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Q13485 (SMAD4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 163. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mothers against decapentaplegic homolog 4

Short name=MAD homolog 4
Short name=Mothers against DPP homolog 4
Alternative name(s):
Deletion target in pancreatic carcinoma 4
SMAD family member 4
Short name=SMAD 4
Short name=Smad4
Short name=hSMAD4
Gene names
Name:SMAD4
Synonyms:DPC4, MADH4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length552 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8 By similarity. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.

Subunit structure

Interacts with CITED2 By similarity. Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) By similarity. Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.28 Ref.29

Subcellular location

Cytoplasm. Nucleus. Note: Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD. PDPK1 prevents its nuclear translocation in response to TGF-beta. Ref.18 Ref.20

Domain

The MH1 domain is required for DNA binding. Ref.11

The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import. Ref.11

Post-translational modification

Phosphorylated by PDPK1. Ref.20

Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling.

Involvement in disease

Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
Note: The gene represented in this entry may be involved in disease pathogenesis.

Juvenile polyposis syndrome (JPS) [MIM:174900]: 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.30 Ref.31

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 etiology of this association is unknown.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.32

Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
Note: The disease may be caused by mutations affecting the gene represented in this entry.

SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.

Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.34 Ref.35

Sequence similarities

Belongs to the dwarfin/SMAD family.

Contains 1 MH1 (MAD homology 1) domain.

Contains 1 MH2 (MAD homology 2) domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   LigandDNA-binding
Metal-binding
Zinc
   PTMAcetylation
Isopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processBMP signaling pathway

Inferred from direct assay Ref.7. Source: BHF-UCL

SMAD protein complex assembly

Inferred from direct assay PubMed 10823886. Source: BHF-UCL

SMAD protein signal transduction

Inferred from direct assay Ref.9PubMed 9732876. Source: BHF-UCL

atrioventricular canal development

Inferred from electronic annotation. Source: Ensembl

atrioventricular valve formation

Inferred from electronic annotation. Source: Ensembl

axon guidance

Inferred from electronic annotation. Source: Ensembl

brainstem development

Inferred from electronic annotation. Source: Ensembl

branching involved in ureteric bud morphogenesis

Inferred from electronic annotation. Source: Ensembl

cardiac septum development

Inferred from electronic annotation. Source: Ensembl

cell proliferation

Inferred from electronic annotation. Source: Ensembl

developmental growth

Inferred from electronic annotation. Source: Ensembl

endocardial cell differentiation

Inferred from electronic annotation. Source: Ensembl

endoderm development

Inferred from electronic annotation. Source: Ensembl

endothelial cell activation

Inferred from electronic annotation. Source: Ensembl

epithelial to mesenchymal transition involved in endocardial cushion formation

Inferred from electronic annotation. Source: Ensembl

formation of anatomical boundary

Inferred from electronic annotation. Source: Ensembl

gastrulation with mouth forming second

Inferred from electronic annotation. Source: Ensembl

gene expression

Traceable author statement. Source: Reactome

in utero embryonic development

Inferred from electronic annotation. Source: Ensembl

intracellular signal transduction

Inferred from direct assay Ref.7. Source: GOC

mesoderm development

Inferred from electronic annotation. Source: Ensembl

metanephric mesenchyme morphogenesis

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell death

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell growth

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein catabolic process

Inferred from mutant phenotype PubMed 20097766. Source: BHF-UCL

negative regulation of transcription from RNA polymerase II promoter

Traceable author statement. Source: Reactome

negative regulation of transcription, DNA-templated

Inferred from direct assay Ref.2. Source: BHF-UCL

nephrogenic mesenchyme morphogenesis

Inferred from electronic annotation. Source: Ensembl

neural crest cell differentiation

Inferred from electronic annotation. Source: Ensembl

neuron fate commitment

Inferred from electronic annotation. Source: Ensembl

palate development

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of BMP signaling pathway

Inferred from mutant phenotype PubMed 19366699. Source: BHF-UCL

positive regulation of SMAD protein import into nucleus

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of cell proliferation involved in heart valve morphogenesis

Inferred from electronic annotation. Source: Ensembl

positive regulation of epithelial to mesenchymal transition

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of pathway-restricted SMAD protein phosphorylation

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 18832382. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from direct assay Ref.9. Source: UniProtKB

positive regulation of transforming growth factor beta receptor signaling pathway

