ID SMAD4_MOUSE Reviewed; 551 AA. AC P97471; Q6GTP6; Q9CW56; DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 27-MAR-2024, entry version 211. DE RecName: Full=Mothers against decapentaplegic homolog 4; DE Short=MAD homolog 4; DE Short=Mothers against DPP homolog 4; DE AltName: Full=Deletion target in pancreatic carcinoma 4 homolog; DE AltName: Full=SMAD family member 4; DE Short=SMAD 4; DE Short=Smad4; GN Name=Smad4; Synonyms=Dpc4, Madh4; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC STRAIN=A/J; TISSUE=Lung; RX PubMed=9166592; DOI=10.1007/s003359900465; RA Anna C.H., Devereux T.R.; RT "Sequence and chromosomal mapping of the mouse homolog (Madh4) of the human RT DPC4/MADH4 gene."; RL Mamm. Genome 8:443-444(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Olfactory epithelium; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 67-551. RC STRAIN=C57BL/6J; TISSUE=Lung; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [5] RP INTERACTION WITH ZNF8. RX PubMed=12370310; DOI=10.1128/mcb.22.21.7633-7644.2002; RA Jiao K., Zhou Y., Hogan B.L.M.; RT "Identification of mZnf8, a mouse Kruppel-like transcriptional repressor, RT as a novel nuclear interaction partner of Smad1."; RL Mol. Cell. Biol. 22:7633-7644(2002). RN [6] RP FUNCTION, DNA-BINDING, AND IDENTIFICATION IN A COMPLEX WITH SMAD1 AND YY1. RX PubMed=15329343; DOI=10.1242/dev.01344; RA Lee K.H., Evans S., Ruan T.Y., Lassar A.B.; RT "SMAD-mediated modulation of YY1 activity regulates the BMP response and RT cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 RT enhancer."; RL Development 131:4709-4723(2004). RN [7] RP INTERACTION WITH ZC3H3. RX PubMed=16115198; DOI=10.1111/j.1365-2443.2005.00887.x; RA Collart C., Remacle J.E., Barabino S., van Grunsven L.A., Nelles L., RA Schellens A., Van de Putte T., Pype S., Huylebroeck D., Verschueren K.; RT "Smicl is a novel Smad interacting protein and cleavage and polyadenylation RT specificity factor associated protein."; RL Genes Cells 10:897-906(2005). RN [8] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Lung; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [9] RP INTERACTION WITH SMAD2 AND SMAD3. RX PubMed=21145499; DOI=10.1016/j.devcel.2010.11.012; RA Varelas X., Samavarchi-Tehrani P., Narimatsu M., Weiss A., Cockburn K., RA Larsen B.G., Rossant J., Wrana J.L.; RT "The Crumbs complex couples cell density sensing to Hippo-dependent control RT of the TGF-beta-SMAD pathway."; RL Dev. Cell 19:831-844(2010). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=24076600; DOI=10.1038/ng.2772; RA Sartori R., Schirwis E., Blaauw B., Bortolanza S., Zhao J., Enzo E., RA Stantzou A., Mouisel E., Toniolo L., Ferry A., Stricker S., Goldberg A.L., RA Dupont S., Piccolo S., Amthor H., Sandri M.; RT "BMP signaling controls muscle mass."; RL Nat. Genet. 45:1309-1318(2013). RN [11] RP X-RAY CRYSTALLOGRAPHY (2.71 ANGSTROMS) OF 9-140 IN COMPLEX WITH DNA, RP ZINC_BINDING SITES, AND SUBUNIT. RX PubMed=20147459; DOI=10.1093/nar/gkq046; RA Baburajendran N., Palasingam P., Narasimhan K., Sun W., Prabhakar S., RA Jauch R., Kolatkar P.R.; RT "Structure of Smad1 MH1/DNA complex reveals distinctive rearrangements of RT BMP and TGF-beta effectors."; RL Nucleic Acids Res. 38:3477-3488(2010). 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. May act as a tumor CC suppressor. Positively regulates PDPK1 kinase activity by stimulating CC its dissociation from the 14-3-3 protein YWHAQ which acts as a negative CC regulator (By similarity). Acts synergistically with SMAD1 and YY1 in CC bone morphogenetic protein (BMP)-mediated cardiac-specific gene CC expression (PubMed:15329343). Binds to SMAD binding elements (SBEs) CC (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac CC activating regions (PubMed:15329343). In muscle physiology, plays a CC central role in the balance between atrophy and hypertrophy. When CC 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 {ECO:0000250, ECO:0000269|PubMed:15329343, CC ECO:0000269|PubMed:24076600}. 