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P97471 (SMAD4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 136. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·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 homolog
SMAD family member 4
Short name=SMAD 4
Short name=Smad4
Gene names
Name:Smad4
Synonyms:Dpc4, Madh4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length551 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 By similarity. 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.

Subunit structure

Monomer By similarity. Heterotrimer; with a C-terminally phosphorylated R-SMAD molecule and to form the transcriptionally active SMAD2/3-SMAD4 complex By similarity. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2 By similarity. 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 By similarity. Interactions with VPS39 and SMAD2 may be mutually exclusive By similarity. Ref.6

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Note: In the cytoplasm in the absence of ligand. Migration to the nucleus when complexed with R-SMAD. PDPK1 prevents its nuclear translocation By similarity.

Tissue specificity

Ubiquitous.

Domain

The MH1 domain is required for DNA binding By similarity.

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

Post-translational modification

Phosphorylated by PDPK1 By similarity.

Monoubiquitinated on Lys-518 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 By similarity.

Disruption phenotype

Conditional knockout in muscle leads to muscle atrophy and weakness. Mutant mice loose significantly more muscle mass after denervation as compared to wild-type animals and show excessive proteolysis in denervated muscle. The loss of maximal absolute force after fasting is greater in mutant mice than in controls.

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
   LigandDNA-binding
Metal-binding
Zinc
   PTMAcetylation
Isopeptide bond
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processBMP signaling pathway

Inferred from electronic annotation. Source: Ensembl

SMAD protein complex assembly

Inferred from electronic annotation. Source: Ensembl

SMAD protein signal transduction

Inferred from electronic annotation. Source: Ensembl

anterior/posterior pattern specification

Inferred from mutant phenotype PubMed 15215210. Source: MGI

atrioventricular canal development

Inferred from genetic interaction PubMed 21330551. Source: BHF-UCL

atrioventricular valve formation

Inferred from genetic interaction PubMed 21330551. Source: BHF-UCL

axon guidance

Inferred from mutant phenotype PubMed 21300867. Source: MGI

brainstem development

Inferred from mutant phenotype PubMed 21300867. Source: MGI

branching involved in ureteric bud morphogenesis

Inferred from genetic interaction PubMed 15925496. Source: MGI

cardiac septum development

Inferred from genetic interaction PubMed 21330551. Source: BHF-UCL

cell proliferation

Inferred from mutant phenotype PubMed 9420335. Source: MGI

developmental growth

Inferred from mutant phenotype PubMed 9420335. Source: MGI

endocardial cell differentiation

Inferred from mutant phenotype PubMed 21330551. Source: BHF-UCL

endoderm development

Inferred from mutant phenotype PubMed 9420335. Source: MGI

endothelial cell activation

Inferred from mutant phenotype PubMed 21330551. Source: BHF-UCL

epithelial to mesenchymal transition involved in endocardial cushion formation

Inferred from mutant phenotype PubMed 21330551. Source: BHF-UCL

formation of anatomical boundary

Inferred from mutant phenotype PubMed 9420335. Source: MGI

gastrulation

Inferred from mutant phenotype PubMed 9420335. Source: MGI

gastrulation with mouth forming second

Inferred from mutant phenotype PubMed 15215210. Source: MGI

in utero embryonic development

Inferred from mutant phenotype PubMed 9420335. Source: MGI

kidney development

Inferred from mutant phenotype PubMed 15342483. Source: MGI

mesoderm development

Inferred from mutant phenotype PubMed 9420335. Source: MGI

metanephric mesenchyme morphogenesis

Inferred from mutant phenotype PubMed 15342483. Source: UniProtKB

negative regulation of cell death

Inferred from mutant phenotype PubMed 15342483. Source: UniProtKB

negative regulation of cell growth

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from genetic interaction PubMed 10626800PubMed 11197776PubMed 15925496PubMed 9506519. Source: MGI

negative regulation of protein catabolic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: Ensembl

nephrogenic mesenchyme morphogenesis

Inferred from mutant phenotype PubMed 15342483. Source: UniProtKB

neural crest cell differentiation

Inferred from mutant phenotype PubMed 19793887. Source: MGI

neuron fate commitment

Inferred from mutant phenotype PubMed 17698011. Source: MGI

palate development

Inferred from mutant phenotype PubMed 14691138. Source: BHF-UCL

positive regulation of BMP signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of SMAD protein import into nucleus

