O70436 (SMAD2_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mothers against decapentaplegic homolog 2
Short name=MAD homolog 2
Short name=Mothers against DPP homolog 2

Alternative name(s):
Mad-related protein 2
SMAD family member 2
Short name=SMAD 2
Short name=Smad2

Gene names

Name:	Smad2
Synonyms:	Madh2

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. 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	Momomer; the absence of TGF-beta By similarity. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4 By similarity. Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta. Interacts with ACVR1B, SMAD3 and TRIM33. Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with FOXH1, homeobox protein TGIF, PEBP2-alpha subunit, CREB-binding protein (CBP), EP300, SKI and SNW1. Interacts with SNON; when phosphorylated at Ser-465/467. Interacts (via PY-motif) with SMURF2. Interacts with AIP1 and HGS. Interacts with NEDD4L in response to TGF-beta. Interacts with SKOR1 and SKOR2. Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3. Interacts with RBPMS. Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination ot the TGF-beta signaling. Interacts with PML By similarity. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15 By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4. On dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 By similarity.
Post-translational modification	In response to TGF-beta, phosphorylated on the C-terminal SXS motif by TGF-beta and activin type 1 receptor kinases. Phosphorylation in this motif is required for interaction with a number of proteins including SMURF2, SNON and SMAD4 in response to TGF-beta. Dephosphorylated in this motif by PPM1A leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of the TGF-beta signaling. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin By similarity. Phosphorylated by PDPK1 By similarity. In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes By similarity. Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity 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 Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	SMAD protein complex assembly Inferred from electronic annotation. Source: Compara anterior/posterior pattern specification Inferred from sequence or structural similarity. Source: UniProtKB cell fate commitment Inferred from sequence or structural similarity. Source: UniProtKB common-partner SMAD protein phosphorylation Inferred from electronic annotation. Source: Compara developmental growth Inferred from electronic annotation. Source: Compara embryonic cranial skeleton morphogenesis Inferred from electronic annotation. Source: Compara embryonic foregut morphogenesis Inferred from electronic annotation. Source: Compara endoderm development Inferred from electronic annotation. Source: Compara in utero embryonic development Inferred from electronic annotation. Source: Compara insulin secretion Inferred from electronic annotation. Source: Compara intracellular signal transduction Inferred from sequence or structural similarity. Source: UniProtKB lung development Inferred from electronic annotation. Source: Compara mesoderm formation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell proliferation Inferred from mutant phenotype PubMed 15987742. Source: RGD negative regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara nodal signaling pathway Inferred from electronic annotation. Source: Compara organ growth Inferred from electronic annotation. Source: Compara palate development Inferred from electronic annotation. Source: Compara pancreas development Inferred from electronic annotation. Source: Compara paraxial mesoderm morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB pericardium development Inferred from electronic annotation. Source: Compara positive regulation of BMP signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of epithelial to mesenchymal transition Inferred from electronic annotation. Source: Compara positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB post-embryonic development Inferred from electronic annotation. Source: Compara regulation of binding Inferred from sequence or structural similarity. Source: UniProtKB regulation of transforming growth factor beta receptor signaling pathway Inferred from electronic annotation. Source: Compara response to cholesterol Inferred from electronic annotation. Source: Compara response to glucose stimulus Inferred from electronic annotation. Source: Compara signal transduction involved in regulation of gene expression Inferred from mutant phenotype PubMed 22073128. Source: BHF-UCL transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB ureteric bud development Inferred from electronic annotation. Source: Compara zygotic specification of dorsal/ventral axis Inferred from electronic annotation. Source: Compara
Cellular_component	SMAD protein complex Inferred from electronic annotation. Source: Compara activin responsive factor complex Inferred from electronic annotation. Source: Compara cytoplasm Inferred from direct assay PubMed 16570350. Source: RGD transcription factor complex Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	chromatin binding Inferred from electronic annotation. Source: Compara double-stranded DNA binding Inferred from sequence or structural similarity. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara transcription factor binding Inferred from sequence or structural similarity. Source: UniProtKB transforming growth factor beta receptor, pathway-specific 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
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 467	466	Mothers against decapentaplegic homolog 2		PRO_0000090854
Regions
	Domain	10 – 176	167	MH1
	Domain	274 – 467	194	MH2
	Motif	221 – 225	5	PY-motif By similarity
Sites
	Metal binding	74	1	Zinc By similarity
	Metal binding	149	1	Zinc By similarity
	Metal binding	161	1	Zinc By similarity
	Metal binding	166	1	Zinc By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylserine By similarity
	Modified residue	8	1	Phosphothreonine By similarity
	Modified residue	19	1	N6-acetyllysine By similarity
	Modified residue	240	1	Phosphoserine; by CAMK2 By similarity
	Modified residue	458	1	Phosphoserine By similarity
	Modified residue	460	1	Phosphoserine By similarity
	Modified residue	464	1	Phosphoserine By similarity
	Modified residue	465	1	Phosphoserine; by TGFBR1 By similarity
	Modified residue	467	1	Phosphoserine; by TGFBR1 By similarity