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 (PubMed:21145499). CC Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. CC Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and CC TRIM33. Found in a complex with SMAD1 and YY1 (PubMed:15329343). CC Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and CC SMAD4 (By similarity). Associates with ZNF423 or ZNF521 in response to CC BMP2 leading to activate transcription of BMP target genes. Interacts CC with USP9X. Interacts with RBPMS. Interacts with WWTR1 (via coiled-coil CC domain). Interacts with CITED1 and CITED2 (By similarity). Interacts CC with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this CC interaction affects heterodimer formation with SMAD3, but not with CC SMAD2, and leads to inhibition of SMAD3-dependent transcription CC activation (By similarity). Interactions with VPS39 and SMAD2 may be CC mutually exclusive (By similarity). Interacts (via MH2 domain) with CC ZNF451 (via N-terminal zinc-finger domains) (By similarity). Found in a CC complex with SMAD1 and YY1 (PubMed:15329343). Interacts with ZC3H3 CC (PubMed:16115198). Interacts weakly with ZNF8 (PubMed:12370310). 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 a CREB3L1 CC coactivator to induce the expression of genes involved in the assembly CC of collagen extracellular matrix (By similarity). Interacts with DLX1 CC (By similarity). Interacts with ZBTB7A; the interaction is direct and CC stimulated by TGFB1 (By similarity). Interacts with CREBBP; the CC recruitment of this transcriptional coactivator is negatively regulated CC by ZBTB7A (By similarity). Interacts with EP300; the interaction with CC this 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). Interacts (via N-terminus) with TSC22D1 (By CC similarity). {ECO:0000250|UniProtKB:O70437, CC ECO:0000250|UniProtKB:Q13485, ECO:0000269|PubMed:12370310, CC ECO:0000269|PubMed:15329343, ECO:0000269|PubMed:16115198, CC ECO:0000269|PubMed:20147459, ECO:0000269|PubMed:21145499}. CC -!- INTERACTION: CC P97471; Q8R1H0: Hopx; NbExp=2; IntAct=EBI-5259270, EBI-6913924; CC P97471; Q60698: Ski; NbExp=3; IntAct=EBI-5259270, EBI-15969860; CC P97471; Q8BUN5: Smad3; NbExp=6; IntAct=EBI-5259270, EBI-2337983; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13485}. Nucleus CC {ECO:0000250|UniProtKB:Q13485}. Note=In the cytoplasm in the absence of CC ligand. Migration to the nucleus when complexed with R-SMAD. PDPK1 CC prevents its nuclear translocation. {ECO:0000250|UniProtKB:Q13485}. CC -!- TISSUE SPECIFICITY: Ubiquitous. CC -!- DOMAIN: The MH1 domain is required for DNA binding. 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: Phosphorylated by PDPK1. {ECO:0000250}. CC -!- PTM: Monoubiquitinated on Lys-518 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. Deubiquitination by USP9X restores its competence to CC mediate TGF-beta signaling (By similarity). {ECO:0000250}. CC -!- DISRUPTION PHENOTYPE: Conditional knockout in muscle leads to muscle CC atrophy and weakness. Mutant mice loose significantly more muscle mass CC after denervation as compared to wild-type animals and show excessive CC proteolysis in denervated muscle. The loss of maximal absolute force CC after fasting is greater in mutant mice than in controls. CC {ECO:0000269|PubMed:24076600}. CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U79748; AAB57905.1; -; mRNA. DR EMBL; CH466528; EDL09560.1; -; Genomic_DNA. DR EMBL; BC046584; AAH46584.1; -; mRNA. DR EMBL; AK004804; BAB23576.1; -; mRNA. DR CCDS; CCDS29337.1; -. DR RefSeq; NP_032566.2; NM_008540.2. DR PDB; 3QSV; X-ray; 2.71 A; A/B/C/D=9-140. DR PDBsum; 3QSV; -. DR AlphaFoldDB; P97471; -. DR SMR; P97471; -. DR BioGRID; 201277; 33. DR ComplexPortal; CPX-10; SMAD2-SMAD3-SMAD4 complex. DR ComplexPortal; CPX-146; SMAD1-SMAD4 complex. DR ComplexPortal; CPX-3251; SMAD2-SMAD4 complex. DR ComplexPortal; CPX-3286; SMAD3-SMAD4 complex. DR CORUM; P97471; -. DR DIP; DIP-29718N; -. DR IntAct; P97471; 10. DR MINT; P97471; -. DR STRING; 10090.ENSMUSP00000025393; -. DR