Q15796 (SMAD2_HUMAN) 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):
JV18-1
Mad-related protein 2
Short name=hMAD-2
SMAD family member 2
Short name=SMAD 2
Short name=Smad2
Short name=hSMAD2

Gene names

Name:	SMAD2
Synonyms:	MADH2, MADR2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

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 protein 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. Ref.15 Ref.24 Ref.28 Ref.30 Ref.34
Subunit structure	Momomer; the absence of TGF-beta. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4. Interacts with AIP1, HGS, PML and WWP1 By similarity. Interacts with NEDD4L in response to TGF-beta 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 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 PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Ref.8 Ref.9 Ref.10 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.27 Ref.28 Ref.29 Ref.32 Ref.34 Ref.35 Ref.38 Ref.43 Ref.44
Subcellular location	Cytoplasm. Nucleus. 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. Ref.9 Ref.24 Ref.34
Tissue specificity	Expressed at high levels in skeletal muscle, heart and placenta.
Post-translational modification	Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-beta and activin type 1 receptor kinases. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. 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. Phosphorylated by PDPK1. Ref.3 Ref.8 Ref.12 Ref.13 Ref.19 Ref.20 Ref.24 Ref.28 In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation By similarity. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta.
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
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	DNA-binding Metal-binding Zinc
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	SMAD protein complex assembly Inferred from direct assay PubMed 9111321. Source: BHF-UCL 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 direct assay PubMed 16806156. Source: MGI 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 electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Traceable author statement. Source: Reactome negative regulation of transforming growth factor beta receptor signaling pathway Traceable author statement. Source: Reactome nodal signaling pathway Inferred from mutant phenotype PubMed 15150278. Source: BHF-UCL organ growth Inferred from electronic annotation. Source: Compara palate development Inferred from sequence or structural similarity. Source: BHF-UCL 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 mutant phenotype PubMed 19366699. Source: BHF-UCL positive regulation of epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry Inferred from mutant phenotype PubMed 17239842. Source: BHF-UCL 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 primary miRNA processing Traceable author statement PubMed 19018011. Source: BHF-UCL regulation of binding Inferred from sequence or structural similarity. Source: UniProtKB response to cholesterol Inferred from direct assay PubMed 17878231. Source: BHF-UCL response to glucose stimulus Inferred from electronic annotation. Source: Compara transcription initiation from RNA polymerase II promoter Traceable author statement. Source: Reactome transforming growth factor beta receptor signaling pathway Inferred from direct assay Ref.3Ref.4PubMed 9732876. Source: BHF-UCL ureteric bud development Inferred from electronic annotation. Source: Compara zygotic specification of dorsal/ventral axis Inferred from mutant phenotype PubMed 9436979. Source: BHF-UCL
Cellular_component	SMAD protein complex Inferred from direct assay PubMed 18832382. Source: UniProtKB activin responsive factor complex Inferred from direct assay Ref.4. Source: BHF-UCL cytosol Traceable author statement. Source: Reactome
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 direct assay Ref.4. Source: BHF-UCL transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity Inferred from direct assay PubMed 9256479Ref.4. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CHGB	P05060	2	EBI-1040141,EBI-712619
DAB2	P98082	4	EBI-1040141,EBI-1171238
DOCK9	Q9BZ29	3	EBI-1040141,EBI-2695893
NEFM	P07197	3	EBI-1040141,EBI-1105035
RHOA	P61586	2	EBI-1040141,EBI-446668
SMAD3	P84022	2	EBI-1040141,EBI-347161
SMAD4	Q13485	12	EBI-1040141,EBI-347263
SNW1	Q13573	3	EBI-1040141,EBI-632715
TP63	Q9H3D4	3	EBI-1040141,EBI-2337775
TRIM33	Q9UPN9	6	EBI-1040141,EBI-2214398
WWP2	O00308	4	EBI-1040141,EBI-743923
ZFR	Q96KR1	2	EBI-1040141,EBI-2513582

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: Q15796-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: Q15796-2)

Also known as: Smad2Deltaexon3;

The sequence of this isoform differs from the canonical sequence as follows:
     79-108: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.7

