SMAD4_MOUSE
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 03-AUG-2022, entry version 202.
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 CREB3L1 coactivator
CC to induce the expression of genes involved in the assembly of collagen
CC extracellular matrix (By similarity). Interacts with DLX1 (By
CC 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). {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}.
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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 iPTMnet; P97471; -.
DR PhosphoSitePlus; P97471; -.
DR EPD; P97471; -.
DR MaxQB; P97471; -.
DR PaxDb; P97471; -.
DR PRIDE; P97471; -.
DR ProteomicsDB; 261087; -.
DR Antibodypedia; 3711; 1102 antibodies from 45 providers.
DR DNASU; 17128; -.
DR Ensembl; ENSMUST00000025393; ENSMUSP00000025393; ENSMUSG00000024515.
DR Ensembl; ENSMUST00000114939; ENSMUSP00000110589; ENSMUSG00000024515.
DR GeneID; 17128; -.
DR KEGG; mmu:17128; -.
DR UCSC; uc008fou.1; mouse.
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; 905048at2759; -.
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 78 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 271 other tissues.
DR Genevisible; P97471; MM.
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: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:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0007568; P:aging; 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: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:0006879; P:cellular iron ion homeostasis; IMP:BHF-UCL.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISO:MGI.
DR GO; GO:0048589; P:developmental growth; IMP:MGI.
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: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: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: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: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:0060548; P:negative regulation of cell death; IMP:UniProtKB.
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: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:0045892; P:negative regulation of transcription, DNA-templated; ISO:MGI.
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: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:0030513; P:positive regulation of BMP signaling pathway; ISO: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:0010718; P:positive regulation of epithelial to mesenchymal transition; IMP:BHF-UCL.
DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IMP:MGI.
DR GO; GO:0051571; P:positive regulation of histone H3-K4 methylation; IMP:BHF-UCL.
DR GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; IMP:BHF-UCL.
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:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; 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:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISO:MGI.
DR GO; GO:0051098; P:regulation of binding; IDA:MGI.
DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:MGI.
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:0007183; P:SMAD protein complex assembly; ISO:MGI.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISO:MGI.
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:0006351; P:transcription, DNA-templated; ISO: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 GO; GO:0042060; P:wound healing; ISO:MGI.
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 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 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
