ID SMAD3_HUMAN Reviewed; 425 AA. AC P84022; A8K4B6; B7Z4Z5; B7Z9Q2; O09064; O09144; O14510; O35273; AC Q92940; Q93002; Q9GKR4; DT 05-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-NOV-2012, entry version 113. DE RecName: Full=Mothers against decapentaplegic homolog 3; DE Short=MAD homolog 3; DE Short=Mad3; DE Short=Mothers against DPP homolog 3; DE Short=hMAD-3; DE AltName: Full=JV15-2; DE AltName: Full=SMAD family member 3; DE Short=SMAD 3; DE Short=Smad3; DE Short=hSMAD3; GN Name=SMAD3; Synonyms=MADH3; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PHOSPHORYLATION. RC TISSUE=Placenta; RX MEDLINE=96371046; PubMed=8774881; DOI=10.1038/383168a0; RA Zhang Y., Feng X.-H., Wu R.-Y., Derynck R.; RT "Receptor-associated Mad homologues synergize as effectors of the TGF- RT beta response."; RL Nature 383:168-172(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX MEDLINE=96259564; PubMed=8673135; DOI=10.1038/ng0796-347; RA Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., RA Kern S.E., Hamilton S.R., Willson J.K.V., Markowitz S.D., RA Kinzler K.W., Vogelstein B.V.; RT "Mad-related genes in the human."; RL Nat. Genet. 13:347-349(1996). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Colon carcinoma; RX MEDLINE=98124152; PubMed=9464505; DOI=10.1016/S0304-3835(97)00384-4; RA Arai T., Akiyama Y., Okabe S., Ando M., Endo M., Yuasa Y.; RT "Genomic structure of the human Smad3 gene and its infrequent RT alterations in colorectal cancers."; RL Cancer Lett. 122:157-163(1998). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Hagiwara K., Yang K., McMenamin M.G., Freeman A.H., Bennett W.P., RA Nagashima M., Minter A.R., Miyazono K., Takenoshita S., Harris C.C.; RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., RA Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human RT chromosome 15."; RL Nature 440:671-675(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Pancreas; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP INTERACTION WITH TGFBR1. RX PubMed=9311995; DOI=10.1093/emboj/16.17.5353; RA Nakao A., Imamura T., Souchelnytskyi S., Kawabata M., Ishisaki A., RA Oeda E., Tamaki K., Hanai J., Heldin C.H., Miyazono K., ten Dijke P.; RT "TGF-beta receptor-mediated signalling through Smad2, Smad3 and RT Smad4."; RL EMBO J. 16:5353-5362(1997). RN [10] RP INTERACTION WITH ZFYVE9. RX PubMed=9865696; DOI=10.1016/S0092-8674(00)81701-8; RA Tsukazaki T., Chiang T.A., Davison A.F., Attisano L., Wrana J.L.; RT "SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta RT receptor."; RL Cell 95:779-791(1998). RN [11] RP SUBUNIT. RX PubMed=9670020; DOI=10.1093/emboj/17.14.4056; RA Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K.; RT "Smad proteins exist as monomers in vivo and undergo homo- and hetero- RT oligomerization upon activation by serine/threonine kinase RT receptors."; RL EMBO J. 17:4056-4065(1998). RN [12] RP PHOSPHORYLATION, AND INTERACTION WITH EP300. RX PubMed=9843571; RA Shen X., Hu P.P., Liberati N.T., Datto M.B., Frederick J.P., RA Wang X.F.; RT "TGF-beta-induced phosphorylation of Smad3 regulates its interaction RT with coactivator p300/CREB-binding protein."; RL Mol. Biol. Cell 9:3309-3319(1998). RN [13] RP INTERACTION WITH MECOM. RX PubMed=9665135; DOI=10.1038/27945; RA Kurokawa M., Mitani K., Irie K., Matsuyama T., Takahashi T., Chiba S., RA Yazaki Y., Matsumoto K., Hirai H.; RT "The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting RT Smad3."; RL Nature 394:92-96(1998). RN [14] RP IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, RP INTERACTION WITH JUN AND FOS, DNA-BINDING, AND FUNCTION. RX PubMed=9732876; DOI=10.1038/29814; RA Zhang Y., Feng X.H., Derynck R.; RT "Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta- RT induced transcription."; RL Nature 394:909-913(1998). RN [15] RP INTERACTION WITH ACVR1B, AND FUNCTION. RX PubMed=9892009; DOI=10.1210/me.13.1.15; RA Lebrun J.J., Takabe K., Chen Y., Vale W.; RT "Roles of pathway-specific and inhibitory Smads in activin receptor RT signaling."; RL Mol. Endocrinol. 