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Protein

Mothers against decapentaplegic homolog 2

Gene

SMAD2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi74ZincBy similarity1
Metal bindingi149ZincBy similarity1
Metal bindingi161ZincBy similarity1
Metal bindingi166ZincBy similarity1

GO - Molecular functioni

  • activating transcription factor binding Source: UniProtKB
  • chromatin binding Source: Ensembl
  • co-SMAD binding Source: BHF-UCL
  • disordered domain specific binding Source: CAFA
  • DNA binding transcription factor activity Source: BHF-UCL
  • double-stranded DNA binding Source: UniProtKB
  • enhancer binding Source: BHF-UCL
  • I-SMAD binding Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW
  • phosphatase binding Source: UniProtKB
  • primary miRNA binding Source: BHF-UCL
  • protein heterodimerization activity Source: Ensembl
  • protein homodimerization activity Source: Ensembl
  • RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • RNA polymerase II transcription factor activity, sequence-specific DNA binding Source: NTNU_SB
  • R-SMAD binding Source: BHF-UCL
  • SMAD binding Source: UniProtKB
  • transcriptional activator activity, RNA polymerase II proximal promoter sequence-specific DNA binding Source: NTNU_SB
  • transcription factor binding Source: UniProtKB
  • transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity Source: BHF-UCL
  • transforming growth factor beta receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionDNA-binding
Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-1181150 Signaling by NODAL
R-HSA-1502540 Signaling by Activin
R-HSA-2173788 Downregulation of TGF-beta receptor signaling
R-HSA-2173789 TGF-beta receptor signaling activates SMADs
R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-3304356 SMAD2/3 Phosphorylation Motif Mutants in Cancer
R-HSA-3311021 SMAD4 MH2 Domain Mutants in Cancer
R-HSA-3315487 SMAD2/3 MH2 Domain Mutants in Cancer
R-HSA-3656532 TGFBR1 KD Mutants in Cancer
R-HSA-452723 Transcriptional regulation of pluripotent stem cells
R-HSA-5689880 Ub-specific processing proteases
SignaLinkiQ15796
SIGNORiQ15796

Names & Taxonomyi

Protein namesi
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 namesi
Name:SMAD2
Synonyms:MADH2, MADR2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 18

Organism-specific databases

EuPathDBiHostDB:ENSG00000175387.15
HGNCiHGNC:6768 SMAD2
MIMi601366 gene
neXtProtiNX_Q15796

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi19K → R: Loss of acetylation. 1 Publication1
Mutagenesisi20K → R: No effect on acetylation. 1 Publication1
Mutagenesisi221 – 225Missing : Loss of binding to SMURF2. 1 Publication5
Mutagenesisi368W → A: Loss of interaction with PMEPA1. 1 Publication1
Mutagenesisi381N → S: Loss of binding to SARA. 1 Publication1
Mutagenesisi398V → R: Increased binding to PPM1A. 1 Publication1
Mutagenesisi464S → A: Loss of phosphorylation by TGFBR1; when associated with A-465 and A-467. 1 Publication1
Mutagenesisi465 – 467SMS → AMA: Binds RANBP3. 1 Publication3
Mutagenesisi465 – 467SMS → DMD: Greatly reduced RANBP2 binding. 1 Publication3
Mutagenesisi465S → A: No change in binding to PPM1A. Loss of phosphorylation by TGFBR1; when associated with A-464 and A-467. 2 Publications1
Mutagenesisi465S → D: No change in binding to PPM1A. 2 Publications1
Mutagenesisi467S → A: No change in binding to PPM1A. Loss of phosphorylation by TGFBR1; when associated with A-464 and A-465. 2 Publications1
Mutagenesisi467S → D: No change in binding to PPM1A. 2 Publications1

Organism-specific databases

DisGeNETi4087
MalaCardsiSMAD2
OpenTargetsiENSG00000175387
PharmGKBiPA134959722

Chemistry databases

ChEMBLiCHEMBL2396512
DrugBankiDB04522 Phosphonoserine

Polymorphism and mutation databases

BioMutaiSMAD2
DMDMi13633914

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources1 Publication
ChainiPRO_00000908522 – 467Mothers against decapentaplegic homolog 2Add BLAST466

