SMAD3_PIG
ID SMAD3_PIG Reviewed; 425 AA.
AC P84024; O09064; O09144; O14510; O35273; Q92940; Q93002; Q9GKR4;
DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Mothers against decapentaplegic homolog 3;
DE Short=MAD homolog 3;
DE Short=Mad3;
DE Short=Mothers against DPP homolog 3;
DE AltName: Full=SMAD family member 3;
DE Short=SMAD 3;
DE Short=Smad3;
GN Name=SMAD3; Synonyms=MADH3;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Muscle;
RA Yoshiyasu I., Takashi A., Ito Y., Awata T.;
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular
CC signal transducer and transcriptional modulator activated by TGF-beta
CC (transforming growth factor) and activin type 1 receptor kinases. Binds
CC the TRE element in the promoter region of many genes that are regulated
CC by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates
CC transcription. Can also form a SMAD3/SMAD4/JUN/FOS complex at the AP-
CC 1/SMAD site to regulate TGF-beta-mediated transcription. Has an
CC inhibitory effect on wound healing probably by modulating both growth
CC and migration of primary keratinocytes and by altering the TGF-mediated
CC chemotaxis of monocytes. This effect on wound healing appears to be
CC hormone-sensitive. Regulator of chondrogenesis and osteogenesis and
CC inhibits early healing of bone fractures. Positively regulates PDPK1
CC kinase activity by stimulating its dissociation from the 14-3-3 protein
CC YWHAQ which acts as a negative regulator.
CC {ECO:0000250|UniProtKB:P84022}.
CC -!- SUBUNIT: Monomer; in the absence of TGF-beta (By similarity).
CC Homooligomer; in the presence of TGF-beta (By similarity).
CC Heterotrimer; forms a heterotrimer in the presence of TGF-beta
CC consisting of two molecules of C-terminally phosphorylated SMAD2 or
CC SMAD3 and one of SMAD4 to form the transcriptionally active
CC SMAD2/SMAD3-SMAD4 complex (By similarity). Part of a complex consisting
CC of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Forms a complex with
CC SMAD2 and TRIM33 upon addition of TGF-beta (By similarity). Found in a
CC complex composed of SMAD3, RAN and XPO4; within the complex interacts
CC directly with XPO4 (By similarity). Component of the multimeric complex
CC SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for
CC synergistic transcriptional activity in response to TGF-beta (By
CC similarity). Interacts (via an N-terminal domain) with JUN (via its
CC basic DNA binding and leucine zipper domains); this interaction is
CC essential for DNA binding and cooperative transcriptional activity in
CC response to TGF-beta (By similarity). Identified in a complex that
CC contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity).
CC Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-
CC terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex,
CC nuclear export and termination of TGF-beta signaling (By similarity).
CC Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the
CC TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4
CC transcriptional complex (By similarity). Interacts (when
CC phosphorylated) with RNF111; RNF111 acts as an enhancer of the
CC transcriptional responses by mediating ubiquitination and degradation
CC of SMAD3 inhibitors (By similarity). Interacts (dephosphorylated form
CC via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain);
CC the interaction results in the export of dephosphorylated SMAD3 out of
CC the nucleus and termination of the TGF-beta signaling (By similarity).
CC Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3
CC transcriptional activity through preventing the formation of the
CC heteromeric complex with SMAD4 and translocation to the nucleus (By
CC similarity). Interacts (via the linker region) with EP300 (C-terminal);
CC the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta
CC phosphorylation in the C-terminal of SMAD3 (By similarity). This
CC interaction can be blocked by competitive binding of adenovirus
CC oncoprotein E1A to the same C-terminal site on EP300, which then
CC results in partially inhibited SMAD3/SMAD4 transcriptional activity (By
CC similarity). Interacts with TGFBR1 (By similarity). Interacts with
CC TGFB1I1 (By similarity). Interacts with PRDM16 (By similarity).
CC Interacts with SNW1 (By similarity). Interacts (via MH2 domain) with
CC ZFYVE9 (By similarity). Interacts with HDAC1 (By similarity). Interacts
CC with TGIF2 (By similarity). Interacts with SKOR1 (By similarity).
CC Interacts with SKOR2 (By similarity). Interacts with DACH1; the
CC interaction inhibits the TGF-beta signaling (By similarity). Interacts
CC with RBPMS (By similarity). Interacts (via MH2 domain) with MECOM (By
CC similarity). Interacts with WWTR1 (via its coiled-coil domain) (By
CC similarity). Interacts with SKI; the interaction represses SMAD3
CC transcriptional activity (By similarity). Interacts with MEN1 (By
CC similarity). Interacts with IL1F7 (By similarity). Interaction with
CC CSNK1G2 (By similarity). Interacts with PDPK1 (via PH domain) (By
CC similarity). Interacts with DAB2; the interactions are enhanced upon
CC TGF-beta stimulation (By similarity). Interacts with USP15 (By
CC similarity). Interacts with PPP5C; the interaction decreases SMAD3
CC phosphorylation and protein levels (By similarity). Interacts with
CC LDLRAD4 (via the SMAD interaction motif) (By similarity). Interacts
CC with PMEPA1 (By similarity). Interacts with ZNF451 (By similarity).