Inferred from direct assay PubMed 19328798. Source: BHF-UCL

regulation of binding

Inferred from electronic annotation. Source: Ensembl

regulation of hair follicle development

Inferred from electronic annotation. Source: Ensembl

regulation of transforming growth factor beta receptor signaling pathway

Inferred from mutant phenotype Ref.2. Source: BHF-UCL

regulation of transforming growth factor beta2 production

Inferred from mutant phenotype PubMed 12411310. Source: BHF-UCL

response to hypoxia

Inferred from mutant phenotype PubMed 12411310. Source: BHF-UCL

response to transforming growth factor beta

Inferred from direct assay Ref.9. Source: UniProtKB

sebaceous gland development

Inferred from electronic annotation. Source: Ensembl

somite rostral/caudal axis specification

Inferred from electronic annotation. Source: Ensembl

transcription initiation from RNA polymerase II promoter

Traceable author statement. Source: Reactome

transcription, DNA-templated

Traceable author statement. Source: Reactome

transforming growth factor beta receptor signaling pathway

Inferred from direct assay Ref.7PubMed 9732876. Source: BHF-UCL

   Cellular_componentSMAD protein complex

Inferred from direct assay PubMed 18832382. Source: UniProtKB

activin responsive factor complex

Inferred from direct assay Ref.7. Source: BHF-UCL

centrosome

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from direct assay PubMed 12161428PubMed 9311995Ref.7. Source: BHF-UCL

cytosol

Traceable author statement. Source: Reactome

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 12161428PubMed 9311995Ref.7. Source: BHF-UCL

transcription factor complex

Inferred from physical interaction PubMed 12374795. Source: UniProtKB

   Molecular_functionI-SMAD binding

Inferred from physical interaction PubMed 9256479. Source: BHF-UCL

R-SMAD binding

Inferred from physical interaction Ref.2PubMed 9111321PubMed 9311995PubMed 9732876. Source: BHF-UCL

RNA polymerase II transcription factor binding transcription factor activity

Inferred from electronic annotation. Source: Ensembl

chromatin binding

Inferred from electronic annotation. Source: Ensembl

core promoter proximal region sequence-specific DNA binding

Inferred from direct assay PubMed 18832382. Source: UniProtKB

identical protein binding

Inferred from physical interaction PubMed 9111321. Source: BHF-UCL

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein homodimerization activity

Inferred from physical interaction Ref.2. Source: BHF-UCL

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: Ensembl

transcription regulatory region DNA binding

Inferred from direct assay PubMed 17438144. Source: BHF-UCL

transforming growth factor beta receptor, common-partner cytoplasmic mediator activity

Inferred from direct assay Ref.7. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 552552Mothers against decapentaplegic homolog 4
PRO_0000090861

Regions

Domain18 – 142125MH1
Domain323 – 552230MH2
Region275 – 32046SAD
Compositional bias451 – 46616Poly-Ala

Sites

Metal binding711Zinc By similarity
Metal binding1151Zinc By similarity
Metal binding1271Zinc By similarity
Metal binding1321Zinc By similarity
Site5151Necessary for heterotrimerization

Amino acid modifications

Modified residue371N6-acetyllysine Ref.23
Modified residue4281N6-acetyllysine Ref.23
Modified residue5071N6-acetyllysine Ref.23
Cross-link519Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Natural variant131N → S. Ref.25
Corresponds to variant rs281875323 [ dbSNP | Ensembl ].
VAR_066870
Natural variant1011W → G.
Corresponds to variant rs2229083 [ dbSNP | Ensembl ].
VAR_052022
Natural variant1301P → S in a colorectal cancer sample; somatic mutation. Ref.33
VAR_036475
Natural variant3301E → G in JPS. Ref.31
Corresponds to variant rs281875324 [ dbSNP | Ensembl ].
VAR_022833
Natural variant3511D → N in a colorectal cancer sample; somatic mutation. Ref.33
VAR_036476
Natural variant3521G → R in JP/HHT and JPS. Ref.31 Ref.32
Corresponds to variant rs121912581 [ dbSNP | Ensembl ].
VAR_019571
Natural variant3611R → C in JPS. Ref.30
Corresponds to variant rs80338963 [ dbSNP | Ensembl ].
VAR_019572
Natural variant3611R → H in a colorectal cancer sample; somatic mutation. Ref.33
VAR_036477
Natural variant3861G → D in JP/HHT. Ref.32
Corresponds to variant rs28936393 [ dbSNP | Ensembl ].
VAR_019573
Natural variant4931D → H in pancreatic carcinoma. Ref.1
Corresponds to variant rs28936392 [ dbSNP | Ensembl ].
VAR_011380
Natural variant5001I → M in MYHRS. Ref.35
Corresponds to variant rs281875320 [ dbSNP | Ensembl ].
VAR_067602
Natural variant5001I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. Ref.34 Ref.35
Corresponds to variant rs281875321 [ dbSNP | Ensembl ].
VAR_067603
Natural variant5001I → V in MYHRS. Ref.34 Ref.35
Corresponds to variant rs281875322 [ dbSNP | Ensembl ].
VAR_067604