Chain

2 – 467

466

Mothers against decapentaplegic homolog 2

PRO_0000090852

Regions

Domain

10 – 176

167

MH1

Domain

274 – 467

194

MH2

Motif

221 – 225

5

PY-motif

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 Ref.7 Ref.36

Modified residue

8

1

Phosphothreonine; by MAPK3 Ref.20 Ref.31 Ref.36

Modified residue

19

1

N6-acetyllysine Ref.26

Modified residue

220

1

Phosphothreonine Probable

Modified residue

240

1

Phosphoserine; by CAMK2 Ref.19

Modified residue

245

1

Phosphoserine Probable

Modified residue

250

1

Phosphoserine Probable

Modified residue

255

1

Phosphoserine Probable

Modified residue

458

1

Phosphoserine Ref.33 Ref.36

Modified residue

460

1

Phosphoserine Ref.36

Modified residue

464

1

Phosphoserine

Modified residue

465

1

Phosphoserine; by TGFBR1 Ref.12 Ref.13

Modified residue

467

1

Phosphoserine; by TGFBR1 Ref.12 Ref.13

Natural variations

Alternative sequence

79 – 108

30

Missing in isoform Short.

VSP_006178

Natural variant

133

1

R → C in a colorectal carcinoma sample. Ref.3

VAR_011375

Natural variant

300

1

D → V in a colorectal cancer sample; somatic mutation. Ref.45

VAR_036473

Natural variant

344 – 358

15

Missing in a colorectal carcinoma sample.

VAR_011376

Natural variant

440

1

L → R in a colorectal carcinoma sample. Ref.3

VAR_011377

Natural variant

445

1

P → H in a colorectal carcinoma sample. Ref.3

VAR_011378

Natural variant

450

1

D → E in a colorectal carcinoma sample. Ref.3

VAR_011379

Experimental info

Mutagenesis

19

1

K → R: Loss of acetylation. Ref.26

Mutagenesis

20

1

K → R: No effect on acetylation. Ref.26

Mutagenesis

221 – 225

5

Missing: Loss of binding to SMURF2. Ref.18

Mutagenesis

381

1

N → S: Loss of binding to SARA. Ref.43

Mutagenesis

398

1

V → R: Increased binding to PPM1A. Ref.24

Mutagenesis

464

1

S → A: Loss of phosphorylation by TGFBR1; when associated with A-465 and A-467. Ref.8

Mutagenesis

465 – 467

3

SMS → AMA: Binds RANBP3. Ref.8 Ref.24 Ref.34

Mutagenesis

465 – 467

3

SMS → DMD: Greatly reduced RANBP2 binding. Ref.8 Ref.24 Ref.34

Mutagenesis

465

1

S → A: No change in binding to PPM1A. Loss of phosphorylation by TGFBR1; when associated with A-464 and A-467. Ref.8 Ref.24

Mutagenesis

465

1

S → D: No change in binding to PPM1A. Ref.8 Ref.24

Mutagenesis

467

1

S → A: No change in binding to PPM1A. Loss of phosphorylation by TGFBR1; when associated with A-464 and A-465. Ref.8 Ref.24

Mutagenesis

467

1

S → D: No change in binding to PPM1A. Ref.8 Ref.24

Secondary structure

1

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467

Helix Strand Turn

Details...

