Mothers against decapentaplegic homolog 7

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Reviewed, UniProtKB/Swiss-Prot O15105 (SMAD7_HUMAN)

Last modified June 16, 2009. Version 93. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Mothers against decapentaplegic homolog 7
      Short name=Mothers against DPP homolog 7
Alternative name(s):
    SMAD 7
      Short name=Smad7
    hSMAD7

Gene names

Name:	SMAD7
Synonyms:	MADH7, MADH8

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	426 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Ref.10 Ref.14
Subunit structure	Interacts with TGF-beta type I receptor. Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with SMURF2. Ref.14 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17
Subcellular location	Nucleus. Cytoplasm. Note: Interaction with NEDD4L or RNF111 induces translocation from the nucleus to the cytoplasm. Ref.13 Ref.17
Tissue specificity	Ubiquitous with higher expression in the lung and vascular endothelium.
Induction	By TGF-beta.
Post-translational modification	Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription By similarity. Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation. In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation. Acetylation prevents ubiquitination and degradation mediated by SMURF1.
Involvement in disease	Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:612229]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber. Ref.19
Sequence similarities	Belongs to the dwarfin/SMAD family. Contains 1 MH1 (MAD homology 1) domain. Contains 1 MH2 (MAD homology 2) domain.

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Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	BMP signaling pathway Inferred from Experiment. Source: Reactome adherens junction assembly Inferred from mutant phenotype. Source: UniProtKB artery morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB cellular protein complex localization Inferred from direct assay. Source: UniProtKB negative regulation of BMP signaling pathway Inferred from direct assay. Source: UniProtKB negative regulation of cell migration Traceable author statement. Source: UniProtKB negative regulation of epithelial to mesenchymal transition Traceable author statement. Source: UniProtKB negative regulation of pathway-restricted SMAD protein phosphorylation Inferred from direct assay. Source: UniProtKB negative regulation of peptidyl-serine phosphorylation Inferred from direct assay. Source: UniProtKB negative regulation of peptidyl-threonine phosphorylation Inferred from direct assay. Source: UniProtKB negative regulation of protein ubiquitination Inferred from direct assay. Source: UniProtKB negative regulation of specific transcription from RNA polymerase II promoter Inferred from direct assay. Source: UniProtKB negative regulation of transcription by competitive promoter binding Inferred from direct assay. Source: UniProtKB negative regulation of transcription factor activity Inferred from direct assay. Source: UniProtKB negative regulation of ubiquitin-protein ligase activity Inferred from direct assay. Source: UniProtKB pathway-restricted SMAD protein phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of anti-apoptosis Traceable author statement. Source: UniProtKB positive regulation of cell-cell adhesion Inferred from direct assay. Source: UniProtKB positive regulation of proteasomal ubiquitin-dependent protein catabolic process Inferred from direct assay. Source: UniProtKB positive regulation of protein ubiquitination Inferred from direct assay. Source: UniProtKB protein stabilization Inferred from direct assay. Source: UniProtKB regulation of activin receptor signaling pathway Inferred from direct assay. Source: UniProtKB regulation of ventricular cardiomyocyte membrane depolarization Inferred by curator. Source: UniProtKB response to laminar fluid shear stress Ref.2 Inferred from expression pattern. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW ventricular cardiac muscle morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB ventricular septum morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytosol Inferred from Experiment. Source: Reactome transcription factor complex Inferred from electronic annotation. Source: InterPro
Molecular function	I-SMAD binding Ref.2 Inferred from physical interaction. Source: UniProtKB activin binding Inferred from physical interaction. Source: UniProtKB beta-catenin binding Inferred from physical interaction. Source: UniProtKB promoter binding Inferred from direct assay. Source: UniProtKB transcription factor activity Inferred from electronic annotation. Source: InterPro transforming growth factor beta receptor, inhibitory cytoplasmic mediator activity Ref.2 Inferred from direct assay. Source: UniProtKB type I transforming growth factor beta receptor binding Inferred from physical interaction. Source: UniProtKB ubiquitin binding Inferred from direct assay. Source: UniProtKB ubiquitin protein ligase binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 426

426

Mothers against decapentaplegic homolog 7

PRO_0000090872

Regions

Domain

64 – 207

144

MH1

Domain

261 – 426

166

MH2

Region

208 – 217

Important for interaction with SMURF2

Motif

208 – 211

PY-motif

Compositional bias

27 – 35

Poly-Gly

Compositional bias

49 – 56

Poly-Gly

Compositional bias

207 – 210

Poly-Pro

Amino acid modifications

Modified residue

N6-acetyllysine; alternate Ref.12

Modified residue

N6-acetyllysine; alternate Ref.12

Modified residue

249

Phosphoserine By similarity

Cross-link

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate Ref.12

Cross-link

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate Ref.12

Experimental info

Mutagenesis

K → A: Loss of acetylation, and of SMURF1-dependent degradation; when associated with A-70. Ref.12