Inferred from mutant phenotype PubMed 14691138. Source: BHF-UCL

positive regulation of cell proliferation involved in heart valve morphogenesis

Inferred from mutant phenotype PubMed 21330551. Source: BHF-UCL

positive regulation of epithelial to mesenchymal transition

Inferred from mutant phenotype PubMed 14691138. Source: BHF-UCL

positive regulation of pathway-restricted SMAD protein phosphorylation

Inferred from mutant phenotype PubMed 14691138. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 21330551. Source: BHF-UCL

positive regulation of transcription, DNA-templated

Inferred from direct assay PubMed 15282343. Source: MGI

positive regulation of transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

regulation of binding

Inferred from direct assay PubMed 15282343. Source: MGI

regulation of cell proliferation

Inferred from mutant phenotype PubMed 10708962. Source: MGI

regulation of hair follicle development

Inferred from mutant phenotype PubMed 18692037. Source: MGI

regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 12270938. Source: MGI

regulation of transforming growth factor beta2 production

Inferred from electronic annotation. Source: Ensembl

response to hypoxia

Inferred from electronic annotation. Source: Ensembl

sebaceous gland development

Inferred from mutant phenotype PubMed 18692037. Source: MGI

somite rostral/caudal axis specification

Inferred from mutant phenotype PubMed 9420335. Source: MGI

tissue morphogenesis

Inferred from mutant phenotype PubMed 9420335. Source: MGI

transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 21330551. Source: GOC

transforming growth factor beta receptor signaling pathway

Inferred from genetic interaction PubMed 18212064. Source: MGI

   Cellular_componentSMAD protein complex

Inferred from electronic annotation. Source: Ensembl

activin responsive factor complex

Inferred from electronic annotation. Source: Ensembl

centrosome

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay PubMed 14691138. Source: BHF-UCL

nucleus

Inferred from direct assay PubMed 14691138. Source: BHF-UCL

transcription factor complex

Inferred from physical interaction PubMed 9288972. Source: UniProtKB

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12270938PubMed 14764653PubMed 15459107. Source: MGI

RNA polymerase II transcription factor binding

Inferred from physical interaction PubMed 21330551. Source: BHF-UCL

RNA polymerase II transcription factor binding transcription factor activity

Inferred from direct assay PubMed 21330551. Source: BHF-UCL

chromatin binding

Inferred from direct assay PubMed 15657445PubMed 18212064. Source: MGI

collagen binding

Inferred from physical interaction PubMed 14559231. Source: MGI

core promoter proximal region sequence-specific DNA binding

Inferred from electronic annotation. Source: Ensembl

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 12943993PubMed 14633973PubMed 16556916. Source: MGI

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

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 551551Mothers against decapentaplegic homolog 4
PRO_0000090862

Regions

Domain18 – 142125MH1
Domain322 – 551230MH2
Region274 – 31946SAD
Compositional bias450 – 46516Poly-Ala

Sites

Metal binding711Zinc By similarity
Metal binding1151Zinc By similarity
Metal binding1271Zinc By similarity
Metal binding1321Zinc By similarity
Site5141Necessary for heterotrimerization By similarity

Amino acid modifications

Modified residue371N6-acetyllysine By similarity
Modified residue4271N6-acetyllysine By similarity
Modified residue5061N6-acetyllysine By similarity
Cross-link518Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Sequence conflict2571A → S in AAB57905. Ref.1
Sequence conflict2921P → R in AAB57905. Ref.1

Secondary structure

......................... 551
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P97471 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 4FBDF5DED4442F86

FASTA55160,342
        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 NAPSMLVKDE YVHDFEGQPS LPTEGHSIQT 

       190        200        210        220        230        240 
IQHPPSNRAS TETYSAPALL APAESNATST TNFPNIPVAS TSQPASILAG SHSEGLLQIA 

