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Protein

Mothers against decapentaplegic homolog 3

Gene

SMAD3

Organism
Sus scrofa (Pig)
Status
Reviewed-Annotation score: -Experimental evidence at transcript 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

Sites

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

Keywordsi

Biological processTranscription, Transcription regulation
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-SSC-1181150 Signaling by NODAL
R-SSC-1502540 Signaling by Activin
R-SSC-2173788 Downregulation of TGF-beta receptor signaling
R-SSC-2173789 TGF-beta receptor signaling activates SMADs
R-SSC-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-SSC-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-SSC-5689880 Ub-specific processing proteases
R-SSC-8941855 RUNX3 regulates CDKN1A 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
OrganismiSus scrofa (Pig)
Taxonomic identifieri9823 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaSuinaSuidaeSus
Proteomesi
  • UP000008227 Componenti: Chromosome 1

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000908582 – 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
Cross-linki33Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki81Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
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 annotationBy similarity1
Modified residuei423Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity1
Modified residuei425Phosphoserine; by TGFBR1PROSITE-ProRule annotationBy similarity1

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
Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.By similarity
Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. 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. Undergoes STUB1-mediated ubiquitination and degradation.By similarity

Keywords - PTMi

Acetylation, ADP-ribosylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP84024
PeptideAtlasiP84024
PRIDEiP84024

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

ExpressionAtlasiP84024 baseline and differential

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. 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). 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. Interacts with ZFHX3. Interacts with ZNF451. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts weakly with ZNF8. Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors. Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

MINTiP84024
STRINGi9823.ENSSSCP00000005327

Structurei

3D structure databases

ProteinModelPortaliP84024
SMRiP84024
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

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

Region

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

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

Phylogenomic databases

eggNOGiKOG3701 Eukaryota
ENOG410XQKU LUCA
GeneTreeiENSGT00760000119091
HOVERGENiHBG053353
InParanoidiP84024
KOiK04500

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-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, 1 hit
PROSITEiView protein in PROSITE
PS51075 MH1, 1 hit
PS51076 MH2, 1 hit

Sequencei

Sequence statusi: Complete.

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

P84024-1 [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
AB052738 mRNA Translation: BAB19634.1
RefSeqiNP_999302.1, NM_214137.1
UniGeneiSsc.15913

Genome annotation databases

EnsembliENSSSCT00000005464; ENSSSCP00000005327; ENSSSCG00000004952
GeneIDi397260
KEGGissc:397260

Similar proteinsi

Entry informationi

Entry nameiSMAD3_PIG
AccessioniPrimary (citable) accession number: P84024
Secondary accession number(s): O09064
, O09144, O14510, O35273, Q92940, Q93002, Q9GKR4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 5, 2004
Last sequence update: July 5, 2004
Last modified: September 12, 2018
This is version 122 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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