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineCombined sources1 Publication1
Modified residuei8Phosphothreonine; by MAPK3Combined sources1 Publication1
Modified residuei19N6-acetyllysine1 Publication1
Modified residuei220Phosphothreonine1 Publication1
Modified residuei240Phosphoserine; by CAMK2PROSITE-ProRule annotation1 Publication1
Modified residuei245Phosphoserine1 Publication1
Modified residuei250Phosphoserine1 Publication1
Modified residuei255Phosphoserine1 Publication1
Modified residuei458PhosphoserineCombined sources1
Modified residuei460PhosphoserineCombined sources1
Modified residuei464PhosphoserinePROSITE-ProRule annotation1 Publication1
Modified residuei465Phosphoserine; by TGFBR1PROSITE-ProRule annotation4 Publications1
Modified residuei467Phosphoserine; by TGFBR1PROSITE-ProRule annotation4 Publications1

Post-translational modificationi

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. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. 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 PDPK1.8 Publications
In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity).By similarity1 Publication
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.3 Publications

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ15796
PaxDbiQ15796
PeptideAtlasiQ15796
PRIDEiQ15796

PTM databases

iPTMnetiQ15796
PhosphoSitePlusiQ15796

Expressioni

Tissue specificityi

Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta.1 Publication

Gene expression databases

BgeeiENSG00000175387
CleanExiHS_SMAD2
ExpressionAtlasiQ15796 baseline and differential
GenevisibleiQ15796 HS

Organism-specific databases

HPAiCAB025507
CAB073546
HPA067203

Interactioni

Subunit structurei

Monomer; 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 of the TGF-beta signaling. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C. Interacts with ZNF580. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif). Interacts with ZFHX3. Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity).By similarity28 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • activating transcription factor binding Source: UniProtKB
  • co-SMAD binding Source: BHF-UCL
  • disordered domain specific binding Source: CAFA
  • I-SMAD binding Source: BHF-UCL
  • phosphatase binding Source: UniProtKB
  • protein heterodimerization activity Source: Ensembl
  • protein homodimerization activity Source: Ensembl
  • R-SMAD binding Source: BHF-UCL
  • SMAD binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB
  • transforming growth factor beta receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110262, 264 interactors
CORUMiQ15796
DIPiDIP-29716N
IntActiQ15796, 233 interactors
MINTiQ15796
STRINGi9606.ENSP00000262160

Structurei

Secondary structure

1467
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi264 – 267Combined sources4
Beta strandi274 – 281Combined sources8
Beta strandi290 – 292Combined sources3
Beta strandi294 – 302Combined sources9
Beta strandi305 – 307Combined sources3
Beta strandi310 – 312Combined sources3
Helixi313 – 315Combined sources3
Helixi323 – 329Combined sources7
Turni330 – 334Combined sources5
Beta strandi336 – 341Combined sources6
Beta strandi344 – 349Combined sources6
Beta strandi351 – 353Combined sources3
Beta strandi355 – 358Combined sources4
Helixi360 – 365Combined sources6
Beta strandi374 – 376Combined sources3
Beta strandi381 – 386Combined sources6
Helixi387 – 397Combined sources11
Helixi398 – 400Combined sources3
Helixi402 – 406Combined sources5
Helixi407 – 412Combined sources6
Beta strandi413 – 419Combined sources7
Beta strandi423 – 427Combined sources5
Helixi431 – 433Combined sources3
Beta strandi434 – 442Combined sources9
Helixi443 – 453Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1DEVX-ray2.20A/C261-456[»]
1KHXX-ray1.80A241-467[»]
1U7VX-ray2.70A/C270-467[»]
2LB3NMR-B217-224[»]
ProteinModelPortaliQ15796
SMRiQ15796
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15796

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 176MH1PROSITE-ProRule annotationAdd BLAST167
Domaini274 – 467MH2PROSITE-ProRule annotationAdd BLAST194

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi221 – 225PY-motif5

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated

Phylogenomic databases

eggNOGiKOG3701 Eukaryota
ENOG410XQKU LUCA
GeneTreeiENSGT00760000119091
HOGENOMiHOG000286018
HOVERGENiHBG053353
InParanoidiQ15796
KOiK04500
OMAiDEICINP
OrthoDBiEOG091G082C
PhylomeDBiQ15796
TreeFamiTF314923