Mutagenesis

K → A: Loss of acetylation, and of SMURF1-dependent degradation; when associated with A-64. Ref.12

Mutagenesis

207 – 211

Missing: Diminishes interaction with SMURF2. Ref.10

Mutagenesis

211

Y → A: Diminishes interaction with SMURF2 and reduces inhibition of TGF-beta signaling. Ref.10

Mutagenesis

409 – 426

Missing: 90% reduction in TGF-beta receptor binding. Ref.1

Sequence conflict

G → C in AAB81354. Ref.3

Secondary structure

426

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

O15105-1 [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 5B76EC986776C102
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FASTA

426

46,426

        10         20         30         40         50         60 
MFRTKRSALV RRLWRSRAPG GEDEEEGAGG GGGGGELRGE GATDSRAHGA GGGGPGRAGC 

        70         80         90        100        110        120 
CLGKAVRGAK GHHHPHPPAA GAGAAGGAEA DLKALTHSVL KKLKERQLEL LLQAVESRGG 

       130        140        150        160        170        180 
TRTACLLLPG RLDCRLGPGA PAGAQPAQPP SSYSLPLLLC KVFRWPDLRH SSEVKRLCCC 

       190        200        210        220        230        240 
ESYGKINPEL VCCNPHHLSR LCELESPPPP YSRYPMDFLK PTADCPDAVP SSAETGGTNY 

       250        260        270        280        290        300 
LAPGGLSDSQ LLLEPGDRSH WCVVAYWEEK TRVGRLYCVQ EPSLDIFYDL PQGNGFCLGQ 

       310        320        330        340        350        360 
LNSDNKSQLV QKVRSKIGCG IQLTREVDGV WVYNRSSYPI FIKSATLDNP DSRTLLVHKV 

       370        380        390        400        410        420 
FPGFSIKAFD YEKAYSLQRP NDHEFMQQPW TGFTVQISFV KGWGQCYTRQ FISSCPCWLE 


VIFNSR

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling." Hayashi H., Abdollah S., Qiu Y., Cai J., Xu Y.-Y., Grinnell B.W., Richardson M.A., Topper J.N., Gimbrone M.A. Jr., Wrana J.L., Falb D. Cell 89:1165-1173(1997) [PubMed: 9215638] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 409-ARG--ARG-426. Tissue: Umbilical vein endothelial cell.
[2]	"Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium." Topper J.N., Cai J., Qui Y., Anderson K.R., Xu Y.-Y., Deeds J.D., Feeley R., Gimeno C.J., Woolf E.A., Tayber O., Mays G.G., Sampson B.A., Schoen F.J., Gimbrone M.A. Jr., Falb D. Proc. Natl. Acad. Sci. U.S.A. 94:9314-9319(1997) [PubMed: 9256479] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Umbilical vein endothelial cell.
[3]	"Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling." Nakao A., Afrakhte M., Moren A., Nakayama T., Christian J.L., Heuchel R., Itoh S., Kawabata M., Heldin N.-E., Heldin C.-H., ten Dijke P. Nature 389:631-635(1997) [PubMed: 9335507] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[4]	Hagiwara K., Yang K., McMenamin M.G., Freeman A.H., Bennett W.P., Nagashima M., Minter A.R., Miyazono K., Takenoshita S., Harris C.C. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[6]	"TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract] Cited for: REVIEW.
[7]	"Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells." Verschueren K., Huylebroeck D. Cytokine Growth Factor Rev. 10:187-199(1999) [PubMed: 10647776] [Abstract] Cited for: REVIEW.
[8]	"The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract] Cited for: REVIEW.
[9]	"TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract] Cited for: REVIEW.
[10]	"Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-beta receptor for degradation." Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H., Thomsen G.H., Wrana J.L. Mol. Cell 6:1365-1375(2000) [PubMed: 11163210] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF TYR-211 AND 207-PRO--TYR-211.
[11]	"Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads." Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S. EMBO J. 20:4132-4142(2001) [PubMed: 11483516] [Abstract] Cited for: INTERACTION WITH STAMBP.
[12]	"Control of Smad7 stability by competition between acetylation and ubiquitination." Gronroos E., Hellman U., Heldin C.H., Ericsson J. Mol. Cell 10:483-493(2002) [PubMed: 12408818] [Abstract] Cited for: INTERACTION WITH EP300, ACETYLATION AT LYS-64 AND LYS-70, UBIQUITINATION AT LYS-64 AND LYS-70, MUTAGENESIS OF LYS-64 AND LYS-70.
[13]	"Arkadia amplifies TGF-beta superfamily signaling through degradation of Smad7." Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A., Ebina M., Nukiwa T., Miyazawa K., Imamura T., Miyazono K. EMBO J. 22:6458-6470(2003) [PubMed: 14657019] [Abstract] Cited for: INTERACTION WITH RNF111, UBIQUITINATION, SUBCELLULAR LOCATION.
[14]	"GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor." Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X. J. Cell Biol. 164:291-300(2004) [PubMed: 14718519] [Abstract] Cited for: FUNCTION, INTERACTION WITH PPP1R15A.
[15]	"Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation." Kim B.-C., Lee H.-J., Park S.H., Lee S.R., Karpova T.S., McNally J.G., Felici A., Lee D.K., Kim S.-J. Mol. Cell. Biol. 24:2251-2262(2004) [PubMed: 14993265] [Abstract] Cited for: INTERACTION WITH COPS5.
[16]	"Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain." Ogunjimi A.A., Briant D.J., Pece-Barbara N., Le Roy C., Di Guglielmo G.M., Kavsak P., Rasmussen R.K., Seet B.T., Sicheri F., Wrana J.L. Mol. Cell 19:297-308(2005) [PubMed: 16061177] [Abstract] Cited for: INTERACTION WITH SMURF2.
[17]	"Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia." Liu W., Rui H., Wang J., Lin S., He Y., Chen M., Li Q., Ye Z., Zhang S., Chan S.C., Chen Y.-G., Han J., Lin S.-C. EMBO J. 25:1646-1658(2006) [PubMed: 16601693] [Abstract] Cited for: INTERACTION WITH AXIN1 AND AXIN2, UBIQUITINATION, SUBCELLULAR LOCATION.
[18]	"An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2." Chong P.A., Lin H., Wrana J.L., Forman-Kay J.D. J. Biol. Chem. 281:17069-17075(2006) [PubMed: 16641086] [Abstract] Cited for: STRUCTURE BY NMR OF 203-217 IN COMPLEX WITH SMURF2.
[19]	"A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk." Members of the CORGI consortium Broderick P., Carvajal-Carmona L., Pittman A.M., Webb E., Howarth K., Rowan A., Lubbe S., Spain S., Sullivan K., Fielding S., Jaeger E., Vijayakrishnan J., Kemp Z., Gorman M., Chandler I., Papaemmanuil E., Penegar S., Wood W. Houlston R.S. Nat. Genet. 39:1315-1317(2007) [PubMed: 17934461] [Abstract] Cited for: INVOLVEMENT IN CRCS3.

