Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (SMAD family member 4) (SMAD 4) (Smad4)

 SMAD4_RAT               Reviewed;         552 AA.
 O70437;
 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
 01-AUG-1998, sequence version 1.
 02-DEC-2020, entry version 152.
 RecName: Full=Mothers against decapentaplegic homolog 4;
          Short=MAD homolog 4;
          Short=Mothers against DPP homolog 4;
 AltName: Full=SMAD family member 4;
          Short=SMAD 4;
          Short=Smad4;
 Name=Smad4; Synonyms=Madh4;
 Rattus norvegicus (Rat).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
 Murinae; Rattus.
 NCBI_TaxID=10116;
 [1]
 NUCLEOTIDE SEQUENCE [MRNA].
 TISSUE=Skeletal muscle;
 Miyakita A., Okuno S., Watanabe T.K., Oga K., Tsuji A., Hishigaki H.,
 Suto T., Nakagawa K., Nakahara Y., Higashi K.;
 "Molecular cloning of rat Smad4 gene.";
 Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases.
 [2]
 NUCLEOTIDE SEQUENCE [MRNA].
 PubMed=10670756; DOI=10.1507/endocrj.46.695;
 Osaki M., Tsukazaki T., Ono N., Yonekura A., Hirota Y., Miyazaki Y.,
 Shindo H., Sonta S., Yamashita S.;
 "cDNA cloning and chromosomal mapping of rat Smad2 and Smad4 and their
 expression in cultured rat articular chondrocytes.";
 Endocr. J. 46:695-701(1999).
 [3]
 INTERACTION WITH CITED2.
 PubMed=16619037; DOI=10.1038/sj.onc.1209552;
 Chou Y.T., Wang H., Chen Y., Danielpour D., Yang Y.C.;
 "Cited2 modulates TGF-beta-mediated upregulation of MMP9.";
 Oncogene 25:5547-5560(2006).
 -!- FUNCTION: Common SMAD (co-SMAD) is the coactivator and mediator of
     signal transduction by TGF-beta (transforming growth factor). Component
     of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the
     nucleus and is required for the TGF-mediated signaling. Promotes
     binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an
     activation function required for SMAD1 or SMAD2 to stimulate
     transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex
     which forms at the AP1 promoter site; required for synergistic
     transcriptional activity in response to TGF-beta. Acts synergistically
     with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated
     cardiac-specific gene expression. Binds to SMAD binding elements (SBEs)
     (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac
     activating regions. May act as a tumor suppressor. Positively regulates
     PDPK1 kinase activity by stimulating its dissociation from the 14-3-3
     protein YWHAQ which acts as a negative regulator. In muscle physiology,
     plays a central role in the balance between atrophy and hypertrophy.
     When recruited by MSTN, promotes atrophy response via phosphorylated
     SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment
     by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8
     (By similarity). {ECO:0000250}.
 -!- SUBUNIT: Monomer; in the absence of TGF-beta activation (By
     similarity). Heterotrimer; on TGF-beta activation (By similarity).
     Heterotrimer composed of two molecules of a C-terminally phosphorylated
     R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the
     transcriptional active SMAD2/SMAD3-SMAD4 complex (By similarity). Found
     in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found
     in a complex with SMAD1 and YY1. Identified in a complex that contains
     at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity).Interacts with
     ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33.
     Associates with ZNF423 or ZNF521 in response to BMP2 leading to
     activate transcription of BMP target genes. Interacts with USP9X.
     Interacts with RBPMS. Interacts with WWTR1 (via coiled-coil domain).
     Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain).
     Interacts with VPS39; this interaction affects heterodimer formation
     with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-
     dependent transcription activation. Interactions with VPS39 and SMAD2
     may be mutually exclusive (By similarity). Interacts (via MH2 domain)
     with ZNF451 (via N-terminal zinc-finger domains) (By similarity).
     Interacts with ZC3H3 (By similarity). Interacts weakly with ZNF8 (By
     similarity). Interacts with NUP93 and IPO7; translocates SMAD4 to the
     nucleus through the NPC upon BMP7 stimulation resulting in activation
     of SMAD4 signaling (By similarity). Interacts with CREB3L1, the
     interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1
     coactivator to induce the expression of genes involved in the assembly
     of collagen extracellular matrix (By similarity). Interacts with DLX1
     (By similarity). Interacts with ZBTB7A; the interaction is direct and
     stimulated by TGFB1 (By similarity). Interacts with CREBBP; the
     recruitment of this transcriptional coactivator is negatively regulated
     by ZBTB7A (By similarity). Interacts with EP300; the interaction with
     this transcriptional coactivator is negatively regulated by ZBTB7A (By
     similarity). Interacts with HDAC1 (By similarity). Interacts (via MH2
     domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling
     pathway increases the activity of the SMAD3/SMAD4 transcriptional
     complex (By similarity). {ECO:0000250|UniProtKB:P97471,
     ECO:0000250|UniProtKB:Q13485, ECO:0000269|PubMed:16619037}.
