Mothers against decapentaplegic homolog 4

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Reviewed, UniProtKB/Swiss-Prot Q13485 (SMAD4_HUMAN)

Last modified November 25, 2008. Version 102. History...

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

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Names and origin

Protein names

Recommended name:
    Mothers against decapentaplegic homolog 4
      Short name=Mothers against DPP homolog 4
Alternative name(s):
    SMAD 4
    hSMAD4
    Deletion target in pancreatic carcinoma 4

Gene names

Name:	SMAD4
Synonyms:	DPC4, MADH4

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	552 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	Common mediator of signal transduction by TGF-beta (transforming growth factor) superfamily; SMAD4 is the common SMAD (co-SMAD). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. May act as a tumor suppressor.
Subunit structure	May form trimers with receptor-regulated SMAD (R-SMAD). Found in a ternary complex composed of SMAD4, STK11 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes.
Subcellular location	Cytoplasm. Nucleus. Note= Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD.
Involvement in disease	Defects in SMAD4 are a cause of pancreatic carcinoma [MIM:260350]. Defects in SMAD4 are a cause of juvenile polyposis syndrome (JPS) [MIM:174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. Defects in SMAD4 are a cause of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]. JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown. Defects in SMAD4 may be a cause of colorectal cancer (CRC) [MIM:114500].
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
Coding sequence diversity	Polymorphism
Disease	Disease mutation
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	BMP signaling pathway Inferred from Experiment. Source: Reactome SMAD protein complex assembly Inferred from direct assay. Source: UniProtKB negative regulation of cell growth Ref.2 Inferred from direct assay. Source: UniProtKB negative regulation of transcription, DNA-dependent Ref.2 Inferred from direct assay. Source: UniProtKB regulation of transforming growth factor beta receptor signaling pathway Ref.2 Inferred from mutant phenotype. Source: UniProtKB regulation of transforming growth factor-beta2 production Inferred from mutant phenotype. Source: UniProtKB response to hypoxia Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytosol Inferred from Experiment. Source: Reactome transcription factor complex Inferred from physical interaction. Source: UniProtKB
Molecular function	SMAD binding Ref.2 Inferred from physical interaction. Source: UniProtKB protein homodimerization activity Ref.2 Inferred from physical interaction. Source: UniProtKB sequence-specific DNA binding Inferred from direct assay. Source: UniProtKB transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
CEBPB	P17676	1	EBI-347263,EBI-969696
DACH1	Q9UI36	3	EBI-347263,EBI-347111
SKI	P12755	2	EBI-347263,EBI-347281

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 552

552

Mothers against decapentaplegic homolog 4

PRO_0000090861

Regions

Domain

18 – 142

125

MH1

Domain

323 – 552

230

MH2

Region

275 – 320

SAD

Compositional bias

451 – 466

Poly-Ala

Natural variations

Natural variant

130

P → S in a colorectal cancer sample; somatic mutation.

VAR_036475

Natural variant

330

E → G in JPS.

VAR_022833

Natural variant

351

D → N in a colorectal cancer sample; somatic mutation.

VAR_036476

Natural variant

352

G → R in JP/HHT and JPS.

VAR_019571

Natural variant

361

R → C in JPS.

VAR_019572

Natural variant

361

R → H in a colorectal cancer sample; somatic mutation.

VAR_036477

Natural variant

386

G → D in JP/HHT.

VAR_019573

Natural variant

493

D → H in pancreatic carcinoma.

VAR_011380

Secondary structure

552

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

Q13485-1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 7EE3C4647712DA90
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FASTA

552

60,439

        10         20         30         40         50         60 
MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA 

        70         80         90        100        110        120 
ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD 

       130        140        150        160        170        180 
LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPSSMMVKD EYVHDFEGQP SLSTEGHSIQ 

       190        200        210        220        230        240 
TIQHPPSNRA STETYSTPAL LAPSESNATS TANFPNIPVA STSQPASILG GSHSEGLLQI 

       250        260        270        280        290        300 
ASGPQPGQQQ NGFTGQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH 

       310        320        330        340        350        360 
YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV DGYVDPSGGD 

       370        380        390        400        410        420 
RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR CLSDHAVFVQ SYYLDREAGR 

       430        440        450        460        470        480 
APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ AATAQAAAAA QAAAVAGNIP GPGSVGGIAP 

       490        500        510        520        530        540 
AISLSAAAGI GVDDLRRLCI LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL 