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Cross-references

Sequence databases

AF010193 mRNA. Translation: AAB81246.1.
AF015261 mRNA. Translation: AAB81354.1.
AF026559

AF026558 Genomic DNA. Translation: AAL68977.1.
BC074818 mRNA. Translation: AAH74818.2.
BC074819 mRNA. Translation: AAH74819.2.

IPI

IPI00005079.

RefSeq

NP_005895.1.

UniGene

Hs.465087

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2DJY	NMR	-	B	203-217	[»]

ModBase

Search...

PTM databases

PhosphoSite

O15105.

Proteomic databases

PRIDE

O15105.

Genome annotation databases

Ensembl

ENSG00000101665. Homo sapiens. [Contig view]

GeneID

4092.

KEGG

hsa:4092.

Organism-specific databases

GeneCards

GC18M044700.

H-InvDB

HIX0039705.

HGNC

HGNC:6773. SMAD7.

MIM

602932. gene.
612229. phenotype.

PharmGKB

PA134875286.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O15105.

HOVERGEN

O15105.

OMA

O15105. SAYSLPL.

Enzyme and pathway databases

Pathway_Interaction_DB

bmppathway. BMP receptor signaling.
ifngpathway. IFN-gamma pathway.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
hdac_classi_pathway. Signaling events mediated by HDAC Class I.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_12034. Signaling by BMP.
REACT_6844. Signaling by TGF beta.

Gene expression databases

ArrayExpress

O15105.

Bgee

O15105.

CleanEx

HS_SMAD7.

GermOnline

ENSG00000101665. Homo sapiens.

Family and domain databases

InterPro

IPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
[Graphical view]

Gene3D

G3DSA:3.90.520.10. MAD_MH1. 1 hit.
G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit.

PANTHER

PTHR13703. Dwarfin. 1 hit.

Pfam

PF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]

SMART

SM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]

PROSITE

PS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

16046.

SOURCE

Search...

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Entry information

Entry name

SMAD7_HUMAN

Accession

Primary (citable) accession number: O15105
Secondary accession number(s): O14740, Q6DK23

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 4, 2001
Last sequence update:	January 1, 1998
Last modified:	June 16, 2009
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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