CC Interacts with ZFHX3 (By similarity). Interacts weakly with ZNF8 (By
CC similarity). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and
CC HSP90AB1 (By similarity). Interacts with YAP1 (when phosphorylated at
CC 'Ser-55') (By similarity). Interacts with AIP1 (By similarity).
CC Interacts (via MH2 domain) with CITED2 (via C-terminus) (By
CC similarity). Interacts with HGS (By similarity). Interacts with WWP1
CC (By similarity). Interacts with TTRAP (By similarity). Interacts with
CC FOXL2 (By similarity). Interacts with PML (By similarity). Interacts
CC with NEDD4L; the interaction requires TGF-beta stimulation (By
CC similarity). Interacts with ZC3H3 (By similarity). Interacts with TGIF.
CC Interacts with CREBBP. Interacts with ATF2.
CC {ECO:0000250|UniProtKB:P84022, ECO:0000250|UniProtKB:P84025,
CC ECO:0000250|UniProtKB:Q8BUN5}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P84022}. Nucleus
CC {ECO:0000250|UniProtKB:P84022}. Note=Cytoplasmic and nuclear in the
CC absence of TGF-beta (By similarity). On TGF-beta stimulation, migrates
CC to the nucleus when complexed with SMAD4 (By similarity). Through the
CC action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex,
CC and exported out of the nucleus by interaction with RANBP1 (By
CC similarity). Co-localizes with LEMD3 at the nucleus inner membrane (By
CC similarity). MAPK-mediated phosphorylation appears to have no effect on
CC nuclear import (By similarity). PDPK1 prevents its nuclear
CC translocation in response to TGF-beta (By similarity). Localized mainly
CC to the nucleus in the early stages of embryo development with
CC expression becoming evident in the cytoplasm of the inner cell mass at
CC the blastocyst stage (By similarity). {ECO:0000250|UniProtKB:P84022,
CC ECO:0000250|UniProtKB:Q8BUN5}.
CC -!- TISSUE SPECIFICITY: Highly expressed in the brain and ovary. Detected
CC in the pyramidal cells of the hippocampus, granule cells of the dentate
CC gyrus, granular cells of the cerebral cortex and the granulosa cells of
CC the ovary.
CC -!- DOMAIN: The MH1 domain is required for DNA binding (By similarity).
CC Also binds zinc ions which are necessary for the DNA binding.
CC {ECO:0000250}.
CC -!- DOMAIN: The MH2 domain is required for both homomeric and heteromeric
CC interactions and for transcriptional regulation. Sufficient for nuclear
CC import (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The linker region is required for the TGFbeta-mediated
CC transcriptional activity and acts synergistically with the MH2 domain.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylated on serine and threonine residues. Enhanced
CC phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on
CC EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated
CC phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle
CC dependent manner and inhibits both the transcriptional activity and
CC antiproliferative functions of SMAD3. This phosphorylation is inhibited
CC by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also
CC phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1
CC and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is
CC required for interaction with SMAD4, nuclear location and
CC transactivational activity, and appears to be a prerequisite for the
CC TGF-beta mediated phosphorylation in the linker region.
CC Dephosphorylated in the C-terminal SXS motif by PPM1A. This
CC dephosphorylation disrupts the interaction with SMAD4, promotes nuclear
CC export and terminates TGF-beta-mediated signaling. Phosphorylation at
CC Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and
CC subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-
CC beta responses. Phosphorylated by PDPK1 (By similarity).
CC {ECO:0000250|UniProtKB:P84022}.
CC -!- PTM: Acetylation in the nucleus by EP300 in the MH2 domain regulates
CC positively its transcriptional activity and is enhanced by TGF-beta.
CC {ECO:0000250|UniProtKB:P84022}.
CC -!- PTM: Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation
CC negatively regulates SMAD3 transcriptional responses during the course
CC of TGF-beta signaling. {ECO:0000250|UniProtKB:P84022}.
CC -!- PTM: Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding.
CC Deubiquitination by USP15 alleviates inhibition and promotes activation
CC of TGF-beta target genes. Ubiquitinated by RNF111, leading to its
CC degradation: only SMAD3 proteins that are 'in use' are targeted by
CC RNF111, RNF111 playing a key role in activating SMAD3 and regulating
CC its turnover. Undergoes STUB1-mediated ubiquitination and degradation.
CC {ECO:0000250|UniProtKB:P84022, ECO:0000250|UniProtKB:Q8BUN5}.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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DR EMBL; AB052738; BAB19634.1; -; mRNA.
DR RefSeq; NP_999302.1; NM_214137.1.
DR AlphaFoldDB; P84024; -.
DR SMR; P84024; -.
DR MINT; P84024; -.
DR STRING; 9823.ENSSSCP00000005327; -.
DR PaxDb; P84024; -.
DR PeptideAtlas; P84024; -.
DR PRIDE; P84024; -.