Experimental info

Mutagenesis4161R → S: No effect on heterotrimerization. Partially diminished transcriptional activation. Ref.28
Mutagenesis4961R → S: No effect on heterotrimerization. Partially diminished transcriptional activation.
Mutagenesis5021R → S: No effect on heterotrimerization. Greatly reduced transcriptional activation. Ref.28
Mutagenesis5151R → S: Reduced heterotrimerization. Ref.28
Mutagenesis5191K → R: Abolishes ubiquitination. Ref.22

Secondary structure

......................................... 552
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q13485 [UniParc].

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

FASTA55260,439
        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 

« Hide

References

« Hide '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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Muscle.
[7]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors."
Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K.
EMBO J. 17:4056-4065(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT.
[9]"Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator."
Shioda T., Lechleider R.J., Dunwoodie S.L., Li H., Yahata T., de Caestecker M.P., Fenner M.H., Roberts A.B., Isselbacher K.J.
Proc. Natl. Acad. Sci. U.S.A. 95:9785-9790(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CITED1.
[10]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZNF423.
[11]"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] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF SAD DOMAIN.
[12]"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] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11/LKB1 AND STK11IP, INTERACTION WITH STK11/LKB1 AND STK11IP.
[13]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH COPS5.
[14]"TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling."
Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M., Karpova T.S., McNally J.G., Roberts A.B.
EMBO J. 22:4465-4477(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH VPS39.
[15]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DACH1.
[16]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZNF521.
[17]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRIM33.
[18]"Nuclear targeting of transforming growth factor-beta-activated Smad complexes."
Chen H.B., Rud J.G., Lin K., Xu L.
J. Biol. Chem. 280:21329-21336(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, SUBCELLULAR LOCATION.
[19]"Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS."
Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., Song H., Ye Q.
Nucleic Acids Res. 34:6314-6326(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RBPMS.
[20]"3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins."
Seong H.A., Jung H., Kim K.T., Ha H.
J. Biol. Chem. 282:12272-12289(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, INTERACTION WITH PDPK1.
[21]"TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal."
Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L.
Nat. Cell Biol. 10:837-848(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH WWTR1.
[22]"FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination."
Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L., Adorno M., Martello G., Stinchfield M.J., Soligo S., Morsut L., Inui M., Moro S., Modena N., Argenton F., Newfeld S.J., Piccolo S.
Cell 136:123-135(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH USP9X, UBIQUITINATION, MUTAGENESIS OF LYS-519.
[23]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-37; LYS-428 AND LYS-507, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[24]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[25]"Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension."
Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M., Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M., Gibbs J.S., Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B., Coulet F., Soubrier F. expand/collapse author list , Humbert M., Morrell N.W., Trembath R.C., Machado R.D.
Hum. Mutat. 32:1385-1389(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: POSSIBLE INVOLVEMENT IN PULMONARY HYPERTENSION, VARIANT SER-13.
[26]"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] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
[27]"Crystal structure of a transcriptionally active Smad4 fragment."
Qin B., Lam S.S., Lin K.
Structure 7:1493-1503(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
[28]"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] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552 OF WILD TYPE AND MUTANTS ARG-416; ARG-502 AND ARG-515 IN COMPLEX WITH SMAD3, SUBUNIT, MUTAGENESIS OF ARG-416; ARG-502 AND ARG-515.
[29]"Structural basis of heteromeric smad protein assembly in TGF-beta signaling."
Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J., De Caestecker M., Lin K.
Mol. Cell 15:813-823(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 314-552 IN COMPLEX WITH SMAD2 OR SMAD3, SUBUNIT.
[30]"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] [Europe PMC] [Abstract]
Cited for: VARIANT JPS CYS-361.
[31]"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] [Europe PMC] [Abstract]
Cited for: VARIANTS JPS GLY-330 AND ARG-352.
[32]"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] [Europe PMC] [Abstract]
Cited for: VARIANTS JP/HHT ARG-352 AND ASP-386.
[33]"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. expand/collapse author list , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E.
Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361.
[34]"A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome."
Caputo V., Cianetti L., Niceta M., Carta C., Ciolfi A., Bocchinfuso G., Carrani E., Dentici M.L., Biamino E., Belligni E., Garavelli L., Boccone L., Melis D., Andria G., Gelb B.D., Stella L., Silengo M., Dallapiccola B., Tartaglia M.
Am. J. Hum. Genet. 90:161-169(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MYHRS THR-500 AND VAL-500.
[35]"Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome."
Le Goff C., Mahaut C., Abhyankar A., Le Goff W., Serre V., Afenjar A., Destree A., di Rocco M., Heron D., Jacquemont S., Marlin S., Simon M., Tolmie J., Verloes A., Casanova J.L., Munnich A., Cormier-Daire V.
Nat. Genet. 44:85-88(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS MYHRS MET-500; THR-500 AND VAL-500, CHARACTERIZATION OF VARIANT MYHRS THR-500.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF045447 expand/collapse EMBL AC list , AF045438, AF045439, AF045440, AF045441, AF045442, AF045443, AF045444, AF045445, AF045446 Genomic DNA. Translation: AAC03051.1.
U44378 mRNA. Translation: AAA91041.1.
AK290770 mRNA. Translation: BAF83459.1.
CH471096 Genomic DNA. Translation: EAW62985.1.
BC002379 mRNA. Translation: AAH02379.1.
PIRS71811.
RefSeqNP_005350.1. NM_005359.5.
UniGeneHs.75862.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1DD1X-ray2.62A/B/C285-552[»]
1G88X-ray3.00A/B/C285-552[»]
1MR1X-ray2.85A/B319-552[»]
1U7FX-ray2.60B314-552[»]
1U7VX-ray2.70B314-549[»]
1YGSX-ray2.10A319-552[»]
DisProtDP00464.
ProteinModelPortalQ13485.
SMRQ13485. Positions 10-138, 285-552.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110264. 190 interactions.
DIPDIP-31512N.
IntActQ13485. 71 interactions.
MINTMINT-244037.
STRING9606.ENSP00000341551.