Beta strand

264 – 267

4

Beta strand

274 – 281

8

Beta strand

290 – 292

3

Beta strand

294 – 302

9

Beta strand

305 – 307

3

Beta strand

310 – 312

3

Helix

313 – 315

3

Helix

323 – 329

7

Turn

330 – 334

5

Beta strand

336 – 341

6

Beta strand

344 – 349

6

Beta strand

351 – 353

3

Beta strand

355 – 358

4

Helix

360 – 365

6

Beta strand

374 – 376

3

Beta strand

381 – 386

6

Helix

387 – 397

11

Helix

398 – 400

3

Helix

402 – 406

5

Helix

407 – 412

6

Beta strand

413 – 419

7

Beta strand

423 – 427

5

Helix

431 – 433

3

Beta strand

434 – 442

9

Helix

443 – 453

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 95406DB5FC0AA4C9	FASTA	467	52,306
	10 20 30 40 50 60 MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK KLKKTGRLDE 70 80 90 100 110 120 LEKAITTQNC NTKCVTIPST CSEIWGLSTP NTIDQWDTTG LYSFSEQTRS LDGRLQVSHR 130 140 150 160 170 180 KGLPHVIYCR LWRWPDLHSH HELKAIENCE YAFNLKKDEV 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
	Isoform Short (Smad2Deltaexon3) [UniParc]. Checksum: 0E2FF38B009D2F9E	FASTA	437	48,956
	10 20 30 40 50 60 MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK KLKKTGRLDE 70 80 90 100 110 120 LEKAITTQNC NTKCVTIPRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH HELKAIENCE 130 140 150 160 170 180 YAFNLKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEILTEL PPLDDYTHSI PENTNFPAGI 190 200 210 220 230 240 EPQSNYIPET PPPGYISEDG ETSDQQLNQS MDTGSPAELS PTTLSPVNHS LDLQPVTYSE 250 260 270 280 290 300 PAFWCSIAYY ELNQRVGETF HASQPSLTVD GFTDPSNSER FCLGLLSNVN RNATVEMTRR 310 320 330 340 350 360 HIGRGVRLYY IGGEVFAECL SDSAIFVQSP NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF 370 380 390 400 410 420 AALLAQSVNQ GFEAVYQLTR MCTIRMSFVK GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD 430 KVLTQMGSPS VRCSSMS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mad-related genes in the human." Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., Kern S.E., Hamilton S.R., Willson J.K.V., Markowitz S.D., Kinzler K.W., Vogelstein B.V. Nat. Genet. 13:347-349(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), VARIANT 344-GLU--GLN-358 DEL.
[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 [MRNA] (ISOFORM LONG). Tissue: Placenta.
[3]	"MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma." Eppert K., Scherer S.W., Ozcelik H., Pirone R., Hoodless P., Kim H., Tsui L.-C., Bapat B., Gallinger S., Andrulis I.L., Thomsen G.H., Wrana J.L., Attisano L. Cell 86:543-552(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), PHOSPHORYLATION BY TGFBR1, VARIANTS CYS-133; ARG-440; HIS-445 AND GLU-450. Tissue: Kidney.
[4]	"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: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
[5]	"Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming growth factor-beta and activin signal transduction pathway." Takenoshita S., Mogi A., Nagashima M., Yang K., Yagi K., Hanyu A., Nagamachi Y., Miyazono K., Hagiwara K. Genomics 48:1-11(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS LONG AND SHORT).
[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] (ISOFORM LONG). Tissue: Kidney, Pancreas and Spleen.
[7]	Bienvenut W.V., von Kriegsheim A., Kolch W. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-14 AND 170-182, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT SER-2, MASS SPECTROMETRY. Tissue: Chronic myeloid leukemia cell.
[8]	"MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling." Macias-Silva M., Abdollah S., Hoodless P.A., Pirone R., Attisano L., Wrana J.L. Cell 87:1215-1224(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TGFBR1, PHOSPHORYLATION BY TGFBR1, MUTAGENESIS OF SER-464; SER-465 AND SER-467.
[9]	"SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor." Tsukazaki T., Chiang T.A., Davison A.F., Attisano L., Wrana J.L. Cell 95:779-791(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZFYVE9, SUBCELLULAR LOCATION.
[10]	"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.
[11]	"Alternatively spliced variant of Smad2 lacking exon 3. Comparison with wild-type Smad2 and Smad3." Yagi K., Goto D., Hamamoto T., Takenoshita S., Kato M., Miyazono K. J. Biol. Chem. 274:703-709(1999) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORMS LONG AND SHORT).
[12]	"The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase." Kretzschmar M., Liu F., Hata A., Doody J., Massague J. Genes Dev. 11:984-995(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-465 AND SER-467.
[13]	"TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling." Abdollah S., Macias-Silva M., Tsukazaki T., Hayashi H., Attisano L., Wrana J.L. J. Biol. Chem. 272:27678-27685(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-465 AND SER-467 BY TGFBR1.
[14]	"Characterization of human FAST-1, a TGF beta and activin signal transducer." Zhou S., Zawel L., Lengauer C., Kinzler K.W., Vogelstein B. Mol. Cell 2:121-127(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FOXH1. Tissue: Colon adenocarcinoma.
[15]	"Roles of pathway-specific and inhibitory Smads in activin receptor signaling." Lebrun J.J., Takabe K., Chen Y., Vale W. Mol. Endocrinol. 13:15-23(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ACVR1B, FUNCTION.
[16]	"The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway." Hocevar B.A., Smine A., Xu X.X., Howe P.H. EMBO J. 20:2789-2801(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DAB2.
[17]	"Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription." Leong G.M., Subramaniam N., Figueroa J., Flanagan J.L., Hayman M.J., Eisman J.A., Kouzmenko A.P. J. Biol. Chem. 276:18243-18248(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SNW1.
