External links

Nomenclature
HGNC (Hugo)SMAD4   6770
Cards
AtlasSMAD4ID371
Entrez_Gene (NCBI)SMAD4  4089  SMAD family member 4
GeneCards (Weizmann)SMAD4
Ensembl (Hinxton)ENSG00000141646 [Gene_View]  chr18:48556583-48611411 [Contig_View]  SMAD4 [Vega]
ICGC DataPortalENSG00000141646
cBioPortalSMAD4
AceView (NCBI)SMAD4
Genatlas (Paris)SMAD4
WikiGenes4089
SOURCE (Princeton)NM_005359
Genomic and cartography
GoldenPath (UCSC)SMAD4  -  18q21.2   chr18:48556583-48611411 +  18q21.1   [Description]    (hg19-Feb_2009)
EnsemblSMAD4 - 18q21.1 [CytoView]
Mapping of homologs : NCBISMAD4 [Mapview]
OMIM139210   174900   175050   600993   
Gene and transcription
Genbank (Entrez)AK290770 AU120224 BC002379 BM701399 BX647129
RefSeq transcript (Entrez)NM_005359
RefSeq genomic (Entrez)AC_000150 NC_000018 NC_018929 NG_013013 NT_010966 NW_001838468 NW_004929410
Consensus coding sequences : CCDS (NCBI)SMAD4
Cluster EST : UnigeneHs.75862 [ NCBI ]
CGAP (NCI)Hs.75862
Alternative Splicing : Fast-db (Paris)GSHG0014050
Alternative Splicing GalleryENSG00000141646
Gene ExpressionSMAD4 [ NCBI-GEO ]     SMAD4 [ SEEK ]   SMAD4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13485 (Uniprot)
NextProtQ13485  [Medical]
With graphics : InterProQ13485
Splice isoforms : SwissVarQ13485 (Swissvar)
Domaine pattern : Prosite (Expaxy)MH1 (PS51075)    MH2 (PS51076)   
Domains : Interpro (EBI)Dwarfin [organisation]   MAD_homology1_Dwarfin-type [organisation]   MAD_homology_MH1 [organisation]   SMAD_dom-like [organisation]   SMAD_dom_Dwarfin-type [organisation]   SMAD_FHA_domain [organisation]  
Related proteins : CluSTrQ13485
Domain families : Pfam (Sanger)MH1 (PF03165)    MH2 (PF03166)   
Domain families : Pfam (NCBI)pfam03165    pfam03166   
Domain families : Smart (EMBL)DWA (SM00523)  DWB (SM00524)  
DMDM Disease mutations4089
Blocks (Seattle)Q13485
PDB (SRS)1DD1    1G88    1MR1    1U7F    1U7V    1YGS   
PDB (PDBSum)1DD1    1G88    1MR1    1U7F    1U7V    1YGS   
PDB (IMB)1DD1    1G88    1MR1    1U7F    1U7V    1YGS   
PDB (RSDB)1DD1    1G88    1MR1    1U7F    1U7V    1YGS   
Human Protein AtlasENSG00000141646 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ13485
HPRD02995
IPIIPI00013404   IPI00909962   IPI01014946   
Protein Interaction databases
DIP (DOE-UCLA)Q13485
IntAct (EBI)Q13485
FunCoupENSG00000141646
BioGRIDSMAD4
InParanoidQ13485
Interologous Interaction database Q13485
IntegromeDBSMAD4
STRING (EMBL)SMAD4
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  core promoter proximal region sequence-specific DNA binding  protein binding transcription factor activity  RNA polymerase II transcription factor binding transcription factor activity  RNA polymerase II transcription factor binding  branching involved in ureteric bud morphogenesis  response to hypoxia  in utero embryonic development  gastrulation with mouth forming second  atrioventricular valve formation  epithelial to mesenchymal transition involved in endocardial cushion formation  positive regulation of cell proliferation involved in heart valve morphogenesis  cardiac septum development  brainstem development  DNA binding  chromatin binding  sequence-specific DNA binding transcription factor activity  protein binding  collagen binding  nucleus  nucleoplasm  transcription factor complex  transcription factor complex  nucleolus  cytoplasm  centrosome  cytosol  transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  transforming growth factor beta receptor signaling pathway  transforming growth factor beta receptor signaling pathway  SMAD protein complex assembly  axon guidance  endoderm development  mesoderm development  cell proliferation  negative regulation of cell proliferation  gene expression  positive regulation of epithelial to mesenchymal transition  positive regulation of pathway-restricted SMAD protein phosphorylation  neural crest cell differentiation  regulation of transforming growth factor beta receptor signaling pathway  negative regulation of cell growth  BMP signaling pathway  BMP signaling pathway  positive regulation of transforming growth factor beta receptor signaling pathway  positive regulation of BMP signaling pathway  transforming growth factor beta receptor, common-partner cytoplasmic mediator activity  activin responsive factor complex  somite rostral/caudal axis specification  regulation of transforming growth factor beta2 production  atrioventricular canal development  endothelial cell activation  negative regulation of protein catabolic process  identical protein binding  protein homodimerization activity  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of transcription, DNA-dependent  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  developmental growth  neuron fate commitment  sebaceous gland development  formation of anatomical boundary  regulation of binding  regulation of hair follicle development  palate development  