Family and domain databases

Gene3Di2.60.200.10, 1 hit
InterProiView protein in InterPro
IPR013790 Dwarfin
IPR003619 MAD_homology1_Dwarfin-type
IPR013019 MAD_homology_MH1
IPR017855 SMAD-like_dom_sf
IPR001132 SMAD_dom_Dwarfin-type
IPR008984 SMAD_FHA_dom_sf
IPR036578 SMAD_MH1_sf
PANTHERiPTHR13703 PTHR13703, 1 hit
PfamiView protein in Pfam
PF03165 MH1, 1 hit
PF03166 MH2, 1 hit
SMARTiView protein in SMART
SM00523 DWA, 1 hit
SM00524 DWB, 1 hit
SUPFAMiSSF49879 SSF49879, 1 hit
SSF56366 SSF56366, 2 hits
PROSITEiView protein in PROSITE
PS51075 MH1, 1 hit
PS51076 MH2, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Long (identifier: Q15796-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK
60 70 80 90 100
KLKKTGRLDE LEKAITTQNC NTKCVTIPST CSEIWGLSTP NTIDQWDTTG
110 120 130 140 150
LYSFSEQTRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH HELKAIENCE
160 170 180 190 200
YAFNLKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEILTEL PPLDDYTHSI
210 220 230 240 250
PENTNFPAGI EPQSNYIPET PPPGYISEDG ETSDQQLNQS MDTGSPAELS
260 270 280 290 300
PTTLSPVNHS LDLQPVTYSE PAFWCSIAYY ELNQRVGETF HASQPSLTVD
310 320 330 340 350
GFTDPSNSER FCLGLLSNVN RNATVEMTRR HIGRGVRLYY IGGEVFAECL
360 370 380 390 400
SDSAIFVQSP NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF AALLAQSVNQ
410 420 430 440 450
GFEAVYQLTR MCTIRMSFVK GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD
460
KVLTQMGSPS VRCSSMS
Length:467
Mass (Da):52,306
Last modified:November 1, 1996 - v1
Checksum:i95406DB5FC0AA4C9
GO
Isoform Short (identifier: Q15796-2) [UniParc]FASTAAdd to basket
Also known as: Smad2Deltaexon3

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

Show »
Length:437
Mass (Da):48,956
Checksum:i0E2FF38B009D2F9E
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_011375133R → C in a colorectal carcinoma sample. 1 Publication1
Natural variantiVAR_036473300D → V in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_011376344 – 358Missing in a colorectal carcinoma sample. 1 PublicationAdd BLAST15
Natural variantiVAR_011377440L → R in a colorectal carcinoma sample. 1 Publication1
Natural variantiVAR_011378445P → H in a colorectal carcinoma sample. 1 Publication1
Natural variantiVAR_011379450D → E in a colorectal carcinoma sample. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_00617879 – 108Missing in isoform Short. CuratedAdd BLAST30

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS11934.1 [Q15796-1]
PIRiS71797
RefSeqiNP_001003652.1, NM_001003652.3 [Q15796-1]
NP_005892.1, NM_005901.5 [Q15796-1]
XP_005258316.1, XM_005258259.3 [Q15796-1]
XP_006722514.1, XM_006722451.3 [Q15796-1]
XP_016881234.1, XM_017025745.1 [Q15796-1]
XP_016881235.1, XM_017025746.1 [Q15796-2]
UniGeneiHs.12253
Hs.705764
Hs.741342

Genome annotation databases

EnsembliENST00000262160; ENSP00000262160; ENSG00000175387 [Q15796-1]
ENST00000356825; ENSP00000349282; ENSG00000175387 [Q15796-2]
ENST00000402690; ENSP00000384449; ENSG00000175387 [Q15796-1]
ENST00000586040; ENSP00000466193; ENSG00000175387 [Q15796-2]
GeneIDi4087
KEGGihsa:4087
UCSCiuc010xdc.4 human [Q15796-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiSMAD2_HUMAN
AccessioniPrimary (citable) accession number: Q15796
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: November 1, 1996
Last modified: April 25, 2018
This is version 209 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health