PTM databases

PhosphoSiteQ13485.

Polymorphism databases

DMDM13959561.

Proteomic databases

PaxDbQ13485.
PeptideAtlasQ13485.
PRIDEQ13485.

Protocols and materials databases

DNASU4089.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000342988; ENSP00000341551; ENSG00000141646.
ENST00000398417; ENSP00000381452; ENSG00000141646.
GeneID4089.
KEGGhsa:4089.
UCSCuc002lfb.4. human.

Organism-specific databases

CTD4089.
GeneCardsGC18P048494.
HGNCHGNC:6770. SMAD4.
HPACAB002312.
HPA019154.
MIM114500. phenotype.
139210. phenotype.
174900. phenotype.
175050. phenotype.
260350. phenotype.
600993. gene.
neXtProtNX_Q13485.
Orphanet1333. Familial pancreatic carcinoma.
329971. Generalized juvenile polyposis/juvenile polyposis coli.
774. Hereditary hemorrhagic telangiectasia.
2588. Myhre syndrome.
PharmGKBPA30527.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG286923.
HOGENOMHOG000286019.
HOVERGENHBG053353.
InParanoidQ13485.
KOK04501.
OMAAQPATYH.
OrthoDBEOG712TW5.
PhylomeDBQ13485.
TreeFamTF314923.

Enzyme and pathway databases

ReactomeREACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_71. Gene Expression.
SignaLinkQ13485.

Gene expression databases

ArrayExpressQ13485.
BgeeQ13485.
CleanExHS_SMAD4.
GenevestigatorQ13485.

Family and domain databases

Gene3D2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProIPR013790. Dwarfin.
IPR003619. MAD_homology1_Dwarfin-type.
IPR013019. MAD_homology_MH1.
IPR017855. SMAD_dom-like.
IPR001132. SMAD_dom_Dwarfin-type.
IPR008984. SMAD_FHA_domain.
[Graphical view]
PANTHERPTHR13703. PTHR13703. 1 hit.
PfamPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSMAD4. human.
EvolutionaryTraceQ13485.
GeneWikiMothers_against_decapentaplegic_homolog_4.
GenomeRNAi4089.
NextBio16030.
PROQ13485.
SOURCESearch...

Entry information

Entry nameSMAD4_HUMAN
AccessionPrimary (citable) accession number: Q13485
Secondary accession number(s): A8K405
Entry history
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 163 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 18

Human chromosome 18: entries, gene names and cross-references to MIM