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Mothers against decapentaplegic homolog 3



Mus musculus (Mouse)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


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 SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity).By similarity5 Publications


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei40Required for trimerizationBy similarity1
Sitei41Required for interaction with DNA and JUN and for functional cooperation with JUNBy similarity1
Metal bindingi64ZincBy similarity1
Metal bindingi109ZincBy similarity1
Metal bindingi121ZincBy similarity1
Metal bindingi126ZincBy similarity1

GO - Molecular functioni

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: MGI
  • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway Source: Ensembl
  • activin receptor signaling pathway Source: MGI
  • canonical Wnt signaling pathway Source: Ensembl
  • cell-cell junction organization Source: MGI
  • cell cycle arrest Source: MGI
  • cellular response to transforming growth factor beta stimulus Source: MGI
  • developmental growth Source: MGI
  • embryonic cranial skeleton morphogenesis Source: MGI
  • embryonic foregut morphogenesis Source: MGI
  • embryonic pattern specification Source: MGI
  • endoderm development Source: MGI
  • evasion or tolerance of host defenses by virus Source: MGI
  • extrinsic apoptotic signaling pathway Source: MGI
  • gastrulation Source: MGI
  • heart looping Source: MGI
  • immune response Source: MGI
  • immune system development Source: MGI
  • in utero embryonic development Source: MGI
  • lens fiber cell differentiation Source: MGI
  • liver development Source: MGI
  • mesoderm formation Source: MGI
  • negative regulation of apoptotic process Source: Ensembl
  • negative regulation of cardiac muscle hypertrophy in response to stress Source: Ensembl
  • negative regulation of cell growth Source: MGI
  • negative regulation of cytosolic calcium ion concentration Source: MGI
  • negative regulation of fat cell differentiation Source: MGI
  • negative regulation of inflammatory response Source: UniProtKB
  • negative regulation of lung blood pressure Source: Ensembl
  • negative regulation of mitotic cell cycle Source: MGI
  • negative regulation of osteoblast differentiation Source: MGI
  • negative regulation of osteoblast proliferation Source: UniProtKB
  • negative regulation of protein catabolic process Source: Ensembl
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • negative regulation of wound healing Source: UniProtKB
  • nodal signaling pathway Source: MGI
  • osteoblast development Source: MGI
  • osteoblast differentiation Source: UniProtKB
  • paraxial mesoderm morphogenesis Source: MGI
  • pericardium development Source: MGI
  • positive regulation of alkaline phosphatase activity Source: Ensembl
  • positive regulation of bone mineralization Source: Ensembl
  • positive regulation of catenin import into nucleus Source: Ensembl
  • positive regulation of cell migration Source: Ensembl
  • positive regulation of chondrocyte differentiation Source: UniProtKB
  • positive regulation of epithelial to mesenchymal transition Source: MGI
  • positive regulation of extracellular matrix assembly Source: MGI
  • positive regulation of focal adhesion assembly Source: Ensembl
  • positive regulation of gene expression Source: MGI
  • positive regulation of interleukin-1 beta production Source: Ensembl
  • positive regulation of nitric oxide biosynthetic process Source: MGI
  • positive regulation of positive chemotaxis Source: Ensembl
  • positive regulation of pri-miRNA transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of stress fiber assembly Source: Ensembl
  • positive regulation of transcription, DNA-templated Source: MGI
  • positive regulation of transcription factor import into nucleus Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of transforming growth factor beta3 production Source: Ensembl
  • protein stabilization Source: Ensembl
  • regulation of binding Source: MGI
  • regulation of epithelial cell proliferation Source: MGI
  • regulation of immune response Source: UniProtKB
  • regulation of striated muscle tissue development Source: MGI
  • regulation of transcription from RNA polymerase II promoter Source: MGI
  • regulation of transforming growth factor beta2 production Source: MGI
  • regulation of transforming growth factor beta receptor signaling pathway Source: MGI
  • response to hypoxia Source: MGI
  • signal transduction involved in regulation of gene expression Source: Ensembl
  • skeletal system development Source: MGI
  • SMAD protein complex assembly Source: MGI
  • SMAD protein signal transduction Source: MGI
  • somitogenesis Source: MGI
  • T cell activation Source: UniProtKB
  • thyroid gland development Source: MGI
  • transcription from RNA polymerase II promoter Source: ProtInc
  • transdifferentiation Source: Ensembl
  • transforming growth factor beta receptor signaling pathway Source: MGI
  • transport Source: MGI
  • ureteric bud development Source: UniProtKB


Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-1181150. Signaling by NODAL.
R-MMU-1502540. Signaling by Activin.
R-MMU-2173788. Downregulation of TGF-beta receptor signaling.
R-MMU-2173789. TGF-beta receptor signaling activates SMADs.
R-MMU-2173795. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
R-MMU-2173796. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
R-MMU-5689880. Ub-specific processing proteases.
R-MMU-8941855. RUNX3 regulates CDKN1A transcription.

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 3
Short name:
MAD homolog 3
Short name:
Short name:
Mothers against DPP homolog 3
Short name:
Alternative name(s):
SMAD family member 3
Short name:
Short name:
Gene namesi
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:1201674. Smad3.