 -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13485}. Nucleus
     {ECO:0000250|UniProtKB:Q13485}. Note=In the cytoplasm in the absence of
     ligand. Migration to the nucleus when complexed with R-SMAD. PDPK1
     prevents its nuclear translocation. {ECO:0000250|UniProtKB:Q13485}.
 -!- DOMAIN: The MH1 domain is required for DNA binding. {ECO:0000250}.
 -!- DOMAIN: The MH2 domain is required for both homomeric and heteromeric
     interactions and for transcriptional regulation. Sufficient for nuclear
     import (By similarity). {ECO:0000250}.
 -!- PTM: Phosphorylated by PDPK1. {ECO:0000250}.
 -!- PTM: Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase
     TRIM33. Monoubiquitination hampers its ability to form a stable complex
     with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP
     signaling cascade. Deubiquitination by USP9X restores its competence to
     mediate TGF-beta signaling (By similarity). {ECO:0000250}.
 -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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 EMBL; AB010954; BAA83092.1; -; mRNA.
 EMBL; AF056002; AAC12781.1; -; mRNA.
 RefSeq; NP_062148.1; NM_019275.3.
 SMR; O70437; -.
 IntAct; O70437; 1.
 MINT; O70437; -.
 STRING; 10116.ENSRNOP00000021113; -.
 iPTMnet; O70437; -.
 PhosphoSitePlus; O70437; -.
 jPOST; O70437; -.
 PRIDE; O70437; -.
 GeneID; 50554; -.
 KEGG; rno:50554; -.
 CTD; 4089; -.
 RGD; 3033; Smad4.
 eggNOG; KOG3701; Eukaryota.
 InParanoid; O70437; -.
 OrthoDB; 905048at2759; -.
 PhylomeDB; O70437; -.
 Reactome; R-RNO-1181150; Signaling by NODAL.
 Reactome; R-RNO-1502540; Signaling by Activin.
 Reactome; R-RNO-201451; Signaling by BMP.
 Reactome; R-RNO-2173789; TGF-beta receptor signaling activates SMADs.
 Reactome; R-RNO-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
 Reactome; R-RNO-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
 Reactome; R-RNO-5689880; Ub-specific processing proteases.
 Reactome; R-RNO-8941326; RUNX2 regulates bone development.
 Reactome; R-RNO-8941855; RUNX3 regulates CDKN1A transcription.
 Reactome; R-RNO-9617828; FOXO-mediated transcription of cell cycle genes.
 PRO; PR:O70437; -.
 Proteomes; UP000002494; Unplaced.
 GO; GO:0032444; C:activin responsive factor complex; ISO:RGD.
 GO; GO:0005737; C:cytoplasm; IDA:RGD.
 GO; GO:0071144; C:heteromeric SMAD protein complex; IBA:GO_Central.
 GO; GO:0000790; C:nuclear chromatin; ISO:RGD.
 GO; GO:0005634; C:nucleus; IDA:RGD.
 GO; GO:0032991; C:protein-containing complex; IDA:RGD.
 GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISO:RGD.
 GO; GO:0071141; C:SMAD protein complex; ISO:RGD.
 GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
 GO; GO:0003682; F:chromatin binding; ISO:RGD.
 GO; GO:0005518; F:collagen binding; ISO:RGD.
 GO; GO:0003677; F:DNA binding; IDA:RGD.
 GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD.
 GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:RGD.
 GO; GO:0031005; F:filamin binding; IPI:RGD.
 GO; GO:0070411; F:I-SMAD binding; ISO:RGD.
 GO; GO:0042802; F:identical protein binding; ISO:RGD.
 GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
 GO; GO:0070412; F:R-SMAD binding; ISO:RGD.
 GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
 GO; GO:0001085; F:RNA polymerase II transcription factor binding; ISO:RGD.
 GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; ISO:RGD.
 GO; GO:0046332; F:SMAD binding; IPI:RGD.
 GO; GO:0043199; F:sulfate binding; ISO:RGD.
 GO; GO:0001223; F:transcription coactivator binding; ISO:RGD.
