SMAD2 (mothers against decapentaplegic homolog 2 (Drosophila))

Identity

Other names	MADH2
	MADR2
	JV18-1
	JV18
Hugo	SMAD2
Location	18q21.1

DNA/RNA

Description	The gene encompasses 90 kb of DNA; 12 exons.
Transcription	2285 nucleotides mRNA. Alternative splicing was described.

Protein

Description	467 amino acids; 52 kDa protein. A short 438 amino acids isoform was also described. Smad2 belongs to the Darfwin proteins family which are composed of two conserved amino- and carboxyl-terminal domains known as MH1 and MH2, respectively.
Expression	High expression levels in skeletal muscle, heart and placenta.
Function	Smad2 is an intracellular mediator of TGF-beta family and activin type 1 receptor. Smad2 mediate TGF-beta signaling to regulate cell growth and differentiation. Smad2 is released from cytoplasmic retention by TGF-beta receptor-mediated phosphorylation. The phosphorylated Smad2 then forms a heterodimeric complex with Smad4, and this complex translocates from cytoplasm into nucleus. 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

Disease	Colorectal cancers
Oncogenesis	Smad2 was proposed to be a tumor suppressor gene that may function to disrupt TGF-beta signaling. Inactivating mutations in Smad2 have been found in various cancer including colorectal carcinomas. The majority of tumor-derived mutations cluster in the carboxy-terminal MH2 domain, and some of these have been shown to disrupt TGF-beta signaling by blocking receptor-dependent phosphorylation or by preventing heterodimeric interactions between Smads. A mutation at position 133 in the amino-terminal MH1 domain has also been associated with colorectal carcinoma. Nevertheless, loss of Smad2 activation and/or expression was related to occur in less than 10% of colorectal cancers.

To be noted

Smad2 gene has also been found alterated in lung carcinomas, cervical carcinomas and hepatocellular carcinomas.

External links

	Nomenclature
Hugo	SMAD2
GDB	SMAD2
Entrez_Gene	SMAD2  4087  SMAD family member 2
	Cards
Atlas	SMAD2ID370
GeneCards	SMAD2
Ensembl	SMAD2 [Search_View]   ENSG00000175387 [Gene_View]
Genatlas	SMAD2
GeneLynx	SMAD2
eGenome	SMAD2
euGene	4087
	Genomic and cartography
GoldenPath	SMAD2  -  18q21.1   chr18:43613465-43710924 -  18q21.1   [Description]    (hg18-Mar_2006)
Ensembl	SMAD2 - 18q21.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SMAD2
	Gene and transcription
Genbank	AA081871 [ ENTREZ ]
Genbank	AA418737 [ ENTREZ ]
Genbank	AF027964 [ ENTREZ ]
Genbank	AI087928 [ ENTREZ ]
Genbank	AI765747 [ ENTREZ ]
RefSeq	NM_001003652 [ SRS ]    NM_001003652 [ ENTREZ ]
RefSeq	NM_005901 [ SRS ]    NM_005901 [ ENTREZ ]
RefSeq	AC_000061 [ SRS ]    AC_000061 [ ENTREZ ]
RefSeq	NC_000018 [ SRS ]    NC_000018 [ ENTREZ ]
RefSeq	NT_010966 [ SRS ]    NT_010966 [ ENTREZ ]
RefSeq	NW_927106 [ SRS ]    NW_927106 [ ENTREZ ]
AceView	SMAD2 AceView - NCBI
Unigene	Hs.705764 [ SRS ]    Hs.705764 [ NCBI ]     HS705764 [ spliceNest ]
Fast-db	4185 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q15796 [ SRS]    Q15796 [ EXPASY ]     Q15796 [ INTERPRO ]
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	IPR001132 MH2_Dwarfin-type [ SRS ]    IPR001132 MH2_Dwarfin-type [ EBI ]
CluSTr	Q15796
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	Q15796
PDB	1DEV [ SRS ]    1DEV [ PdbSum ],   1DEV [ IMB ]   1DEV [ RSDB ]
PDB	1KHX [ SRS ]    1KHX [ PdbSum ],   1KHX [ IMB ]   1KHX [ RSDB ]
PDB	1U7V [ SRS ]    1U7V [ PdbSum ],   1U7V [ IMB ]   1U7V [ RSDB ]
HPRD	03221
	Protein Interaction databases
DIP	Q15796
IntAct	Q15796
	Polymorphism : SNP, mutations, diseases
OMIM	601366    [ map ]
GENECLINICS	601366
SNP	SMAD2 [dbSNP-NCBI]
SNP	NM_001003652 [SNP-NCI]
SNP	NM_005901 [SNP-NCI]
SNP	SMAD2 [GeneSNPs - Utah]  SMAD2] [HGBASE - SRS]
HAPMAP	SMAD2 [HAPMAP]
COSMIC	SMAD2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	SMAD2
	General knowledge
Family Browser	SMAD2 [UCSC Family Browser]
SOURCE	NM_001003652
SOURCE	NM_005901
SMD	Hs.705764
SAGE	Hs.705764
GO	mesoderm formation [Amigo]  mesoderm formation
GO	double-stranded DNA binding [Amigo]  double-stranded DNA binding
GO	transcription factor activity [Amigo]  transcription factor activity
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	transcription factor complex [Amigo]  transcription factor complex
GO	cytoplasm [Amigo]  cytoplasm
GO	transcription [Amigo]  transcription
GO	intracellular signaling cascade [Amigo]  intracellular signaling cascade
GO	transcription factor binding [Amigo]  transcription factor binding
GO	transcription factor binding [Amigo]  transcription factor binding
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	cell fate commitment [Amigo]  cell fate commitment
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	paraxial mesoderm morphogenesis [Amigo]  paraxial mesoderm morphogenesis
GO	regulation of binding [Amigo]  regulation of binding
BIOCARTA	TGF beta signaling pathway    [Genes]
KEGG	Cell cycle
KEGG	Wnt signaling pathway
KEGG	TGF-beta signaling pathway
KEGG	Adherens junction
KEGG	Colorectal cancer
PubGene	SMAD2
TreeFam	SMAD2
CTD	4087 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	SMAD2 Related clones (RZPD - Berlin)
	PubMed
PubMed	161 Pubmed reference(s) in LocusLink

