SMAD4 (mothers against decapentaplegic homolog 4 (Drosophila))

Identity

Other names	MADH4
	DPC4
	JIP
HGNC	SMAD4
Location	18q21.1
Location_base_pair	Starts at 46810581 and ends at 46865409 bp from pter ( according to hg18-Mar_2006).

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.

External links

	Nomenclature
HGNC	SMAD4   6770
Entrez_Gene	SMAD4  4089  SMAD family member 4
	Cards
Atlas	SMAD4ID371
GeneCards	SMAD4
Ensembl	SMAD4 [Search_View]   ENSG00000141646 [Gene_View]
Genatlas	SMAD4
GeneLynx	SMAD4
eGenome	SMAD4
euGene	4089
	Genomic and cartography
GoldenPath	SMAD4  -  18q21.1   chr18:46810581-46865409 +  18q21.1   [Description]    (hg18-Mar_2006)
Ensembl	SMAD4 - 18q21.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SMAD4
	Gene and transcription
Genbank	AK290770 [ ENTREZ ]
Genbank	AU120224 [ ENTREZ ]
Genbank	BC002379 [ ENTREZ ]
Genbank	BM701399 [ ENTREZ ]
Genbank	BX647129 [ ENTREZ ]
RefSeq	NM_005359 [ SRS ]    NM_005359 [ ENTREZ ]
RefSeq	AC_000061 [ SRS ]    AC_000061 [ ENTREZ ]
RefSeq	AC_000150 [ SRS ]    AC_000150 [ ENTREZ ]
RefSeq	NC_000018 [ SRS ]    NC_000018 [ ENTREZ ]
RefSeq	NT_010966 [ SRS ]    NT_010966 [ ENTREZ ]
RefSeq	NW_001838468 [ SRS ]    NW_001838468 [ ENTREZ ]
RefSeq	NW_927106 [ SRS ]    NW_927106 [ ENTREZ ]
AceView	SMAD4 AceView - NCBI
Unigene	Hs.75862 [ SRS ]    Hs.75862 [ NCBI ]     HS75862 [ spliceNest ]
Fast-db	4546 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q13485 [ SRS]    Q13485 [ EXPASY ]     Q13485 [ INTERPRO ]     Q13485 [ UNIPROT ]
Prosite	PS51075 MH1 [ SRS ]    PS51075 MH1 [ Expasy ]
Prosite	PS51076 MH2 [ SRS ]    PS51076 MH2 [ Expasy ]
Interpro	IPR013790 Dwarfin [ SRS ]    IPR013790 Dwarfin [ EBI ]
Interpro	IPR013019 MAD_MH1 [ SRS ]    IPR013019 MAD_MH1 [ EBI ]
Interpro	IPR003619 MH1_Dwarfin-type [ SRS ]    IPR003619 MH1_Dwarfin-type [ EBI ]
Interpro	IPR017855 SMAD_dom-like [ SRS ]    IPR017855 SMAD_dom-like [ EBI ]
Interpro	IPR001132 SMAD_dom_Dwarfin-type [ SRS ]    IPR001132 SMAD_dom_Dwarfin-type [ EBI ]
CluSTr	Q13485
Pfam	PF03165 MH1 [ SRS ]    PF03165 MH1 [ Sanger ]    pfam03165 [ NCBI-CDD ]
Pfam	PF03166 MH2 [ SRS ]    PF03166 MH2 [ Sanger ]    pfam03166 [ NCBI-CDD ]
Smart	SM00523 DWA [EMBL]
Smart	SM00524 DWB [EMBL]
Blocks	Q13485
PDB	1DD1 [ SRS ]    1DD1 [ PdbSum ],   1DD1 [ IMB ]   1DD1 [ RSDB ]
PDB	1G88 [ SRS ]    1G88 [ PdbSum ],   1G88 [ IMB ]   1G88 [ RSDB ]
PDB	1MR1 [ SRS ]    1MR1 [ PdbSum ],   1MR1 [ IMB ]   1MR1 [ RSDB ]
PDB	1U7F [ SRS ]    1U7F [ PdbSum ],   1U7F [ IMB ]   1U7F [ RSDB ]
PDB	1U7V [ SRS ]    1U7V [ PdbSum ],   1U7V [ IMB ]   1U7V [ RSDB ]
PDB	1YGS [ SRS ]    1YGS [ PdbSum ],   1YGS [ IMB ]   1YGS [ RSDB ]
HPRD	02995
	Protein Interaction databases
DIP	Q13485
IntAct	Q13485
	Polymorphism : SNP, mutations, diseases
OMIM	174900;175050;600993    [ map ]
GENECLINICS	174900;175050;600993
SNP	SMAD4 [dbSNP-NCBI]
SNP	NM_005359 [SNP-NCI]
SNP	SMAD4 [GeneSNPs - Utah]  SMAD4] [HGBASE - SRS]
HAPMAP	SMAD4 [HAPMAP]
COSMIC	SMAD4 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	SMAD4
	General knowledge
Family Browser	SMAD4 [UCSC Family Browser]
SOURCE	NM_005359
SMD	Hs.75862
SAGE	Hs.75862
GO	ureteric bud branching [Amigo]  ureteric bud branching
GO	response to hypoxia [Amigo]  response to hypoxia
GO	kidney development [Amigo]  kidney development
GO	transcription factor activity [Amigo]  transcription factor activity
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	nucleoplasm [Amigo]  nucleoplasm
GO	transcription factor complex [Amigo]  transcription factor complex
GO	cytoplasm [Amigo]  cytoplasm
GO	cytosol [Amigo]  cytosol
GO	transcription [Amigo]  transcription
GO	SMAD protein complex assembly [Amigo]  SMAD protein complex assembly
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	anterior/posterior pattern formation [Amigo]  anterior/posterior pattern formation
GO	transcription activator activity [Amigo]  transcription activator activity
GO	regulation of transforming growth factor beta receptor signaling pathway [Amigo]  regulation of transforming growth factor beta receptor signaling pathway
GO	negative regulation of cell growth [Amigo]  negative regulation of cell growth
GO	BMP signaling pathway [Amigo]  BMP signaling pathway
GO	regulation of transforming growth factor-beta2 production [Amigo]  regulation of transforming growth factor-beta2 production
GO	protein homodimerization activity [Amigo]  protein homodimerization activity
GO	sequence-specific DNA binding [Amigo]  sequence-specific DNA binding
GO	negative regulation of transcription, DNA-dependent [Amigo]  negative regulation of transcription, DNA-dependent
GO	positive regulation of transcription from RNA polymerase II promoter [Amigo]  positive regulation of transcription from RNA polymerase II promoter
GO	SMAD binding [Amigo]  SMAD binding
GO	regulation of binding [Amigo]  regulation of binding
KEGG	Cell cycle
KEGG	Wnt signaling pathway
KEGG	TGF-beta signaling pathway
KEGG	Adherens junction
KEGG	Colorectal cancer
PubGene	SMAD4
TreeFam	SMAD4
CTD	4089 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	SMAD4 Related clones (RZPD - Berlin)
	PubMed
PubMed	229 Pubmed reference(s) in Entrez

Bibliography

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Contributor(s)

Written	08-2004	Raphael 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. August 2004 . URL : http://AtlasGeneticsOncology.org/Genes/SMAD4ID371.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Tue Oct 14 21:25:44 2008