[18]	"TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation." Bonni S., Wang H.R., Causing C.G., Kavsak P., Stroschein S.L., Luo K., Wrana J.L. Nat. Cell Biol. 3:587-595(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SMURF2, MUTAGENESIS OF 221-PRO--TYR-225.
[19]	"Decorin suppresses transforming growth factor-beta-induced expression of plasminogen activator inhibitor-1 in human mesangial cells through a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-240." Abdel-Wahab N., Wicks S.J., Mason R.M., Chantry A. Biochem. J. 362:643-649(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-240.
[20]	"Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase." Funaba M., Zimmerman C.M., Mathews L.S. J. Biol. Chem. 277:41361-41368(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-8; THR-220; SER-245; SER-250 AND SER-255.
[21]	"MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling." Lin F., Morrison J.M., Wu W., Worman H.J. Hum. Mol. Genet. 14:437-445(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LEMD3.
[22]	"The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines." Pan D., Estevez-Salmeron L.D., Stroschein S.L., Zhu X., He J., Zhou S., Luo K. J. Biol. Chem. 280:15992-16001(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LEMD3.
[23]	"Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues." Arndt S., Poser I., Schubert T., Moser M., Bosserhoff A.-K. Lab. Invest. 85:1330-1341(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SKOR2.
[24]	"PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling." Lin X., Duan X., Liang Y.Y., Su Y., Wrighton K.H., Long J., Hu M., Davis C.M., Wang J., Brunicardi F.C., Shi Y., Chen Y.G., Meng A., Feng X.H. Cell 125:915-928(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PPM1A, DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF VAL-398; SER-465 AND SER-467.
[25]	"Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway." He W., Dorn D.C., Erdjument-Bromage H., Tempst P., Moore M.A., Massague J. Cell 125:929-941(2006) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH SMAD3 AND TRIM33, INTERACTION WITH TRIM33.
[26]	"The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation." Simonsson M., Kanduri M., Gronroos E., Heldin C.H., Ericsson J. J. Biol. Chem. 281:39870-39880(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION AT LYS-19, MUTAGENESIS OF LYS-19 AND LYS-20.
[27]	"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.
[28]	"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, PHOSPHORYLATION BY PDPK1, INTERACTION WITH PDPK1.
[29]	"Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling." Arndt S., Poser I., Moser M., Bosserhoff A.-K. Mol. Cell. Neurosci. 34:603-611(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SKOR1.
[30]	"Smad3 is acetylated by p300/CBP to regulate its transactivation activity." Inoue Y., Itoh Y., Abe K., Okamoto T., Daitoku H., Fukamizu A., Onozaki K., Hayashi H. Oncogene 26:500-508(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION, FUNCTION.
[31]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[32]	"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.
[33]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[34]	"Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling." Dai F., Lin X., Chang C., Feng X.H. Dev. Cell 16:345-357(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RANBP3, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF 465-SER--SER-467.
[35]	"SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells." Takahata M., Inoue Y., Tsuda H., Imoto I., Koinuma D., Hayashi M., Ichikura T., Yamori T., Nagasaki K., Yoshida M., Matsuoka M., Morishita K., Yuki K., Hanyu A., Miyazawa K., Inazawa J., Miyazono K., Imamura T. J. Biol. Chem. 284:3334-3344(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PRDM16.
[36]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8; SER-458 AND SER-460, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[37]	"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].
[38]	"USP15 is a deubiquitylating enzyme for receptor-activated SMADs." Inui M., Manfrin A., Mamidi A., Martello G., Morsut L., Soligo S., Enzo E., Moro S., Polo S., Dupont S., Cordenonsi M., Piccolo S. Nat. Cell Biol. 13:1368-1375(2011) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION, DEUBIQUITINATION BY USP15, DNA-BINDING, INTERACTION WITH USP15.
[39]	"TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[40]	"Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells." Verschueren K., Huylebroeck D. Cytokine Growth Factor Rev. 10:187-199(1999) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[41]	"The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[42]	"TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[43]	"Structural basis of Smad2 recognition by the Smad anchor for receptor activation." Wu G., Chen Y.-G., Ozdamar B., Gyuricza C.A., Chong P.A., Wrana J.L., Massague J., Shi Y. Science 287:92-97(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 261-456 IN COMPLEX WITH ZFYVE9, INTERACTION WITH SARA, MUTAGENESIS OF ASN-381.
[44]	"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 270-466 IN COMPLEX WITH SMAD4, SUBUNIT.
[45]	"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. , 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: VARIANT [LARGE SCALE ANALYSIS] VAL-300.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U59911 mRNA. Translation: AAC50789.1.
U68018 mRNA. Translation: AAB17087.1.
U65019 mRNA. Translation: AAB17054.1.
AF027964 mRNA. Translation: AAC51918.1.
U78733 , U78727, U78728, U78729, U78730, U78731, U78732 Genomic DNA. Translation: AAC39657.1.
BC014840 mRNA. Translation: AAH14840.1.
BC025699 mRNA. Translation: AAH25699.1.