DR Ensembl; ENSSSCT00000005464; ENSSSCP00000005327; ENSSSCG00000004952.
DR Ensembl; ENSSSCT00005057440; ENSSSCP00005035375; ENSSSCG00005035367.
DR Ensembl; ENSSSCT00015062164; ENSSSCP00015024943; ENSSSCG00015045925.
DR Ensembl; ENSSSCT00025043673; ENSSSCP00025018565; ENSSSCG00025032064.
DR Ensembl; ENSSSCT00030064740; ENSSSCP00030029587; ENSSSCG00030046321.
DR Ensembl; ENSSSCT00035076339; ENSSSCP00035031189; ENSSSCG00035057061.
DR Ensembl; ENSSSCT00040041424; ENSSSCP00040017352; ENSSSCG00040030551.
DR Ensembl; ENSSSCT00045018396; ENSSSCP00045012692; ENSSSCG00045010800.
DR Ensembl; ENSSSCT00050004607; ENSSSCP00050001837; ENSSSCG00050003377.
DR Ensembl; ENSSSCT00055059976; ENSSSCP00055048056; ENSSSCG00055030102.
DR Ensembl; ENSSSCT00060092092; ENSSSCP00060039794; ENSSSCG00060067444.
DR Ensembl; ENSSSCT00070014919; ENSSSCP00070012342; ENSSSCG00070007681.
DR GeneID; 397260; -.
DR KEGG; ssc:397260; -.
DR CTD; 4088; -.
DR VGNC; VGNC:93217; SMAD3.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000153499; -.
DR InParanoid; P84024; -.
DR OMA; MKHRLGA; -.
DR OrthoDB; 608001at2759; -.
DR Proteomes; UP000008227; Chromosome 1.
DR Proteomes; UP000314985; Chromosome 1.
DR Bgee; ENSSSCG00000004952; Expressed in muscle tissue and 45 other tissues.
DR ExpressionAtlas; P84024; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0071141; C:SMAD protein complex; ISS:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0070411; F:I-SMAD binding; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR001132; SMAD_dom_Dwarfin-type.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036578; SMAD_MH1_sf.
DR PANTHER; PTHR13703; PTHR13703; 1.
DR Pfam; PF03165; MH1; 1.
DR Pfam; PF03166; MH2; 1.
DR SMART; SM00523; DWA; 1.
DR SMART; SM00524; DWB; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 1.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 2: Evidence at transcript level;
KW Acetylation; ADP-ribosylation; Cytoplasm; Isopeptide bond; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT CHAIN 2..425
FT /note="Mothers against decapentaplegic homolog 3"
FT /id="PRO_0000090858"
FT DOMAIN 10..136
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 232..425
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 137..231
FT /note="Linker"
FT REGION 165..208
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 271..324
FT /note="Sufficient for interaction with XPO4"
FT /evidence="ECO:0000250"
FT BINDING 64
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 109
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 121
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 126
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT SITE 40
FT /note="Required for trimerization"
FT /evidence="ECO:0000250"
FT SITE 41
FT /note="Required for interaction with DNA and JUN and for
FT functional cooperation with JUN"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT MOD_RES 8
FT /note="Phosphothreonine; by CDK2 and CDK4"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT MOD_RES 179
FT /note="Phosphothreonine; by CDK2, CDK4 and MAPK"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT MOD_RES 204
FT /note="Phosphoserine; by GSK3 and MAPK"
FT /evidence="ECO:0000250|UniProtKB:P84022,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 208
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000250|UniProtKB:P84022,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 213
FT /note="Phosphoserine; by CDK2 and CDK4"
FT /evidence="ECO:0000250|UniProtKB:P84022,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 378
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT MOD_RES 416
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P84022,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 418
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:P84022,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 422
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000250|UniProtKB:Q8BUN5,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 423
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000250|UniProtKB:Q8BUN5,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 425
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000250|UniProtKB:Q8BUN5,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT CROSSLNK 33
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P84022"
FT CROSSLNK 81
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P84022"
SQ SEQUENCE 425 AA; 48081 MW; 46DF5E8B371321AC CRC64;
MSSILPFTPP IVKRLLGWKK GEQNGQEEKW CEKAVKSLVK KLKKTGQLDE LEKAITTQNV
NTKCITIPRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH HELRAMELCE FAFNMKKDEV
CVNPYHYQRV ETPVLPPVLV PRHTEIPAEF PPLDDYSHSI PENTNFPAGI EPQSNIPETP
PPGYLSEDGE TSDHQMNHSM DAGSPNLSPN PMSPAHNNLD LQPVTYCEPA FWCSISYYEL
NQRVGETFHA SQPSMTVDGF TDPSNSERFC LGLLSNVNRN AAVELTRRHI GRGVRLYYIG
GEVFAECLSD SAIFVQSPNC NQRYGWHPAT VCKIPPGCNL KIFNNQEFAA LLAQSVNQGF
EAVYQLTRMC TIRMSFVKGW GAEYRRQTVT STPCWIELHL NGPLQWLDKV LTQMGSPSIR
CSSVS
