SMAD4_BOVIN
ID SMAD4_BOVIN Reviewed; 553 AA.
AC Q1HE26;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2006, sequence version 1.
DT 03-AUG-2022, entry version 100.
DE RecName: Full=Mothers against decapentaplegic homolog 4;
DE Short=MAD homolog 4;
DE Short=Mothers against DPP homolog 4;
DE AltName: Full=SMAD family member 4;
DE Short=SMAD 4;
DE Short=Smad4;
GN Name=SMAD4;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Zhang X., Xu S., Zhang L., Gao X., Ren H., Chen J.;
RT "Cloning and bioinformatic analysis of cDNA encoding cattle SMAD4 gene.";
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Common SMAD (co-SMAD) is the coactivator and mediator of
CC signal transduction by TGF-beta (transforming growth factor). Component
CC of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the
CC nucleus and is required for the TGF-mediated signaling. Promotes
CC binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an
CC activation function required for SMAD1 or SMAD2 to stimulate
CC transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex
CC which forms at the AP1 promoter site; required for synergistic
CC transcriptional activity in response to TGF-beta. Acts synergistically
CC with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated
CC cardiac-specific gene expression. Binds to SMAD binding elements (SBEs)
CC (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac
CC activating regions. May act as a tumor suppressor. Positively regulates
CC PDPK1 kinase activity by stimulating its dissociation from the 14-3-3
CC protein YWHAQ which acts as a negative regulator. In muscle physiology,
CC plays a central role in the balance between atrophy and hypertrophy.
CC When recruited by MSTN, promotes atrophy response via phosphorylated
CC SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment
CC by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8
CC (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Monomer; in the absence of TGF-beta activation (By
CC similarity). Heterotrimer; on TGF-beta activation (By similarity).
CC Heterotrimer composed of two molecules of a C-terminally phosphorylated
CC R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the
CC transcriptional active SMAD2/SMAD3-SMAD4 complex (By similarity). Found
CC in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found
CC in a complex with SMAD1 and YY1. Identified in a complex that contains
CC at least ZNF451, SMAD2, SMAD3 and SMAD4. Interacts with ATF2, COPS5,
CC DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with
CC ZNF423 or ZNF521 in response to BMP2 leading to activate transcription
CC of BMP target genes. Interacts with USP9X. Interacts with RBPMS.
CC Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1
CC and CITED2. Interacts with PDPK1 (via PH domain). Interacts with VPS39;
CC this interaction affects heterodimer formation with SMAD3, but not with
CC SMAD2, and leads to inhibition of SMAD3-dependent transcription
CC activation. Interactions with VPS39 and SMAD2 may be mutually
CC exclusive. Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-
CC finger domains). Interacts with ZC3H3. Interacts weakly with ZNF8.
CC Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus
CC through the NPC upon BMP7 stimulation resulting in activation of SMAD4
CC signaling (By similarity). Interacts with CREB3L1, the interaction
CC takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator
CC to induce the expression of genes involved in the assembly of collagen
CC extracellular matrix. Interacts with DLX1 (By similarity). Interacts
CC with ZBTB7A; the interaction is direct and stimulated by TGFB1 (By
CC similarity). Interacts with CREBBP; the recruitment of this
CC transcriptional coactivator is negatively regulated by ZBTB7A (By
CC similarity). Interacts with EP300; the interaction with this
CC transcriptional coactivator is negatively regulated by ZBTB7A (By
CC similarity). Interacts with HDAC1 (By similarity). Interacts (via MH2
CC domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling
CC pathway increases the activity of the SMAD3/SMAD4 transcriptional
CC complex (By similarity). {ECO:0000250|UniProtKB:O70437,
CC ECO:0000250|UniProtKB:P97471, ECO:0000250|UniProtKB:Q13485}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13485}. Nucleus
CC {ECO:0000250|UniProtKB:Q13485}. Note=Cytoplasmic in the absence of
CC ligand. Migrates to the nucleus when complexed with R-SMAD. PDPK1
CC prevents its nuclear translocation in response to TGF-beta.
CC {ECO:0000250|UniProtKB:Q13485}.
CC -!- DOMAIN: The MH1 domain is required for DNA binding. {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 -!- PTM: Monoubiquitinated on Lys-520 by E3 ubiquitin-protein ligase
CC TRIM33. Monoubiquitination hampers its ability to form a stable complex
CC with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP
CC signaling cascade (By similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated by PDPK1. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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DR EMBL; DQ494856; ABF50052.1; -; mRNA.
DR RefSeq; NP_001069677.1; NM_001076209.1.
DR AlphaFoldDB; Q1HE26; -.
DR SMR; Q1HE26; -.
DR STRING; 9913.ENSBTAP00000009081; -.
DR PaxDb; Q1HE26; -.
DR GeneID; 540248; -.
DR KEGG; bta:540248; -.
DR CTD; 4089; -.
DR eggNOG; KOG3701; Eukaryota.
DR InParanoid; Q1HE26; -.
DR OrthoDB; 905048at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005667; C:transcription regulator complex; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:InterPro.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:InterPro.
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; Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding;
KW Nucleus; Reference proteome; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc.
FT CHAIN 1..553
FT /note="Mothers against decapentaplegic homolog 4"
FT /id="PRO_0000252360"
FT DOMAIN 18..142
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 324..553
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 1..323
FT /note="Mediates interaction with ZBTB7A"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
FT REGION 168..194
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 275..321
FT /note="SAD"
FT COMPBIAS 171..194
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 71
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 115
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 127
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT SITE 516
FT /note="Necessary for heterotrimerization"
FT /evidence="ECO:0000250"
FT MOD_RES 37
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
FT MOD_RES 429
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
FT MOD_RES 508
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
FT CROSSLNK 113
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
FT CROSSLNK 520
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q13485"
SQ SEQUENCE 553 AA; 60542 MW; 40ECC20C6FE4D2AF CRC64;
MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA
ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD
LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPPSMLVKD EYVHDFEGQP SLSTEGHSIQ
TIQHPPSNRA STETYSTPAL LAPSESNATS TTNFPNIPVA STSQPASILA GSHSEGLLQI
ASGPQPGQQQ NGFTGQPATY HHNSTTTWTG GRTAPYTPNL PHHQNGHLQH HPPMPPHPGH
YWPPVHNELA FQPPISNHPA PEYWCSIAYF EMDVQVGETF KVPSSCPIVT VDGYVDPSGG
DRFCLGQLSN VHRTEAIERA RLHIGKGVQL ECKGEGDVWV RCLSDHAVFV QSYYLDREAG
RAPGDAVHKI YPSAYIKVFD LRQCHRQMQQ QAATAQAAAA AQAAAVAGNI PGPGSVGGIA
PAISLSAAAG IGVDDLRRLC ILRMSFVKGW GPDYPRQSIK ETPCWIEIHL HRALQLLDEV
LHTMPIADPQ PLD