positive regulation of SMAD protein import into nucleus  SMAD protein signal transduction  negative regulation of cell death  endocardial cell differentiation  I-SMAD binding  R-SMAD binding  SMAD protein complex  response to transforming growth factor beta  metanephric mesenchyme morphogenesis  nephrogenic mesenchyme morphogenesis  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  core promoter proximal region sequence-specific DNA binding  protein binding transcription factor activity  RNA polymerase II transcription factor binding transcription factor activity  RNA polymerase II transcription factor binding  branching involved in ureteric bud morphogenesis  response to hypoxia  in utero embryonic development  gastrulation with mouth forming second  atrioventricular valve formation  epithelial to mesenchymal transition involved in endocardial cushion formation  positive regulation of cell proliferation involved in heart valve morphogenesis  cardiac septum development  brainstem development  DNA binding  chromatin binding  sequence-specific DNA binding transcription factor activity  protein binding  collagen binding  nucleus  nucleoplasm  transcription factor complex  transcription factor complex  nucleolus  cytoplasm  centrosome  cytosol  transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  transforming growth factor beta receptor signaling pathway  transforming growth factor beta receptor signaling pathway  SMAD protein complex assembly  axon guidance  endoderm development  mesoderm development  cell proliferation  negative regulation of cell proliferation  gene expression  positive regulation of epithelial to mesenchymal transition  positive regulation of pathway-restricted SMAD protein phosphorylation  neural crest cell differentiation  regulation of transforming growth factor beta receptor signaling pathway  negative regulation of cell growth  BMP signaling pathway  BMP signaling pathway  positive regulation of transforming growth factor beta receptor signaling pathway  positive regulation of BMP signaling pathway  transforming growth factor beta receptor, common-partner cytoplasmic mediator activity  activin responsive factor complex  somite rostral/caudal axis specification  regulation of transforming growth factor beta2 production  atrioventricular canal development  endothelial cell activation  negative regulation of protein catabolic process  identical protein binding  protein homodimerization activity  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of transcription, DNA-dependent  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  developmental growth  neuron fate commitment  sebaceous gland development  formation of anatomical boundary  regulation of binding  regulation of hair follicle development  palate development  positive regulation of SMAD protein import into nucleus  SMAD protein signal transduction  negative regulation of cell death  endocardial cell differentiation  I-SMAD binding  R-SMAD binding  SMAD protein complex  response to transforming growth factor beta  metanephric mesenchyme morphogenesis  nephrogenic mesenchyme morphogenesis  
Pathways : BIOCARTACTCF: First Multivalent Nuclear Factor [Genes]    TGF beta signaling pathway [Genes]    Role of Tob in T-cell activation [Genes]    ALK in cardiac myocytes [Genes]    WNT Signaling Pathway [Genes]    Cell Cycle: G1/S Check Point [Genes]    NFkB activation by Nontypeable Hemophilus influenzae [Genes]   
Pathways : KEGGFoxO signaling pathway    Cell cycle    Wnt signaling pathway    TGF-beta signaling pathway    Hippo signaling pathway    Adherens junction    Hepatitis B    HTLV-I infection    Pathways in cancer    Colorectal cancer    Pancreatic cancer    Chronic myeloid leukemia   
Protein Interaction DatabaseSMAD4
Wikipedia pathwaysSMAD4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SMAD4
snp3D : Map Gene to Disease4089
SNP (GeneSNP Utah)SMAD4
SNP : HGBaseSMAD4
Genetic variants : HAPMAPSMAD4
Exome VariantSMAD4
1000_GenomesSMAD4 
ICGC programENSG00000141646 
Cancer Gene: CensusSMAD4 
Somatic Mutations in Cancer : COSMICSMAD4 
CONAN: Copy Number AnalysisSMAD4 
Mutations and Diseases : HGMDSMAD4
Genomic VariantsSMAD4  SMAD4 [DGVbeta]
dbVarSMAD4
ClinVarSMAD4
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM139210    174900    175050    600993   
MedgenSMAD4
GENETestsSMAD4
Disease Genetic AssociationSMAD4
Huge Navigator SMAD4 [HugePedia]  SMAD4 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneSMAD4
Homology/Alignments : Family Browser (UCSC)SMAD4
Phylogenetic Trees/Animal Genes : TreeFamSMAD4
Chemical/Protein Interactions : CTD4089
Chemical/Pharm GKB GenePA30527
Drug Sensitivity SMAD4
Clinical trialSMAD4
Cancer Resource (Charite)ENSG00000141646
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=SMAD4
Probes
Litterature
PubMed463 Pubmed reference(s) in Entrez
CoreMineSMAD4
iHOPSMAD4