 GO; GO:0008134; F:transcription factor binding; IBA:GO_Central.
 GO; GO:0000976; F:transcription regulatory region sequence-specific DNA binding; ISO:RGD.
 GO; GO:0031625; F:ubiquitin protein ligase binding; IBA:GO_Central.
 GO; GO:0030325; P:adrenal gland development; IEP:RGD.
 GO; GO:0007568; P:aging; IEP:RGD.
 GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
 GO; GO:0009952; P:anterior/posterior pattern specification; ISO:RGD.
 GO; GO:0036302; P:atrioventricular canal development; ISO:RGD.
 GO; GO:0003190; P:atrioventricular valve formation; ISO:RGD.
 GO; GO:0007411; P:axon guidance; ISO:RGD.
 GO; GO:0030509; P:BMP signaling pathway; ISO:RGD.
 GO; GO:0003360; P:brainstem development; ISO:RGD.
 GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; ISO:RGD.
 GO; GO:0003279; P:cardiac septum development; ISO:RGD.
 GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
 GO; GO:0008283; P:cell population proliferation; ISO:RGD.
 GO; GO:0006879; P:cellular iron ion homeostasis; ISO:RGD.
 GO; GO:0071333; P:cellular response to glucose stimulus; IDA:RGD.
 GO; GO:0048589; P:developmental growth; ISO:RGD.
 GO; GO:0042733; P:embryonic digit morphogenesis; ISO:RGD.
 GO; GO:0060956; P:endocardial cell differentiation; ISO:RGD.
 GO; GO:0007492; P:endoderm development; ISO:RGD.
 GO; GO:0042118; P:endothelial cell activation; ISO:RGD.
 GO; GO:0003198; P:epithelial to mesenchymal transition involved in endocardial cushion formation; ISO:RGD.
 GO; GO:0070371; P:ERK1 and ERK2 cascade; IMP:RGD.
 GO; GO:0008585; P:female gonad development; ISO:RGD.
 GO; GO:0061040; P:female gonad morphogenesis; ISO:RGD.
 GO; GO:0048859; P:formation of anatomical boundary; ISO:RGD.
 GO; GO:0007369; P:gastrulation; ISO:RGD.
 GO; GO:0001702; P:gastrulation with mouth forming second; ISO:RGD.
 GO; GO:0001701; P:in utero embryonic development; ISO:RGD.
 GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISO:RGD.
 GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
 GO; GO:0001822; P:kidney development; ISO:RGD.
 GO; GO:0003220; P:left ventricular cardiac muscle tissue morphogenesis; ISO:RGD.
 GO; GO:0008584; P:male gonad development; ISO:RGD.
 GO; GO:0007498; P:mesoderm development; ISO:RGD.
 GO; GO:0072133; P:metanephric mesenchyme morphogenesis; ISO:RGD.
 GO; GO:0010614; P:negative regulation of cardiac muscle hypertrophy; ISO:RGD.
 GO; GO:1905305; P:negative regulation of cardiac myofibril assembly; ISO:RGD.
 GO; GO:0060548; P:negative regulation of cell death; ISO:RGD.
 GO; GO:0030308; P:negative regulation of cell growth; ISO:RGD.
 GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
 GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISO:RGD.
 GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL.
 GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
 GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:RGD.
 GO; GO:0072134; P:nephrogenic mesenchyme morphogenesis; ISO:RGD.
 GO; GO:0014033; P:neural crest cell differentiation; ISO:RGD.
 GO; GO:0048663; P:neuron fate commitment; ISO:RGD.
 GO; GO:0001649; P:osteoblast differentiation; IMP:RGD.
 GO; GO:0003148; P:outflow tract septum morphogenesis; ISO:RGD.
 GO; GO:0001541; P:ovarian follicle development; IEP:RGD.
 GO; GO:0030513; P:positive regulation of BMP signaling pathway; ISO:RGD.
 GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IMP:RGD.
 GO; GO:0003251; P:positive regulation of cell proliferation involved in heart valve morphogenesis; ISO:RGD.
 GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISO:RGD.
 GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; ISO:RGD.
 GO; GO:0051571; P:positive regulation of histone H3-K4 methylation; ISO:RGD.
 GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; ISO:RGD.
 GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; ISO:RGD.
 GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISO:RGD.
 GO; GO:1902895; P:positive regulation of pri-miRNA transcription by RNA polymerase II; ISO:RGD.
 GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; ISO:RGD.
 GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
 GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
 GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISO:RGD.