GlyGen; P97471; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P97471; -. DR PhosphoSitePlus; P97471; -. DR EPD; P97471; -. DR MaxQB; P97471; -. DR PaxDb; 10090-ENSMUSP00000025393; -. DR ProteomicsDB; 261087; -. DR Pumba; P97471; -. DR Antibodypedia; 3711; 1272 antibodies from 45 providers. DR DNASU; 17128; -. DR Ensembl; ENSMUST00000025393.14; ENSMUSP00000025393.8; ENSMUSG00000024515.14. DR Ensembl; ENSMUST00000114939.2; ENSMUSP00000110589.2; ENSMUSG00000024515.14. DR GeneID; 17128; -. DR KEGG; mmu:17128; -. DR UCSC; uc008fou.1; mouse. DR AGR; MGI:894293; -. DR CTD; 4089; -. DR MGI; MGI:894293; Smad4. DR VEuPathDB; HostDB:ENSMUSG00000024515; -. DR eggNOG; KOG3701; Eukaryota. DR GeneTree; ENSGT00940000157435; -. DR HOGENOM; CLU_026736_1_1_1; -. DR InParanoid; P97471; -. DR OMA; CWIEVQI; -. DR OrthoDB; 5395671at2759; -. DR PhylomeDB; P97471; -. DR TreeFam; TF314923; -. DR Reactome; R-MMU-1181150; Signaling by NODAL. DR Reactome; R-MMU-1502540; Signaling by Activin. DR Reactome; R-MMU-201451; Signaling by BMP. DR Reactome; R-MMU-2173789; TGF-beta receptor signaling activates SMADs. DR Reactome; R-MMU-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity. DR Reactome; R-MMU-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription. DR Reactome; R-MMU-5689880; Ub-specific processing proteases. DR Reactome; R-MMU-8941326; RUNX2 regulates bone development. DR Reactome; R-MMU-8941855; RUNX3 regulates CDKN1A transcription. DR Reactome; R-MMU-9617828; FOXO-mediated transcription of cell cycle genes. DR BioGRID-ORCS; 17128; 4 hits in 83 CRISPR screens. DR ChiTaRS; Smad4; mouse. DR EvolutionaryTrace; P97471; -. DR PRO; PR:P97471; -. DR Proteomes; UP000000589; Chromosome 18. DR RNAct; P97471; Protein. DR Bgee; ENSMUSG00000024515; Expressed in rostral migratory stream and 275 other cell types or tissues. DR GO; GO:0032444; C:activin responsive factor complex; ISO:MGI. DR GO; GO:0005813; C:centrosome; ISO:MGI. DR GO; GO:0000785; C:chromatin; ISO:MGI. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0071144; C:heteromeric SMAD protein complex; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL. DR GO; GO:0032991; C:protein-containing complex; ISO:MGI. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IDA:BHF-UCL. DR GO; GO:0071141; C:SMAD protein complex; ISO:MGI. DR GO; GO:0005667; C:transcription regulator complex; IPI:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:MGI. DR GO; GO:0005518; F:collagen binding; IPI:MGI. DR GO; GO:0003677; F:DNA binding; IDA:MGI. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central. DR GO; GO:0031005; F:filamin binding; ISO:MGI. DR GO; GO:0070411; F:I-SMAD binding; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; IPI:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI. DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI. DR GO; GO:0070412; F:R-SMAD binding; ISO:MGI. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:MGI. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:MGI. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL. DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:MGI. DR GO; GO:0046332; F:SMAD binding; ISO:MGI. DR GO; GO:0043199; F:sulfate binding; ISO:MGI. DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:MGI. DR GO; GO:0001223; F:transcription coactivator binding; ISO:MGI. DR GO; GO:0001222; F:transcription corepressor binding; ISO:MGI. DR GO; GO:0032924; P:activin receptor signaling pathway; NAS:ComplexPortal. DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl. DR GO; GO:0009653; P:anatomical structure morphogenesis; IMP:MGI. DR GO; GO:0009952; P:anterior/posterior pattern specification; IMP:MGI. DR GO; GO:0036302; P:atrioventricular canal development; IGI:BHF-UCL. DR GO; GO:0003190; P:atrioventricular valve formation; IGI:BHF-UCL. DR GO; GO:0007411; P:axon guidance; IMP:MGI. DR GO; GO:0030509; P:BMP signaling pathway; IMP:BHF-UCL. DR GO; GO:0003360; P:brainstem development; IMP:MGI. DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IGI:MGI. DR