P97471 (SMAD4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	551 AA.
Sequence status	Complete.
Protein existence	Evidence 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.
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.5
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.
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 process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Ligand	DNA-binding Metal-binding Zinc
PTM	Acetylation Isopeptide bond Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway Inferred from electronic annotation. Source: Compara SMAD protein complex assembly Inferred from electronic annotation. Source: Compara SMAD protein signal transduction Inferred from electronic annotation. Source: Compara 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 with mouth forming second Inferred from mutant phenotype PubMed 15215210. Source: MGI in utero embryonic development Inferred from mutant phenotype PubMed 9420335. 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: Compara 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: Compara negative regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara 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: Compara 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 transforming growth factor beta receptor signaling pathway Inferred from electronic annotation. Source: Compara regulation of binding Inferred from direct assay PubMed 15282343. Source: MGI regulation of hair follicle development Inferred from mutant phenotype PubMed 18692037. Source: MGI regulation of transforming growth factor beta2 production Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara sebaceous gland development Inferred from mutant phenotype PubMed 18692037. Source: MGI somite rostral/caudal axis specification Inferred from mutant phenotype PubMed 9420335. Source: MGI transforming growth factor beta receptor signaling pathway Inferred from genetic interaction PubMed 18212064. Source: MGI
Cellular_component	SMAD protein complex Inferred from electronic annotation. Source: Compara activin responsive factor complex Inferred from electronic annotation. Source: Compara centrosome Inferred from electronic annotation. Source: Compara cytoplasm Inferred from direct assay PubMed 14691138. Source: BHF-UCL transcription factor complex Inferred from physical interaction PubMed 9288972. Source: UniProtKB
Molecular_function	DNA binding Inferred from direct assay PubMed 12270938PubMed 14764653PubMed 15459107. Source: MGI 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 core promoter proximal region sequence-specific DNA binding Inferred from electronic annotation. Source: Compara 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: Compara
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 551

551

Mothers against decapentaplegic homolog 4

PRO_0000090862

Regions

Domain

18 – 142

125

MH1

Domain

322 – 551

230

MH2

Region

274 – 319

46

SAD

Compositional bias

450 – 465

16

Poly-Ala

Sites

Metal binding

71

1

Zinc By similarity

Metal binding

115

1

Zinc By similarity

Metal binding

127

1

Zinc By similarity

Metal binding

132

1

Zinc By similarity

Site

514

1

Necessary for heterotrimerization By similarity

Amino acid modifications

Modified residue

37

1

N6-acetyllysine By similarity

Modified residue

427

1

N6-acetyllysine By similarity

Modified residue

506

1

N6-acetyllysine By similarity

Cross-link

518

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Experimental info

Sequence conflict

257

1

A → S in AAB57905. Ref.1

Sequence conflict

292

1

P → R in AAB57905. Ref.1

Secondary structure

1

.

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551

Helix Strand Turn

Details...

Helix

16 – 24

9

Helix

33 – 47

15

Helix

51 – 62

12

Turn

63 – 65

3

Beta strand

73 – 75

3

Beta strand

82 – 84

3

Beta strand

87 – 89

3

Helix

91 – 99

9

Beta strand

109 – 111

3

Helix

119 – 121

3

Beta strand

124 – 127

4

Helix

130 – 132

3

Beta strand

133 – 135

3

Sequences

	Sequence		Length	Mass (Da)
	P97471 [UniParc]. Last modified July 27, 2011. Version 2. Checksum: 4FBDF5DED4442F86	FASTA	551	60,342
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.

IPI

IPI00125567.

RefSeq

NP_032566.2. NM_008540.2.

UniGene

Mm.100399.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3QSV	X-ray	2.71	A/B/C/D	9-140	[»]

ProteinModelPortal

P97471.

SMR

P97471. Positions 10-138, 284-551.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29718N.

IntAct

P97471. 1 interaction.

MINT

MINT-261841.

PTM databases

PhosphoSite

P97471.

Proteomic databases

PaxDb

P97471.

PRIDE

P97471.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000025393; ENSMUSP00000025393; ENSMUSG00000024515.
ENSMUST00000114939; ENSMUSP00000110589; ENSMUSG00000024515.

GeneID

17128.

KEGG

mmu:17128.

Organism-specific databases

CTD

4089.

MGI

MGI:894293. Smad4.

Phylogenomic databases

eggNOG

NOG286923.

GeneTree

ENSGT00600000084353.

HOGENOM

HOG000286019.

HOVERGEN

HBG053353.

InParanoid

Q6GTP6.

KO

K04501.

OMA

AQPATYH.

OrthoDB

EOG4KPT9S.

Gene expression databases

ArrayExpress

P97471.

Bgee

P97471.

CleanEx

MM_SMAD4.

Genevestigator

P97471.

GermOnline

ENSMUSG00000024515. Mus musculus.

Family and domain databases

Gene3D

2.60.200.10. 1 hit.
3.90.520.10. 1 hit.

InterPro

IPR013790. 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]

PANTHER

PTHR13703. PTHR13703. 1 hit.

Pfam

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

SMART

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

SUPFAM

SSF56366. MAD_MH1. 1 hit.
SSF49879. SMAD_FHA. 1 hit.

PROSITE

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

ProtoNet

Search...

Other

EvolutionaryTrace

P97471.

NextBio

291316.

SOURCE

Search...

Entry information

Entry name

SMAD4_MOUSE

Accession

Primary (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 3, 2013
This is version 128 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program