13:15-23(1999). RN [16] RP INTERACTION WITH JUN IN THE SMAD3/SMAD4/JUN/FOS COMPLEX, DNA-BINDING, RP FUNCTION, AND MUTAGENESIS OF LYS-40; LYS-41; LYS-43; LYS-44 AND RP ARG-74. RX PubMed=10995748; DOI=10.1074/jbc.M004731200; RA Qing J., Zhang Y., Derynck R.; RT "Structural and functional characterization of the transforming growth RT factor-beta -induced Smad3/c-Jun transcriptional cooperativity."; RL J. Biol. Chem. 275:38802-38812(2000). RN [17] RP INTERACTION WITH DAB2. RX PubMed=11387212; DOI=10.1093/emboj/20.11.2789; RA Hocevar B.A., Smine A., Xu X.X., Howe P.H.; RT "The adaptor molecule Disabled-2 links the transforming growth factor RT beta receptors to the Smad pathway."; RL EMBO J. 20:2789-2801(2001). RN [18] RP INTERACTION WITH TGIF2. RX MEDLINE=21402964; PubMed=11427533; DOI=10.1074/jbc.M103377200; RA Melhuish T.A., Gallo C.M., Wotton D.; RT "TGIF2 interacts with histone deacetylase 1 and represses RT transcription."; RL J. Biol. Chem. 276:32109-32114(2001). RN [19] RP SUBUNIT, PHOSPHORYLATION, AND MUTAGENESIS OF 422-SER--SER-425. RX MEDLINE=21127490; PubMed=11224571; DOI=10.1038/84995; RA Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., RA Lin K.; RT "The L3 loop and C-terminal phosphorylation jointly define Smad RT protein trimerization."; RL Nat. Struct. Biol. 8:248-253(2001). RN [20] RP INTERACTION WITH MEN1. RX PubMed=11274402; DOI=10.1073/pnas.061358098; RA Kaji H., Canaff L., Lebrun J.J., Goltzman D., Hendy G.N.; RT "Inactivation of menin, a Smad3-interacting protein, blocks RT transforming growth factor type beta signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 98:3837-3842(2001). RN [21] RP INTERACTION WITH DACH1. RX PubMed=14525983; DOI=10.1074/jbc.M310021200; RA Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K., RA Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G.; RT "DACH1 inhibits transforming growth factor-beta signaling through RT binding Smad4."; RL J. Biol. Chem. 278:51673-51684(2003). RN [22] RP PHOSPHORYLATION AT THR-8; THR-179; SER-204; SER-208 AND SER-213, RP FUNCTION, AND MUTAGENESIS OF THR-8; THR-179; SER-204; SER-208 AND RP SER-213. RX PubMed=15241418; DOI=10.1038/nature02650; RA Matsuura I., Denissova N.G., Wang G., He D., Long J., Liu F.; RT "Cyclin-dependent kinases regulate the antiproliferative function of RT Smads."; RL Nature 430:226-231(2004). RN [23] RP TRANSCRIPTIONAL ACTIVATION DOMAIN, FUNCTION, PHOSPHORYLATION, SUBUNIT, RP AND INTERACTION WITH EP300. RX PubMed=15588252; DOI=10.1042/BJ20041820; RA Wang G., Long J., Matsuura I., He D., Liu F.; RT "The Smad3 linker region contains a transcriptional activation RT domain."; RL Biochem. J. 386:29-34(2005). RN [24] RP PHOSPHORYLATION AT THR-179; SER-204 AND SER-208, SUBCELLULAR LOCATION, RP FUNCTION, AND MUTAGENESIS OF THR-179; SER-204 AND SER-208. RX PubMed=16156666; DOI=10.1021/bi050560g; RA Matsuura I., Wang G., He D., Liu F.; RT "Identification and characterization of ERK MAP kinase phosphorylation RT sites in Smad3."; RL Biochemistry 44:12546-12553(2005). RN [25] RP SUBCELLULAR LOCATION, AND INTERACTION WITH LEMD3. RX PubMed=15601644; DOI=10.1093/hmg/ddi040; RA Lin F., Morrison J.M., Wu W., Worman H.J.; RT "MAN1, an integral protein of the inner nuclear membrane, binds Smad2 RT and Smad3 and antagonizes transforming growth factor-beta signaling."; RL Hum. Mol. Genet. 