IPI

IPI00019548.
IPI00220364.

PIR

S71797.

RefSeq

NP_001003652.1. NM_001003652.3.
NP_005892.1. NM_005901.5.

UniGene

Hs.12253.
Hs.705764.
Hs.741342.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DEV	X-ray	2.20	A/C	261-456	[»]
1KHX	X-ray	1.80	A	241-467	[»]
1U7V	X-ray	2.70	A/C	270-466	[»]
2LB3	NMR	-	B	217-224	[»]

ProteinModelPortal

Q15796.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29716N.

IntAct

Q15796. 135 interactions.

MINT

MINT-5006109.

STRING

9606.ENSP00000262160.

PTM databases

PhosphoSite

Q15796.

Polymorphism databases

DMDM

13633914.

Proteomic databases

PaxDb

Q15796.

PRIDE

Q15796.

Protocols and materials databases

DNASU

4087.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000262160; ENSP00000262160; ENSG00000175387.
ENST00000356825; ENSP00000349282; ENSG00000175387.
ENST00000402690; ENSP00000384449; ENSG00000175387.
ENST00000586040; ENSP00000466193; ENSG00000175387.

GeneID

4087.

KEGG

hsa:4087.

UCSC

uc002lcy.3. human.
uc010xdc.2. human.

Organism-specific databases

CTD

4087.

GeneCards

GC18M045357.

HGNC

HGNC:6768. SMAD2.

HPA

CAB025507.

MIM

601366. gene.

neXtProt

NX_Q15796.

PharmGKB

PA134959722.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG320700.

HOGENOM

HOG000286018.

HOVERGEN

HBG053353.

InParanoid

Q15796.

KO

K04500.

OMA

MNQSMDT.

OrthoDB

EOG48PMK5.

PhylomeDB

Q15796.

Enzyme and pathway databases

Pathway_Interaction_DB

glypican_1pathway. Glypican 1 network.
smad2_3pathway. Regulation of cytoplasmic and nuclear SMAD2/3 signaling.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_71. Gene Expression.

SignaLink

Q15796.

Gene expression databases

ArrayExpress

Q15796.

Bgee

Q15796.

CleanEx

HS_SMAD2.

Genevestigator

Q15796.

GermOnline

ENSG00000175387. Homo sapiens.

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

ChiTaRS

SMAD2. human.

EvolutionaryTrace

Q15796.

GenomeRNAi

4087.

NextBio

16020.

SOURCE

Search...

Entry information

Entry name

SMAD2_HUMAN

Accession

Primary (citable) accession number: Q15796

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	November 1, 1996
Last modified:	May 29, 2013
This is version 159 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.