       550 
HTMPIADPQP LD

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1." Hahn S.A., Schutte M., Shamsul Hoque A.T.M., Moskaluk C.A., da Costa L.T., Rozenblum E., Weinstein C.L., Fischer A., Yeo C.J., Hruban R.H., Kern S.E. Science 271:350-353(1996) [PubMed: 8553070] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT PANCREATIC CARCINOMA HIS-493. Tissue: Fetal brain.
[2]	"Receptor-associated Mad homologues synergize as effectors of the TGF-beta response." Zhang Y., Feng X.-H., Wu R.-Y., Derynck R. Nature 383:168-172(1996) [PubMed: 8774881] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[3]	"Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma." Moskaluk C.A., Hruban R.H., Schutte M., Lietman A.S., Smyrk T., Fusaro L., Fusaro R., Lynch J., Yeo C.J., Jackson C.E., Lynch H.T., Kern S.E. Diagn. Mol. Pathol. 6:85-90(1997) [PubMed: 9098646] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"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: Muscle.
[5]	"Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes." Liu F., Pouponnot C., Massague J. Genes Dev. 11:3157-3167(1997) [PubMed: 9389648] [Abstract] Cited for: FUNCTION.
[6]	"OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways." Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A., Massague J. Cell 100:229-240(2000) [PubMed: 10660046] [Abstract] Cited for: INTERACTION WITH ZNF423.
[7]	"The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain." de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S., Hill C.S., Shioda T., Roberts A.B., Lechleider R.J. J. Biol. Chem. 275:2115-2122(2000) [PubMed: 10636916] [Abstract] Cited for: CHARACTERIZATION OF SAD DOMAIN.
[8]	"LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1." Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M., Ashworth A. Hum. Mol. Genet. 10:2869-2877(2001) [PubMed: 11741830] [Abstract] Cited for: IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11 AND STK11IP, INTERACTS WITH STK11 AND STK11IP.
[9]	"Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation." Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X. EMBO Rep. 3:171-176(2002) [PubMed: 11818334] [Abstract] Cited for: INTERACTION WITH COPS5.
[10]	"DACH1 inhibits transforming growth factor-beta signaling through binding Smad4." Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K., Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G. J. Biol. Chem. 278:51673-51684(2003) [PubMed: 14525983] [Abstract] Cited for: INTERACTION WITH DACH1.
[11]	"Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells." Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N., De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M., Morrone G., Venuta S. Blood 103:2062-2070(2004) [PubMed: 14630787] [Abstract] Cited for: INTERACTION WITH ZNF521.
[12]	"Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase." Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M., Piccolo S. Cell 121:87-99(2005) [PubMed: 15820681] [Abstract] Cited for: INTERACTION WITH TRIM33.
[13]	"A structural basis for mutational inactivation of the tumour suppressor Smad4." Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P. Nature 388:87-93(1997) [PubMed: 9214508] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
[14]	"Crystal structure of a transcriptionally active Smad4 fragment." Qin B., Lam S.S., Lin K. Structure 7:1493-1503(1999) [PubMed: 10647180] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
[15]	"The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization." Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K. Nat. Struct. Biol. 8:248-253(2001) [PubMed: 11224571] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552.
[16]	"TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract] Cited for: REVIEW.
[17]	"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.
[18]	"The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract] Cited for: REVIEW.
[19]	"TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract] Cited for: REVIEW.
[20]	"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 M.A., Leggett B., Neale K., Phillips R., Sheridan E., Hodgson S., Iwama T., Eccles D., Bodmer W., Tomlinson I. Hum. Mol. Genet. 7:1907-1912(1998) [PubMed: 9811934] [Abstract] Cited for: VARIANT JPS CYS-361.
[21]	"Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis." Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L., Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M., Vogelstein B., Howe J.R. Ann. Surg. Oncol. 9:901-906(2002) [PubMed: 12417513] [Abstract] Cited for: VARIANTS JPS GLY-330 AND ARG-352.
[22]	"A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)." Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L., Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A. Lancet 363:852-859(2004) [PubMed: 15031030] [Abstract] Cited for: VARIANTS JP/HHT ARG-352 AND ASP-386.
[23]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361.
+	Additional computationally mapped references.

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Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

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Cross-references

Sequence databases

AF045447

AF045446 Genomic DNA. Translation: AAC03051.1.
U44378 mRNA. Translation: AAA91041.1.
BC002379 mRNA. Translation: AAH02379.1.

PIR

S71811.

RefSeq

NP_005350.1.

UniGene

Hs.592888
Hs.75862

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DD1	X-ray	2.62	A/B/C	285-552	[»]
1G88	X-ray	3.00	A/B/C	285-552	[»]
1MR1	X-ray	2.85	A/B	319-552	[»]
1U7F	X-ray	2.60	B	314-552	[»]
1U7V	X-ray	2.70	B	314-549	[»]
1YGS	X-ray	2.10	A	319-552	[»]