14:437-445(2005). RN [26] RP INTERACTION WITH TGFB1I1. RX PubMed=15561701; DOI=10.1074/jbc.M411575200; RA Wang H., Song K., Sponseller T.L., Danielpour D.; RT "Novel function of androgen receptor-associated protein 55/Hic-5 as a RT negative regulator of Smad3 signaling."; RL J. Biol. Chem. 280:5154-5162(2005). RN [27] RP INTERACTION WITH LEMD3. RX PubMed=15647271; DOI=10.1074/jbc.M411234200; RA Pan D., Estevez-Salmeron L.D., Stroschein S.L., Zhu X., He J., RA Zhou S., Luo K.; RT "The integral inner nuclear membrane protein MAN1 physically interacts RT with the R-Smad proteins to repress signaling by the transforming RT growth factor-{beta} superfamily of cytokines."; RL J. Biol. Chem. 280:15992-16001(2005). RN [28] RP SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=15799969; DOI=10.1074/jbc.M500362200; RA Chen H.B., Rud J.G., Lin K., Xu L.; RT "Nuclear targeting of transforming growth factor-beta-activated Smad RT complexes."; RL J. Biol. Chem. 280:21329-21336(2005). RN [29] RP INTERACTION WITH SKOR2. RX PubMed=16200078; DOI=10.1038/labinvest.3700344; RA Arndt S., Poser I., Schubert T., Moser M., Bosserhoff A.-K.; RT "Cloning and functional characterization of a new Ski homolog, Fussel- RT 18, specifically expressed in neuronal tissues."; RL Lab. Invest. 85:1330-1341(2005). RN [30] RP INTERACTION WITH MECOM. RX PubMed=15897867; DOI=10.1038/sj.onc.1208754; RA Nitta E., Izutsu K., Yamaguchi Y., Imai Y., Ogawa S., Chiba S., RA Kurokawa M., Hirai H.; RT "Oligomerization of Evi-1 regulated by the PR domain contributes to RT recruitment of corepressor CtBP."; RL Oncogene 24:6165-6173(2005). RN [31] RP INTERACTION WITH PPM1A, DEPHOSPHORYLATION, FUNCTION, AND SUBCELLULAR RP LOCATION. RX PubMed=16751101; DOI=10.1016/j.cell.2006.03.044; RA Lin X., Duan X., Liang Y.Y., Su Y., Wrighton K.H., Long J., Hu M., RA Davis C.M., Wang J., Brunicardi F.C., Shi Y., Chen Y.G., Meng A., RA Feng X.H.; RT "PPM1A functions as a Smad phosphatase to terminate TGFbeta RT signaling."; RL Cell 125:915-928(2006). RN [32] RP IDENTIFICATION IN A COMPLEX WITH SMAD2 AND TRIM33, AND INTERACTION RP WITH SMAD2 AND TRIM33. RX PubMed=16751102; DOI=10.1016/j.cell.2006.03.045; RA He W., Dorn D.C., Erdjument-Bromage H., Tempst P., Moore M.A., RA Massague J.; RT "Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of RT the TGFbeta pathway."; RL Cell 125:929-941(2006). RN [33] RP IDENTIFICATION IN A COMPLEX WITH RAN AND XPO4, INTERACTION WITH XPO4, RP AND MUTAGENESIS OF 422-SER--SER-425. RX PubMed=16449645; DOI=10.1128/MCB.26.4.1318-1332.2006; RA Kurisaki A., Kurisaki K., Kowanetz M., Sugino H., Yoneda Y., RA Heldin C.-H., Moustakas A.; RT "The mechanism of nuclear export of Smad3 involves exportin 4 and RT Ran."; RL Mol. Cell. Biol. 26:1318-1332(2006). RN [34] RP INTERACTION WITH RBPMS. RX PubMed=17099224; DOI=10.1093/nar/gkl914; RA Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., RA Song H., Ye Q.; RT "Potentiation of Smad-mediated transcriptional activation by the RNA- RT binding protein RBPMS."; RL Nucleic Acids Res. 34:6314-6326(2006). RN [35] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, AND RP INTERACTION WITH PDPK1. RX PubMed=17327236; DOI=10.1074/jbc.M609279200; RA Seong H.A., Jung H., Kim K.T., Ha H.; RT "3-Phosphoinositide-dependent PDK1 negatively regulates transforming RT growth factor-beta-induced signaling in a kinase-dependent manner RT through physical interaction with Smad proteins."; RL J. Biol. Chem. 282:12272-12289(2007). RN [36] RP INTERACTION WITH SKOR1. RX PubMed=17292623; DOI=10.1016/j.mcn.2007.01.002; RA Arndt S., Poser I., Moser M., Bosserhoff A.