GO; GO:0014898; P:cardiac muscle hypertrophy in response to stress; ISO:MGI. DR GO; GO:0003279; P:cardiac septum development; IGI:BHF-UCL. DR GO; GO:0030154; P:cell differentiation; IMP:MGI. DR GO; GO:0008283; P:cell population proliferation; IMP:MGI. DR GO; GO:0071333; P:cellular response to glucose stimulus; ISO:MGI. DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; ISO:MGI. DR GO; GO:0048589; P:developmental growth; IMP:MGI. DR GO; GO:0006351; P:DNA-templated transcription; ISO:ComplexPortal. DR GO; GO:0042733; P:embryonic digit morphogenesis; IMP:CACAO. DR GO; GO:0060956; P:endocardial cell differentiation; IMP:BHF-UCL. DR GO; GO:0007492; P:endoderm development; IMP:MGI. DR GO; GO:0042118; P:endothelial cell activation; IMP:BHF-UCL. DR GO; GO:0010631; P:epithelial cell migration; ISO:MGI. DR GO; GO:0001837; P:epithelial to mesenchymal transition; ISO:MGI. DR GO; GO:0003198; P:epithelial to mesenchymal transition involved in endocardial cushion formation; IMP:BHF-UCL. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; ISO:MGI. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISO:MGI. DR GO; GO:0008585; P:female gonad development; IGI:MGI. DR GO; GO:0061040; P:female gonad morphogenesis; IMP:MGI. DR GO; GO:0048859; P:formation of anatomical boundary; IMP:MGI. DR GO; GO:0007369; P:gastrulation; IMP:MGI. DR GO; GO:0001702; P:gastrulation with mouth forming second; IMP:MGI. DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI. DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0006879; P:intracellular iron ion homeostasis; IMP:BHF-UCL. DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI. DR GO; GO:0001822; P:kidney development; IMP:MGI. DR GO; GO:0003220; P:left ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL. DR GO; GO:0008584; P:male gonad development; IMP:MGI. DR GO; GO:0048382; P:mesendoderm development; IMP:MGI. DR GO; GO:0007498; P:mesoderm development; IMP:MGI. DR GO; GO:0072133; P:metanephric mesenchyme morphogenesis; IMP:UniProtKB. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI. DR GO; GO:0010614; P:negative regulation of cardiac muscle hypertrophy; IMP:BHF-UCL. DR GO; GO:1905305; P:negative regulation of cardiac myofibril assembly; IMP:BHF-UCL. DR GO; GO:0030308; P:negative regulation of cell growth; ISO:MGI. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IGI:MGI. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISO:MGI. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL. DR GO; GO:0042177; P:negative regulation of protein catabolic process; ISO:MGI. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:BHF-UCL. DR GO; GO:0072134; P:nephrogenic mesenchyme morphogenesis; IMP:UniProtKB. DR GO; GO:0014033; P:neural crest cell differentiation; IMP:MGI. DR GO; GO:0048663; P:neuron fate commitment; IMP:MGI. DR GO; GO:0048665; P:neuron fate specification; ISO:MGI. DR GO; GO:0001649; P:osteoblast differentiation; ISO:MGI. DR GO; GO:0003148; P:outflow tract septum morphogenesis; IGI:BHF-UCL. DR GO; GO:0001541; P:ovarian follicle development; IMP:MGI. DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; ISO:MGI. DR GO; GO:0003251; P:positive regulation of cell proliferation involved in heart valve morphogenesis; IMP:BHF-UCL. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:MGI. DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IMP:BHF-UCL. DR GO; GO:1901203; P:positive regulation of extracellular matrix assembly; ISO:MGI. DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IMP:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI. DR GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; IMP:MGI. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IMP:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI. DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:MGI. DR GO; GO:0006355; P:regulation of DNA-templated transcription; NAS:ComplexPortal. DR GO; GO:0051797; P:regulation of hair follicle development; IMP:MGI. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI. DR GO; GO:0032909; P:regulation of transforming growth factor beta2 production; ISO:MGI. DR GO; GO:0001666; P:response to hypoxia; ISO:MGI. DR GO; GO:0071559; P:response to transforming growth factor beta; ISO:MGI. DR GO; GO:0048733; P:sebaceous gland development; IMP:MGI. DR GO; GO:0062009; P:secondary palate development; IMP:BHF-UCL. DR GO; GO:0072520; P:seminiferous tubule development; IMP:MGI. DR GO; GO:0007338; P:single fertilization; IGI:MGI. DR GO; GO:0060395; P:SMAD protein signal transduction; IMP:BHF-UCL. DR GO; GO:0032525; P:somite rostral/caudal axis specification; IMP:MGI. DR GO; GO:0007283; P:spermatogenesis; IMP:MGI. DR GO; GO:0048729; P:tissue morphogenesis; IMP:MGI. DR GO; GO:0006366; P:transcription by RNA polymerase II; IMP:MGI. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0060065; P:uterus development; IGI:MGI. DR GO; GO:0060412; P:ventricular septum morphogenesis; IMP:BHF-UCL. DR CDD; cd10492; MH1_SMAD_4; 1. DR CDD; cd10498; MH2_SMAD_4; 1. DR Gene3D; 2.60.200.10; -; 1. DR Gene3D; 3.90.520.10; SMAD MH1 domain; 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:SF63; MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 4; 1. DR PANTHER; PTHR13703; SMAD; 1. DR Pfam; PF03165; MH1; 1. DR Pfam; PF03166; MH2; 1. DR SMART; SM00523; DWA; 1. DR SMART; SM00524; DWB; 1. DR SUPFAM; SSF56366; SMAD MH1 domain; 1. DR SUPFAM; SSF49879; SMAD/FHA domain; 1. DR PROSITE; PS51075; MH1; 1. DR PROSITE; PS51076; MH2; 1. DR Genevisible; P97471; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasm; DNA-binding; Isopeptide bond; KW Metal-binding; Nucleus; Reference proteome; Transcription; KW Transcription regulation; Ubl conjugation; Zinc. FT CHAIN 1..551 FT /note="Mothers against decapentaplegic homolog 4" FT /id="PRO_0000090862" FT DOMAIN 18..142 FT /note="MH1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438" FT DOMAIN 322..551 FT /note="MH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439" FT REGION 1..321 FT /note="Mediates interaction with ZBTB7A" FT /evidence="ECO:0000250|UniProtKB:Q13485" FT REGION 44..69 FT /note="Required for interaction with TSC22D1" FT /evidence="ECO:0000250|UniProtKB:Q13485" FT REGION 166..192 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 274..319 FT /note="SAD" FT COMPBIAS 172..192 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 514 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 427 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q13485" FT MOD_RES 506 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 518 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q13485" FT CONFLICT 257 FT /note="A -> S (in Ref. 1; AAB57905)" FT /evidence="ECO:0000305" FT CONFLICT 292 FT /note="P -> R (in Ref. 1; AAB57905)" FT /evidence="ECO:0000305" FT HELIX 16..24 FT /evidence="ECO:0007829|PDB:3QSV" FT HELIX 33..47 FT /evidence="ECO:0007829|PDB:3QSV" FT HELIX 51..62 FT /evidence="ECO:0007829|PDB:3QSV" FT TURN 63..65 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 73..75 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 82..84 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 87..89 FT /evidence="ECO:0007829|PDB:3QSV" FT HELIX 91..99 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 109..111 FT /evidence="ECO:0007829|PDB:3QSV" FT HELIX 119..121 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 124..127 FT /evidence="ECO:0007829|PDB:3QSV" FT HELIX 130..132 FT /evidence="ECO:0007829|PDB:3QSV" FT STRAND 133..135 FT /evidence="ECO:0007829|PDB:3QSV" SQ SEQUENCE 551 AA; 60342 MW; 4FBDF5DED4442F86 CRC64; MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPSMLVKDE YVHDFEGQPS LPTEGHSIQT IQHPPSNRAS TETYSAPALL APAESNATST TNFPNIPVAS TSQPASILAG SHSEGLLQIA SGPQPGQQQN GFTAQPATYH HNSTTTWTGS RTAPYTPNLP HHQNGHLQHH PPMPPHPGHY WPVHNELAFQ PPISNHPAPE YWCSIAYFEM DVQVGETFKV PSSCPVVTVD GYVDPSGGDR FCLGQLSNVH RTEAIERARL HIGKGVQLEC KGEGDVWVRC LSDHAVFVQS YYLDREAGRA PGDAVHKIYP SAYIKVFDLR QCHRQMQQQA ATAQAAAAAQ AAAVAGNIPG PGSVGGIAPA ISLSAAAGIG VDDLRRLCIL RMSFVKGWGP DYPRQSIKET PCWIEIHLHR ALQLLDEVLH TMPIADPQPL D //