O70437 (SMAD4_RAT) 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):
SMAD family member 4
Short name=SMAD 4
Short name=Smad4

Gene names

Name:	Smad4
Synonyms:	Madh4

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	552 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 By similarity. Interacts with CITED2. Interacts with PDPK1 (via PH domain) By similarity. Ref.3
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.
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-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 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
PTM	Acetylation Isopeptide bond Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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_0000090864
Regions
	Domain	18 – 142	125	MH1
	Domain	323 – 552	230	MH2
	Region	275 – 320	46	SAD
	Compositional bias	451 – 466	16	Poly-Ala
Sites
	Site	515	1	Necessary for heterotrimerization By similarity
Amino acid modifications
	Modified residue	37	1	N6-acetyllysine By similarity
	Modified residue	428	1	N6-acetyllysine By similarity
	Modified residue	507	1	N6-acetyllysine By similarity
	Cross-link	519		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Sequences

	Sequence		Length	Mass (Da)
	O70437 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 7AE0540AB4DF0E77	FASTA	552	60,469
	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 NAPPSMLVKD EYVHDFEGQP SLPTEGHSIQ 190 200 210 220 230 240 TIQHPPSNRA STETYSAPAL LAPSESNATS TTNFPNIPVA STSQPASILA GSHSEGLLQI 250 260 270 280 290 300 ASGPQPGQQQ NGFTAQPATY 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

References

[1]	"Molecular cloning of rat Smad4 gene." Miyakita A., Okuno S., Watanabe T.K., Oga K., Tsuji A., Hishigaki H., Suto T., Nakagawa K., Nakahara Y., Higashi K. Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skeletal muscle.
[2]	"cDNA cloning and chromosomal mapping of rat Smad2 and Smad4 and their expression in cultured rat articular chondrocytes." Osaki M., Tsukazaki T., Ono N., Yonekura A., Hirota Y., Miyazaki Y., Shindo H., Sonta S., Yamashita S. Endocr. J. 46:695-701(1999) [PubMed: 10670756] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Cited2 modulates TGF-beta-mediated upregulation of MMP9." Chou Y.T., Wang H., Chen Y., Danielpour D., Yang Y.C. Oncogene 25:5547-5560(2006) [PubMed: 16619037] [Abstract] Cited for: INTERACTION WITH CITED2.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB010954 mRNA. Translation: BAA83092.1. AF056002 mRNA. Translation: AAC12781.1.
IPI	IPI00198545.
RefSeq	NP_062148.1. NM_019275.2.
UniGene	Rn.9774.
3D structure databases
ProteinModelPortal	O70437.
SMR	O70437. Positions 19-138, 285-552.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-2739642.
STRING	O70437.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	50554.
KEGG	rno:50554.
UCSC	NM_019275. rat.
Organism-specific databases
CTD	4089.
RGD	3033. Smad4.
Phylogenomic databases
eggNOG	roNOG04669.
GeneTree	ENSGT00600000084353.
HOVERGEN	HBG053353.
InParanoid	O70437.
OrthoDB	EOG4KPT9S.
Gene expression databases
ArrayExpress	O70437.
Genevestigator	O70437.
GermOnline	ENSRNOG00000015634. Rattus norvegicus.
Family and domain databases
InterPro	IPR013790. Dwarfin. IPR003619. MAD_homology1_Dwarfin-type. IPR013019. MAD_homology_MH1. IPR017855. SMAD_dom-like. IPR001132. SMAD_dom_Dwarfin-type. IPR008984. SMAD_FHA_domain. [Graphical view]
Gene3D	G3DSA:3.90.520.10. MAD_MH1. 1 hit. G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit.
KO	K04501.
PANTHER	PTHR13703. Dwarfin. 1 hit.
Pfam	PF03165. MH1. 1 hit. PF03166. MH2. 1 hit. [Graphical view]
SMART	SM00523. DWA. 1 hit. SM00524. DWB. 1 hit. [Graphical view]
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
NextBio	610352.

Entry information

Entry name

SMAD4_RAT

Accession

Primary (citable) accession number: O70437

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 4, 2001
Last sequence update:	August 1, 1998
Last modified:	January 25, 2012
This is version 92 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program