       250        260        270        280        290        300 
SGPQPGQQQN GFTAQPATYH HNSTTTWTGS RTAPYTPNLP HHQNGHLQHH PPMPPHPGHY 

       310        320        330        340        350        360 
WPVHNELAFQ PPISNHPAPE YWCSIAYFEM DVQVGETFKV PSSCPVVTVD GYVDPSGGDR 

       370        380        390        400        410        420 
FCLGQLSNVH RTEAIERARL HIGKGVQLEC KGEGDVWVRC LSDHAVFVQS YYLDREAGRA 

       430        440        450        460        470        480 
PGDAVHKIYP SAYIKVFDLR QCHRQMQQQA ATAQAAAAAQ AAAVAGNIPG PGSVGGIAPA 

       490        500        510        520        530        540 
ISLSAAAGIG VDDLRRLCIL RMSFVKGWGP DYPRQSIKET PCWIEIHLHR ALQLLDEVLH 

       550 
TMPIADPQPL D 

« Hide

References

« Hide 'large scale' references
[1]"Sequence and chromosomal mapping of the mouse homolog (Madh4) of the human DPC4/MADH4 gene."
Anna C.H., Devereux T.R.
Mamm. Genome 8:443-444(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: A/J.
Tissue: Lung.
[2]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"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: Olfactory epithelium.
[4]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 67-551.
Strain: C57BL/6J.
Tissue: Lung.
[5]"BMP signaling controls muscle mass."
Sartori R., Schirwis E., Blaauw B., Bortolanza S., Zhao J., Enzo E., Stantzou A., Mouisel E., Toniolo L., Ferry A., Stricker S., Goldberg A.L., Dupont S., Piccolo S., Amthor H., Sandri M.
Nat. Genet. 45:1309-1318(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]"Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of BMP and TGF-beta effectors."
Baburajendran N., Palasingam P., Narasimhan K., Sun W., Prabhakar S., Jauch R., Kolatkar P.R.
Nucleic Acids Res. 38:3477-3488(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.71 ANGSTROMS) OF 9-140 IN COMPLEX WITH DNA, ZINC_BINDING SITES, SUBUNIT.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U79748 mRNA. Translation: AAB57905.1.
CH466528 Genomic DNA. Translation: EDL09560.1.
BC046584 mRNA. Translation: AAH46584.1.
AK004804 mRNA. Translation: BAB23576.1.
RefSeqNP_032566.2. NM_008540.2.
UniGeneMm.100399.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3QSVX-ray2.71A/B/C/D9-140[»]
ProteinModelPortalP97471.
SMRP97471. Positions 10-138, 284-551.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid201277. 27 interactions.
DIPDIP-29718N.
IntActP97471. 5 interactions.
MINTMINT-261841.

PTM databases

PhosphoSiteP97471.

Proteomic databases

PaxDbP97471.
PRIDEP97471.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000025393; ENSMUSP00000025393; ENSMUSG00000024515.
ENSMUST00000114939; ENSMUSP00000110589; ENSMUSG00000024515.
GeneID17128.
KEGGmmu:17128.
UCSCuc008fou.1. mouse.

Organism-specific databases

CTD4089.
MGIMGI:894293. Smad4.

Phylogenomic databases

eggNOGNOG286923.
GeneTreeENSGT00600000084353.
HOGENOMHOG000286019.
HOVERGENHBG053353.
InParanoidQ6GTP6.
KOK04501.
OMAAQPATYH.
OrthoDBEOG712TW5.
TreeFamTF314923.

Gene expression databases

ArrayExpressP97471.
BgeeP97471.
CleanExMM_SMAD4.
GenevestigatorP97471.

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

EvolutionaryTraceP97471.
NextBio291316.
PROP97471.
SOURCESearch...

Entry information

Entry nameSMAD4_MOUSE
AccessionPrimary (citable) accession number: P97471
Secondary accession number(s): Q6GTP6, Q9CW56
Entry history
Integrated into UniProtKB/Swiss-Prot: May 4, 2001
Last sequence update: July 27, 2011
Last modified: April 16, 2014
This is version 136 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot