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Protein

Mothers against decapentaplegic homolog 3

Gene

Smad3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 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 similarity1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei40 – 401Required for trimerizationBy similarity
Sitei41 – 411Required for interaction with DNA and JUN and for functional cooperation with JUNBy similarity
Metal bindingi64 – 641ZincBy similarity
Metal bindingi109 – 1091ZincBy similarity
Metal bindingi121 – 1211ZincBy similarity
Metal bindingi126 – 1261ZincBy similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-RNO-1181150. Signaling by NODAL.
R-RNO-1502540. Signaling by Activin.
R-RNO-2173788. Downregulation of TGF-beta receptor signaling.
R-RNO-2173789. TGF-beta receptor signaling activates SMADs.
R-RNO-2173795. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
R-RNO-2173796. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.

Names & Taxonomyi

Protein namesi
Recommended name:
Mothers against decapentaplegic homolog 3
Short name:
MAD homolog 3
Short name:
Mad3
Short name:
Mothers against DPP homolog 3
Alternative name(s):
SMAD family member 3
Short name:
SMAD 3
Short name:
Smad3
Gene namesi
Name:Smad3
Synonyms:Madh3
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 8

Organism-specific databases

RGDi3032. Smad3.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus 1 Publication

  • 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: RGD
  • nuclear chromatin Source: Ensembl
  • nuclear inner membrane Source: Ensembl
  • nucleoplasm Source: Ensembl
  • nucleus Source: BHF-UCL
  • plasma membrane Source: Ensembl
  • protein complex Source: RGD
  • receptor complex Source: Ensembl
  • SMAD2-SMAD3 protein complex Source: Ensembl
  • SMAD protein complex Source: UniProtKB
  • transcription factor complex Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 425424Mothers against decapentaplegic homolog 3PRO_0000090859Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Modified residuei8 – 81Phosphothreonine; by CDK2 and CDK4By similarity
Cross-linki33 – 33Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki81 – 81Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei179 – 1791Phosphothreonine; by CDK2, CDK4 and MAPKBy similarity
Modified residuei204 – 2041Phosphoserine; by GSK3 and MAPKPROSITE-ProRule annotationBy similarity
Modified residuei208 – 2081Phosphoserine; by MAPKPROSITE-ProRule annotationBy similarity
Modified residuei213 – 2131Phosphoserine; by CDK2 and CDK4PROSITE-ProRule annotationBy similarity
Modified residuei378 – 3781N6-acetyllysineBy similarity
Modified residuei416 – 4161PhosphoserinePROSITE-ProRule annotationBy similarity
Modified residuei418 – 4181Phosphoserine; by CK1PROSITE-ProRule annotationBy similarity
Modified residuei422 – 4221Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity
Modified residuei423 – 4231Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity
Modified residuei425 – 4251Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity

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. 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).By similarity
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, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP84025.
PRIDEiP84025.

PTM databases

PhosphoSiteiP84025.

Expressioni

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.

Gene expression databases

GenevisibleiP84025. RN.

Interactioni

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. Interaction with CSNK1G2. 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, PML, TGFB1I1, TTRAP, FOXL2, PRDM16, HGS and WWP1. Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts with MEN1. Interacts (via MH2 domain) with CITED2 (via C-terminus). 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 (By similarity). Interacts with ZFHX3 (By similarity). Interacts with ZNF451. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Akt1P471964EBI-7201857,EBI-7204362

GO - Molecular functioni

  • enzyme binding Source: BHF-UCL
  • SMAD binding Source: RGD
  • transcription factor binding Source: RGD

Protein-protein interaction databases

BioGridi247660. 3 interactions.
IntActiP84025. 1 interaction.
MINTiMINT-2739536.
STRINGi10116.ENSRNOP00000037346.

Chemistry

BindingDBiP84025.

Structurei

3D structure databases

ProteinModelPortaliP84025.
SMRiP84025. Positions 7-132, 228-425.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini10 – 136127MH1PROSITE-ProRule annotationAdd
BLAST
Domaini232 – 425194MH2PROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni137 – 23195LinkerAdd
BLAST
Regioni271 – 32454Sufficient for interaction with XPO4By similarityAdd
BLAST

Domaini

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
Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOVERGENiHBG053353.
InParanoidiP84025.
KOiK04500.
OMAiAVELCEY.
OrthoDBiEOG7W1540.
PhylomeDBiP84025.
TreeFamiTF314923.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProiIPR013790. 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]
PANTHERiPTHR13703. PTHR13703. 1 hit.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

P84025-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSILPFTPP IVKRLLGWKK GEQNGQEEKW CEKAVKSLVK KLKKTGQLDE
60 70 80 90 100
LEKAITTQNV NTKCITIPRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH
110 120 130 140 150
HELRAMELCE FAFNMKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEIPAEF
160 170 180 190 200
PPLDDYSHSI PENTNFPAGI EPQSNIPETP PPGYLSEDGE TSDHQMNHSM
210 220 230 240 250
DAGSPNLSPN PMSPAHNNLD LQPVTYCEPA FWCSISYYEL NQRVGETFHA
260 270 280 290 300
SQPSMTVDGF TDPSNSERFC LGLLSNVNRN AAVELTRRHI GRGVRLYYIG
310 320 330 340 350
GEVFAECLSD SAIFVQSPNC NQRYGWHPAT VCKIPPGCNL KIFNNQEFAA
360 370 380 390 400
LLAQSVNQGF EAVYQLTRMC TIRMSFVKGW GAEYRRQTVT STPCWIELHL
410 420
NGPLQWLDKV LTQMGSPSIR CSSVS
Length:425
Mass (Da):48,081
Last modified:July 5, 2004 - v1
Checksum:i46DF5E8B371321AC
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66479 mRNA. Translation: AAC52944.1.
BC064437 mRNA. Translation: AAH64437.1.
RefSeqiNP_037227.1. NM_013095.3.
UniGeneiRn.10636.

Genome annotation databases

EnsembliENSRNOT00000039730; ENSRNOP00000037346; ENSRNOG00000008620.
GeneIDi25631.
KEGGirno:25631.
UCSCiRGD:3032. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66479 mRNA. Translation: AAC52944.1.
BC064437 mRNA. Translation: AAH64437.1.
RefSeqiNP_037227.1. NM_013095.3.
UniGeneiRn.10636.

3D structure databases

ProteinModelPortaliP84025.
SMRiP84025. Positions 7-132, 228-425.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi247660. 3 interactions.
IntActiP84025. 1 interaction.
MINTiMINT-2739536.
STRINGi10116.ENSRNOP00000037346.

Chemistry

BindingDBiP84025.

PTM databases

PhosphoSiteiP84025.

Proteomic databases

PaxDbiP84025.
PRIDEiP84025.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000039730; ENSRNOP00000037346; ENSRNOG00000008620.
GeneIDi25631.
KEGGirno:25631.
UCSCiRGD:3032. rat.

Organism-specific databases

CTDi4088.
RGDi3032. Smad3.

Phylogenomic databases

eggNOGiKOG3701. Eukaryota.
ENOG410XQKU. LUCA.
GeneTreeiENSGT00760000119091.
HOVERGENiHBG053353.
InParanoidiP84025.
KOiK04500.
OMAiAVELCEY.
OrthoDBiEOG7W1540.
PhylomeDBiP84025.
TreeFamiTF314923.

Enzyme and pathway databases

ReactomeiR-RNO-1181150. Signaling by NODAL.
R-RNO-1502540. Signaling by Activin.
R-RNO-2173788. Downregulation of TGF-beta receptor signaling.
R-RNO-2173789. TGF-beta receptor signaling activates SMADs.
R-RNO-2173795. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
R-RNO-2173796. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.

Miscellaneous databases

NextBioi607435.
PROiP84025.

Gene expression databases

GenevisibleiP84025. RN.

Family and domain databases

Gene3Di2.60.200.10. 1 hit.
3.90.520.10. 1 hit.
InterProiIPR013790. 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]
PANTHERiPTHR13703. PTHR13703. 1 hit.
PfamiPF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]
SMARTiSM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]
SUPFAMiSSF49879. SSF49879. 1 hit.
SSF56366. SSF56366. 1 hit.
PROSITEiPS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Regulation of transforming growth factor beta- and activin-induced transcription by mammalian Mad proteins."
    Chen Y., Lebrun J.-J., Vale W.W.
    Proc. Natl. Acad. Sci. U.S.A. 93:12992-12997(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
    Tissue: Brain.
  2. "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: Prostate.
  3. "Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling."
    Kaji H., Canaff L., Lebrun J.J., Goltzman D., Hendy G.N.
    Proc. Natl. Acad. Sci. U.S.A. 98:3837-3842(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH MEN1.
  4. "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] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CITED2.

Entry informationi

Entry nameiSMAD3_RAT
AccessioniPrimary (citable) accession number: P84025
Secondary accession number(s): O09064
, O09144, O14510, O35273, Q92940, Q93002, Q9GKR4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 5, 2004
Last sequence update: July 5, 2004
Last modified: May 11, 2016
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

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.