-K.; RT "Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP RT signaling."; RL Mol. Cell. Neurosci. 34:603-611(2007). RN [37] RP ACETYLATION AT LYS-378, FUNCTION, AND MUTAGENESIS OF LYS-333; LYS-341; RP LYS-378; LYS-409 AND 422-SER--SER-425. RX PubMed=16862174; DOI=10.1038/sj.onc.1209826; RA Inoue Y., Itoh Y., Abe K., Okamoto T., Daitoku H., Fukamizu A., RA Onozaki K., Hayashi H.; RT "Smad3 is acetylated by p300/CBP to regulate its transactivation RT activity."; RL Oncogene 26:500-508(2007). RN [38] RP INTERACTION WITH WWTR1. RX PubMed=18568018; DOI=10.1038/ncb1748; RA Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., RA Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L.; RT "TAZ controls Smad nucleocytoplasmic shuttling and regulates human RT embryonic stem-cell self-renewal."; RL Nat. Cell Biol. 10:837-848(2008). RN [39] RP INTERACTION WITH CSNK1G2, UBIQUITINATION, PHOSPHORYLATION AT SER-418 RP BY CSNK1G2/CK1, AND MUTAGENESIS OF SER-418. RX PubMed=18794808; DOI=10.1038/onc.2008.337; RA Guo X., Waddell D.S., Wang W., Wang Z., Liberati N.T., Yong S., RA Liu X., Wang X.-F.; RT "Ligand-dependent ubiquitination of Smad3 is regulated by casein RT kinase 1 gamma 2, an inhibitor of TGF-beta signaling."; RL Oncogene 27:7235-7247(2008). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-416, AND MASS RP SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8, AND MASS RP SPECTROMETRY. RC TISSUE=Embryonic kidney; RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., RA Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in RT a refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [42] RP INTERACTION WITH RANBP3, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=19289081; DOI=10.1016/j.devcel.2009.01.022; RA Dai F., Lin X., Chang C., Feng X.H.; RT "Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination RT of TGF-beta signaling."; RL Dev. Cell 16:345-357(2009). RN [43] RP INTERACTION WITH PRDM16; SKI AND HDAC1. RX PubMed=19049980; DOI=10.1074/jbc.M808989200; RA Takahata M., Inoue Y., Tsuda H., Imoto I., Koinuma D., Hayashi M., RA Ichikura T., Yamori T., Nagasaki K., Yoshida M., Matsuoka M., RA Morishita K., Yuki K., Hanyu A., Miyazawa K., Inazawa J., Miyazono K., RA Imamura T.; RT "SKI and MEL1 cooperate to inhibit transforming growth factor-beta RT signal in gastric cancer cells."; RL J. Biol. Chem. 284:3334-3344(2009). RN [44] RP PHOSPHORYLATION AT THR-179; SER-204 AND SER-208, SUBCELLULAR LOCATION, RP FUNCTION, AND MUTAGENESIS OF THR-179; SER-204 AND SER-208. RX PubMed=19218245; DOI=10.1074/jbc.M809281200; RA Wang G., Matsuura I., He D., Liu F.; RT "Transforming growth factor-{beta}-inducible phosphorylation of RT Smad3."; RL J. Biol. Chem. 284:9663-9673(2009). RN [45] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-378, AND MASS SPECTROMETRY. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [46] RP INTERACTION WITH IL1F7. RX PubMed=20935647; DOI=10.1038/ni.1944; RA Nold M.F., Nold-Petry C.A., Zepp J.A., Palmer B.E., Bufler P., RA Dinarello C.A.; RT "IL-37 is a fundamental inhibitor of innate immunity."; RL Nat. Immunol. 