Sequences

	Sequence		Length	Mass (Da)
	O70436 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 3A775444411F6619	FASTA	467	52,239
	10 20 30 40 50 60 MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK KLKKTGRLDE 70 80 90 100 110 120 LEKAITTQNC NTKCVTIPST CSEIWGLSTA NTVDQWDTTG LYSFSEQTRS LDGRLQVSHR 130 140 150 160 170 180 KGLPHVIYCR LWRWPDLHSH HELKAIENCE YAFSLKKDEV CVNPYHYQRV ETPVLPPVLV 190 200 210 220 230 240 PRHTEILTEL PPLDDYTHSI PENTNFPAGI EPQSNYIPET PPPGYISEDG ETSDQQLNQS 250 260 270 280 290 300 MDTGSPAELS PTTLSPVNHS LDLQPVTYSE PAFWCSIAYY ELNQRVGETF HASQPSLTVD 310 320 330 340 350 360 GFTDPSNSER FCLGLLSNVN RNATVEMTRR HIGRGVRLYY IGGEVFAECL SDSAIFVQSP 370 380 390 400 410 420 NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF AALLAQSVNQ GFEAVYQLTR MCTIRMSFVK 430 440 450 460 GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD KVLTQMGSPS VRCSSMS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Involvement of Smad proteins in the differentiation of pancreatic AR42J cells induced by activin A." Zhang Y.-Q., Kanzaki M., Furukawa M., Shibata H., Ozeki M., Kojima I. Diabetologia 42:719-727(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Brain.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Molecular cloning of rat Smad2 gene." Miyakita A., Okuno S., Watanabe T.K., Oga K., Tsuji A., Hishigaki H., Kato S., Sano A., Suto T., Nakagawa K., Nakahara Y., Haraguchi N., Higashi K. Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB017912 mRNA. Translation: BAA33453.1. AF056001 mRNA. Translation: AAC12780.1. AB010147 mRNA. Translation: BAA81909.1. BC127497 mRNA. Translation: AAI27498.1.
IPI	IPI00198544.
RefSeq	NP_001264379.1. NM_001277450.1. NP_062064.1. NM_019191.2.
UniGene	Rn.2755.
3D structure databases
ProteinModelPortal	O70436.
SMR	O70436. Positions 7-172, 265-467.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-2739674.
PTM databases
PhosphoSite	O70436.
Proteomic databases
PaxDb	O70436.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000046847; ENSRNOP00000048329; ENSRNOG00000018140.
GeneID	29357.
KEGG	rno:29357.
Organism-specific databases
CTD	4087.
RGD	3031. Smad2.
Phylogenomic databases
eggNOG	NOG320700.
GeneTree	ENSGT00600000084186.
HOGENOM	HOG000286018.
HOVERGEN	HBG053353.
InParanoid	O70436.
KO	K04500.
OMA	MNQSMDT.
OrthoDB	EOG48PMK5.
Gene expression databases
ArrayExpress	O70436.
Genevestigator	O70436.
GermOnline	ENSRNOG00000018140. Rattus norvegicus.
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
NextBio	608870.

Entry information

Entry name

SMAD2_RAT

Accession

Primary (citable) accession number: O70436
Secondary accession number(s): A0JPM1

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	August 1, 1998
Last modified:	May 29, 2013
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program