Subcellular locationi

  • Cytoplasm 2 Publications
  • Nucleus 2 Publications

  • Note: Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4. Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1. Co-localizes with LEMD3 at the nucleus inner membrane. MAPK-mediated phosphorylation appears to have no effect on nuclear import. PDPK1 prevents its nuclear translocation in response to TGF-beta.By similarity

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: MGI
  • nuclear chromatin Source: MGI
  • nuclear inner membrane Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: UniProtKB
  • plasma membrane Source: MGI
  • receptor complex Source: MGI
  • SMAD2-SMAD3 protein complex Source: MGI
  • SMAD protein complex Source: UniProtKB
  • transcription factor complex Source: UniProtKB

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

SMAD3 null mice exhibit inhibition of proliferation of mammary gland epithelial cells. Fibrobasts are only partially growth inhibited. Defects in osteoblast differentiation are observed. Animals are osteopenic with less cortical and cancellous bone. Facture healing is accelerated. Decreased bone mineral density (BMD) reflects the inability of osteoblasts to balance osteoclast activity. Wound healing is accelerated to about two and a half times that of normal animals. Wound areas are significantly reduced with less quantities of granulation tissue. There is reduced local infiltration of moncytes and keratinocytes show altered patterns of growth and migration. Accelerated wound healing is observed on castration of null male mice, while null female mice exhibited delayed healing following ovariectomy.4 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000908572 – 425Mothers against decapentaplegic homolog 3Add BLAST424

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei8Phosphothreonine; by CDK2 and CDK4By similarity1
Modified residuei179Phosphothreonine; by CDK2, CDK4 and MAPKBy similarity1
Modified residuei204Phosphoserine; by GSK3 and MAPKPROSITE-ProRule annotationBy similarity1
Modified residuei208Phosphoserine; by MAPKPROSITE-ProRule annotationBy similarity1
Modified residuei213Phosphoserine; by CDK2 and CDK4PROSITE-ProRule annotationBy similarity1
Modified residuei378N6-acetyllysineBy similarity1
Modified residuei416PhosphoserinePROSITE-ProRule annotationBy similarity1
Modified residuei418Phosphoserine; by CK1PROSITE-ProRule annotationBy similarity1
Modified residuei422Phosphoserine; by TGFBR1PROSITE-ProRule annotation1 Publication1
Modified residuei423Phosphoserine; by TGFBR1PROSITE-ProRule annotation1 Publication1
Modified residuei425Phosphoserine; by TGFBR1PROSITE-ProRule annotation1 Publication1

Post-translational modificationi

Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G1/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses (By similarity). Phosphorylated by PDPK1 (By similarity).By similarity
Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.By similarity
Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (By similarity). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (PubMed:17341133). Undergoes STUB1-mediated ubiquitination and degradation (By similarity).By similarity1 Publication
Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.By similarity

Keywords - PTMi

Acetylation, ADP-ribosylation, Phosphoprotein, Ubl conjugation

Proteomic databases


PTM databases



Tissue specificityi

Highly expressed in the brain and ovary. Detected in the pyramidal cells of the hippocampus, granule cells of the dentate gyrus, granular cells of the cerebral cortex and the granulosa cells of the ovary.1 Publication

Gene expression databases

ExpressionAtlasiQ8BUN5. baseline and differential.
GenevisibleiQ8BUN5. MM.


Subunit structurei

Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts (via the MH2 domain) with ZFYVE9. Interacts with HDAC1, VDR, TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and SNW1. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via the MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. 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 AIP1, TGFB1I1, TTRAP, FOXL2, PRDM16, HGS and WWP1. Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts with PML. Interacts with MEN1. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1. Interacts with ZC3H3 (PubMed:16115198). Interacts with ZFHX3 (By similarity). Interacts with ZNF451. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity). Interacts weakly with ZNF8 (PubMed:12370310). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (PubMed:17341133). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (By similarity).By similarity13 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi201276. 68 interactors.
IntActiQ8BUN5. 45 interactors.


3D structure databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 136MH1PROSITE-ProRule annotationAdd BLAST127
Domaini232 – 425MH2PROSITE-ProRule annotationAdd BLAST194


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni137 – 231LinkerAdd BLAST95
Regioni271 – 324Sufficient for interaction with XPO4By similarityAdd BLAST54


The MH1 domain is required for DNA binding (By similarity). Also binds zinc ions which are necessary for the 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).By similarity
The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.By similarity

Sequence similaritiesi

Belongs to the dwarfin/SMAD family.Curated

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProiView protein in 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.
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. 1 hit.
PROSITEiView protein in PROSITE
PS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.


Sequence statusi: Complete.

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

Q8BUN5-1 [UniParc]FASTAAdd to basket

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Mass (Da):48,081
Last modified:July 5, 2004 - v2

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti26Q → E in BAC38789 (PubMed:16141072).Curated1
Sequence conflicti269F → L in AAB81755 (Ref. 2) Curated1
Sequence conflicti408D → V in BAC33398 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
Links Updated
AB008192 mRNA. Translation: BAA76956.1.
AF016189 mRNA. Translation: AAB81755.1.
AK048626 mRNA. Translation: BAC33398.1.
AK083158 mRNA. Translation: BAC38789.1.
BC066850 mRNA. Translation: AAH66850.1.
RefSeqiNP_058049.3. NM_016769.4.

Genome annotation databases

EnsembliENSMUST00000034973; ENSMUSP00000034973; ENSMUSG00000032402.
UCSCiuc009qbi.1. mouse.

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiSMAD3_MOUSE
AccessioniPrimary (citable) accession number: Q8BUN5
Secondary accession number(s): O09064
, O09144, O14510, O35273, Q8BX84, Q92940, Q93002, Q9GKR4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 5, 2004
Last sequence update: July 5, 2004
Last modified: June 7, 2017
This is version 150 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Reference proteome


  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families