Bibliography

DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE
Science (New York, N.Y.). 1996 ; 271 (5247) : 350-353.
PMID 8553070
 
DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma.
Kim SK, Fan Y, Papadimitrakopoulou V, Clayman G, Hittelman WN, Hong WK, Lotan R, Mao L
Cancer research. 1996 ; 56 (11) : 2519-2521.
PMID 8653689
 
DPC4 gene in various tumor types.
Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA Jr, Meltzer PS, Hahn SA, Kern SE
Cancer research. 1996 ; 56 (11) : 2527-2530.
PMID 8653691
 
Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.
Thiagalingam S, Lengauer C, Leach FS, Schutte M, Hahn SA, Overhauser J, Willson JK, Markowitz S, Hamilton SR, Kern SE, Kinzler KW, Vogelstein B
Nature genetics. 1996 ; 13 (3) : 343-346.
PMID 8673134
 
Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.
Houlston R, Bevan S, Williams A, Young J, Dunlop M, Rozen P, Eng C, Markie D, Woodford-Richens K, Rodriguez-Bigas MA, Leggett B, Neale K, Phillips R, Sheridan E, Hodgson S, Iwama T, Eccles D, Bodmer W, Tomlinson I
Human molecular genetics. 1998 ; 7 (12) : 1907-1912.
PMID 9811934
 
A gene for familial juvenile polyposis maps to chromosome 18q21.1.
Howe JR, Ringold JC, Summers RW, Mitros FA, Nishimura DY, Stone EM
American journal of human genetics. 1998 ; 62 (5) : 1129-1136.
PMID 9545410
 
Mutations in the SMAD4/DPC4 gene in juvenile polyposis.
Howe JR, Roth S, Ringold JC, Summers RW, Jˆ§rvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA
Science (New York, N.Y.). 1998 ; 280 (5366) : 1086-1088.
PMID 9582123
 
Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.
Shioda T, Lechleider RJ, Dunwoodie SL, Li H, Yahata T, de Caestecker MP, Fenner MH, Roberts AB, Isselbacher KJ
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (17) : 9785-9790.
PMID 9707553
 
Human Smad3 and Smad4 are sequence-specific transcription activators.
Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE
Molecular cell. 1998 ; 1 (4) : 611-617.
PMID 9660945
 
Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells.
Zhou S, Buckhaults P, Zawel L, Bunz F, Riggins G, Dai JL, Kern SE, Kinzler KW, Vogelstein B
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (5) : 2412-2416.
PMID 9482899
 
Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.
Friedl W, Kruse R, Uhlhaas S, Stolte M, Schartmann B, Keller KM, Jungck M, Stern M, Loff S, Back W, Propping P, Jenne DE
Genes, chromosomes & cancer. 1999 ; 25 (4) : 403-406.
PMID 10398437
 
Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.
Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, Hishima T, Koike M, Shitara N, Iwama T, Utsunomiya J, Kuroki T, Mori T
Oncogene. 1999 ; 18 (20) : 3098-3103.
PMID 10340381
 
Smad2 and Smad4 gene mutations in hepatocellular carcinoma.
Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M
Oncogene. 1999 ; 18 (34) : 4879-4883.
PMID 10490821
 
Distinct oligomeric states of SMAD proteins in the transforming growth factor-beta pathway.
Jayaraman L, Massague J
The Journal of biological chemistry. 2000 ; 275 (52) : 40710-40717.
PMID 11018029
 
Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.
Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P
Human genetics. 2002 ; 111 (1) : 108-111.
PMID 12136244
 
Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.
Inman GJ, Nicolˆ°s FJ, Hill CS
Molecular cell. 2002 ; 10 (2) : 283-294.
PMID 12191474
 
Role of Smad4 (DPC4) inactivation in human cancer.
Miyaki M, Kuroki T
Biochemical and biophysical research communications. 2003 ; 306 (4) : 799-804.
PMID 12821112
 
A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).
Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA
Lancet. 2004 ; 363 (9412) : 852-859.
PMID 15031030
 
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Contributor(s)

Written08-2004Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire

Citation

This paper should be referenced as such :
Saffroy, R ; Lemoine, A ; Debuire, B
SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):287-288.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/SMAD4ID371.html

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