Bibliography

A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.

Baker JC, Harland RM

Genes & development. 1996 ; 10 (15) : 1880-1889.

PMID 8756346

MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.

Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L

Cell. 1996 ; 86 (4) : 543-552.

PMID 8752209

MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling.

Macˆ‚as-Silva M, Abdollah S, Hoodless PA, Pirone R, Attisano L, Wrana JL

Cell. 1996 ; 87 (7) : 1215-1224.

PMID 8980228

Mad-related genes in the human.

Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B

Nature genetics. 1996 ; 13 (3) : 347-349.

PMID 8673135

Somatic in vivo alterations of the JV18-1 gene at 18q21 in human lung cancers.

Uchida K, Nagatake M, Osada H, Yatabe Y, Kondo M, Mitsudomi T, Masuda A, Takahashi T, Takahashi T

Cancer research. 1996 ; 56 (24) : 5583-5585.

PMID 8971158

Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway.

Nakao A, Rˆijer E, Imamura T, Souchelnytskyi S, Stenman G, Heldin CH, ten Dijke P

The Journal of biological chemistry. 1997 ; 272 (5) : 2896-2900.

PMID 9006934

Somatic alterations of the SMAD-2 gene in human colorectal cancers.

Takagi Y, Koumura H, Futamura M, Aoki S, Ymaguchi K, Kida H, Tanemura H, Shimokawa K, Saji S

British journal of cancer. 1998 ; 78 (9) : 1152-1155.

PMID 9820171

Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming growth factor-beta and activin signal transduction pathway.

Takenoshita S, Mogi A, Nagashima M, Yang K, Yagi K, Hanyu A, Nagamachi Y, Miyazono K, Hagiwara K

Genomics. 1998 ; 48 (1) : 1-11.

PMID 9503010

Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers.

Takenoshita S, Tani M, Mogi A, Nagashima M, Nagamachi Y, Bennett WP, Hagiwara K, Harris CC, Yokota J

Carcinogenesis. 1998 ; 19 (5) : 803-807.

PMID 9635866

Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo.

Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ

Cell. 1998 ; 92 (6) : 797-808.

PMID 9529255

Evidence that Smad2 is a tumor suppressor implicated in the control of cellular invasion.

Prunier C, Mazars A, Noˆ“ V, Bruyneel E, Mareel M, Gespach C, Atfi A

The Journal of biological chemistry. 1999 ; 274 (33) : 22919-22922.

PMID 10438456

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

Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution.

Funaba M, Mathews LS

Molecular endocrinology (Baltimore, Md.). 2000 ; 14 (10) : 1583-1591.

PMID 11043574

Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal.

Roth S, Johansson M, Loukola A, Peltomˆ§ki P, Jˆ§rvinen H, Mecklin JP, Aaltonen LA

Journal of medical genetics. 2000 ; 37 (4) : 298-300.

PMID 10819637

Structural basis of Smad2 recognition by the Smad anchor for receptor activation.

Wu G, Chen YG, Ozdamar B, Gyuricza CA, Chong PA, Wrana JL, Massaguˆ© J, Shi Y

Science (New York, N.Y.). 2000 ; 287 (5450) : 92-97.

PMID 10615055

Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway.

Xu J, Attisano L

Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (9) : 4820-4825.

PMID 10781087

Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.

Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massaguˆ© J, Shi Y

Molecular cell. 2001 ; 8 (6) : 1277-1289.

PMID 11779503

Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus.

Xu L, Kang Y, Cˆl S, Massaguˆ© J

Molecular cell. 2002 ; 10 (2) : 271-282.

PMID 12191473

Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer.

Maliekal TT, Antony ML, Nair A, Paulmurugan R, Karunagaran D

Oncogene. 2003 ; 22 (31) : 4889-4897.

PMID 12894231

Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis.

Xie W, Rimm DL, Lin Y, Shih WJ, Reiss M

Cancer journal (Sudbury, Mass.). 2003 ; 9 (4) : 302-312.

PMID 12967141

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written	07-2004	Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire

Citation

This paper should be referenced as such :

Saffroy R, Lemoine A, Debuire B . SMAD2 (mothers against decapentaplegic homolog 2 (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. July 2004 . URL : http://AtlasGeneticsOncology.org/Genes/SMAD2ID370.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:27:05 2008