 GO; GO:0051098; P:regulation of binding; ISO:RGD.
 GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD.
 GO; GO:0051797; P:regulation of hair follicle development; ISO:RGD.
 GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:RGD.
 GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; ISO:RGD.
 GO; GO:0032909; P:regulation of transforming growth factor beta2 production; ISO:RGD.
 GO; GO:0001666; P:response to hypoxia; ISO:RGD.
 GO; GO:0071559; P:response to transforming growth factor beta; ISO:RGD.
 GO; GO:0048733; P:sebaceous gland development; ISO:RGD.
 GO; GO:0062009; P:secondary palate development; ISO:RGD.
 GO; GO:0072520; P:seminiferous tubule development; ISO:RGD.
 GO; GO:0007338; P:single fertilization; ISO:RGD.
 GO; GO:0007183; P:SMAD protein complex assembly; ISO:RGD.
 GO; GO:0060395; P:SMAD protein signal transduction; ISO:RGD.
 GO; GO:0032525; P:somite rostral/caudal axis specification; ISO:RGD.
 GO; GO:0007283; P:spermatogenesis; ISO:RGD.
 GO; GO:0048729; P:tissue morphogenesis; ISO:RGD.
 GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISO:RGD.
 GO; GO:0060065; P:uterus development; ISO:RGD.
 GO; GO:0060412; P:ventricular septum morphogenesis; ISO:RGD.
 GO; GO:0042060; P:wound healing; IMP:RGD.
 Gene3D; 2.60.200.10; -; 1.
 Gene3D; 3.90.520.10; -; 1.
 InterPro; IPR013790; Dwarfin.
 InterPro; IPR003619; MAD_homology1_Dwarfin-type.
 InterPro; IPR013019; MAD_homology_MH1.
 InterPro; IPR017855; SMAD-like_dom_sf.
 InterPro; IPR001132; SMAD_dom_Dwarfin-type.
 InterPro; IPR008984; SMAD_FHA_dom_sf.
 InterPro; IPR036578; SMAD_MH1_sf.
 PANTHER; PTHR13703; PTHR13703; 1.
 Pfam; PF03165; MH1; 1.
 Pfam; PF03166; MH2; 1.
 SMART; SM00523; DWA; 1.
 SMART; SM00524; DWB; 1.
 SUPFAM; SSF49879; SSF49879; 1.
 SUPFAM; SSF56366; SSF56366; 1.
 PROSITE; PS51075; MH1; 1.
 PROSITE; PS51076; MH2; 1.
 1: Evidence at protein level;
 Acetylation; Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding;
 Nucleus; Reference proteome; Transcription; Transcription regulation;
 Ubl conjugation; Zinc.
 CHAIN           1..552
                 /note="Mothers against decapentaplegic homolog 4"
                 /id="PRO_0000090864"
 DOMAIN          18..142
                 /note="MH1"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
 DOMAIN          323..552
                 /note="MH2"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
 REGION          1..322
                 /note="Mediates interaction with ZBTB7A"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 REGION          275..320
                 /note="SAD"
 COMPBIAS        451..466
                 /note="Poly-Ala"
 METAL           71
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           115
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           127
                 /note="Zinc"
                 /evidence="ECO:0000250"
 METAL           132
                 /note="Zinc"
                 /evidence="ECO:0000250"
 SITE            515
                 /note="Necessary for heterotrimerization"
                 /evidence="ECO:0000250"
 MOD_RES         37
                 /note="N6-acetyllysine"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 MOD_RES         428
                 /note="N6-acetyllysine"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 MOD_RES         507
                 /note="N6-acetyllysine"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 CROSSLNK        113
                 /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
                 G-Cter in SUMO2)"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 CROSSLNK        519
                 /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
                 G-Cter in ubiquitin)"
                 /evidence="ECO:0000250|UniProtKB:Q13485"
 SEQUENCE   552 AA;  60469 MW;  7AE0540AB4DF0E77 CRC64;
 MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA
 ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD
 LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPPSMLVKD EYVHDFEGQP SLPTEGHSIQ
 TIQHPPSNRA STETYSAPAL LAPSESNATS TTNFPNIPVA STSQPASILA GSHSEGLLQI
 ASGPQPGQQQ NGFTAQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH
 YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV DGYVDPSGGD
 RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR CLSDHAVFVQ SYYLDREAGR
 APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ AATAQAAAAA QAAAVAGNIP GPGSVGGIAP
 AISLSAAAGI GVDDLRRLCI LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL
 HTMPIADPQP LD

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