11:1014-1022(2010). RN [47] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [48] RP UBIQUITINATION, DEUBIQUITINATION BY USP15, DNA-BINDING, INTERACTION RP WITH USP15, UBIQUITINATION AT LYS-33 AND LYS-81, AND MUTAGENESIS OF RP LYS-33; LYS-53 AND LYS-81. RX PubMed=21947082; DOI=10.1038/ncb2346; RA Inui M., Manfrin A., Mamidi A., Martello G., Morsut L., Soligo S., RA Enzo E., Moro S., Polo S., Dupont S., Cordenonsi M., Piccolo S.; RT "USP15 is a deubiquitylating enzyme for receptor-activated SMADs."; RL Nat. Cell Biol. 13:1368-1375(2011). RN [49] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-144. RX MEDLINE=98412654; PubMed=9741623; DOI=10.1016/S0092-8674(00)81600-1; RA Shi Y., Wang Y.-F., Jayaraman L., Yang H., Massague J., RA Pavletich N.P.; RT "Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA RT binding in TGF-beta signaling."; RL Cell 94:585-594(1998). RN [50] RP X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF 220-425 IN COMPLEX WITH RP ZFYVE9. RX PubMed=12154125; DOI=10.1101/gad.1002002; RA Qin B.Y., Lam S.S., Correia J.J., Lin K.; RT "Smad3 allostery links TGF-beta receptor kinase activation to RT transcriptional control."; RL Genes Dev. 16:1950-1963(2002). RN [51] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1-144 IN COMPLEX WITH DNA, RP AND ZINC. RX PubMed=12686552; DOI=10.1074/jbc.C300134200; RA Chai J., Wu J.W., Yan N., Massague J., Pavletich N.P., Shi Y.; RT "Features of a Smad3 MH1-DNA complex. Roles of water and zinc in DNA RT binding."; RL J. Biol. Chem. 278:20327-20331(2003). RN [52] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 228-424 IN COMPLEX WITH RP SMAD4, AND SUBUNIT. RX PubMed=15350224; DOI=10.1016/j.molcel.2004.07.016; RA Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J., RA De Caestecker M., Lin K.; RT "Structural basis of heteromeric smad protein assembly in TGF-beta RT signaling."; RL Mol. Cell 15:813-823(2004). RN [53] RP VARIANT [LARGE SCALE ANALYSIS] LEU-393. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C., RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., RA Vogelstein B., Kinzler K.W., Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal RT cancers."; RL Science 314:268-274(2006). RN [54] RP VARIANTS LDS3 VAL-112; LYS-239 AND LYS-279. RX PubMed=21778426; DOI=10.1161/CIRCRESAHA.111.248161; RA Regalado E.S., Guo D.C., Villamizar C., Avidan N., Gilchrist D., RA McGillivray B., Clarke L., Bernier F., Santos-Cortez R.L., Leal S.M., RA Bertoli-Avella A.M., Shendure J., Rieder M.J., Nickerson D.A., RA Milewicz D.M.; RT "Exome sequencing identifies SMAD3 mutations as a cause of familial RT thoracic aortic aneurysm and dissection with intracranial and other RT arterial aneurysms."; RL Circ. Res. 109:680-686(2011). RN [55] RP VARIANTS LDS3 ILE-261 AND TRP-287. RX PubMed=21217753; DOI=10.1038/ng.744; RA van de Laar I.M., Oldenburg R.A., Pals G., Roos-Hesselink J.W., RA de Graaf B.M., Verhagen J.M., Hoedemaekers Y.M., Willemsen R., RA Severijnen L.A., Venselaar H., Vriend G., Pattynama P.M., Collee M., RA Majoor-Krakauer D., Poldermans D., Frohn-Mulder I.M., Micha D., RA Timmermans J., Hilhorst-Hofstee Y., Bierma-Zeinstra S.M., RA Willems P.J., Kros J.M., Oei E.H., Oostra B.A., Wessels M.W., RA Bertoli-Avella A.M.; RT "Mutations in SMAD3 cause a syndromic form of aortic aneurysms and RT dissections with early-onset osteoarthritis."; RL Nat. Genet. 43:121-126(2011). CC -!- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an CC intracellular signal transducer and transcriptional modulator CC activated by TGF-beta (transforming growth factor) and activin CC type 1 receptor kinases. Binds the TRE element in the promoter CC region of many genes that are regulated by TGF-beta and, on CC formation of the SMAD3/SMAD4 complex, activates transcription. CC Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site CC to regulate TGF-beta-mediated transcription. Has an inhibitory CC effect on wound healing probably by modulating both growth and CC migration of primary keratinocytes and by altering the TGF- CC mediated chemotaxis of monocytes. This effect on wound healing CC appears to be hormone-sensitive. Regulator of chondrogenesis and CC osteogenesis and inhibits early healing of bone fractures (By CC similarity). Positively regulates PDPK1 kinase activity by CC stimulating its dissociation from the 14-3-3 protein YWHAQ which CC acts as a negative regulator. CC -!- SUBUNIT: Monomer; in the absence of TGF-beta. Homooligomer; in the CC presence of TGF-beta. Heterotrimer; forms a heterotrimer in the CC presence of TGF-beta consisting of two molecules of C-terminally CC phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the CC transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with CC TGFBR1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and CC SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, CC HGS and WWP1. Interacts (via MH2 domain) with CITED2 (via C- CC terminus) (By similarity). Interacts with NEDD4L; the interaction CC requires TGF-beta stimulation (By similarity). Interacts (via the CC MH2 domain) with ZFYVE9. Interacts with HDAC1, VDR, TGIF and CC TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and CC TGFB1I1. Interacts with DACH1; the interaction inhibits the TGF- CC beta signaling. Forms a complex with SMAD2 and TRIM33 upon CC addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. CC Interacts in the complex directly with XPO4. Interacts (via the CC 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. CC Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. CC Interacts with WWTR1 (via its coiled-coil domain). Interacts (via CC the linker region) with EP300 (C-terminal); the interaction CC promotes SMAD3 acetylation and is enhanced by TGF-beta CC phosphorylation in the C-terminal of SMAD3. This interaction can CC be blocked by competitive binding of adenovirus oncoprotein E1A to CC the same C-terminal site on EP300, which then results in partially CC inhibited SMAD3/SMAD4 transcriptional activity. Interacts with CC SKI; the interaction represses SMAD3 transcriptional activity. CC Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which CC forms at the AP1 promoter site; required for syngernistic CC transcriptional activity in response to TGF-beta. Interacts (via CC an N-terminal domain) with JUN (via its basic DNA binding and CC leucine zipper domains); this interaction is essential for DNA CC binding and cooperative transcriptional activity in response to CC TGF-beta. Interacts with PPM1A; the interaction dephosphorylates CC SMAD3 in the C-terminal SXS motif leading to disruption of the CC SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta CC signaling. Interacts (dephosphorylated form via the MH1 and MH2 CC domains) with RANBP3 (via its C-terminal R domain); the CC interaction results in the export of dephosphorylated SMAD3 out of CC the nucleus and termination of the TGF-beta signaling. Interacts CC with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. CC Interacts with PDPK1 (via PH domain). Interacts with DAB2; the CC interactions are enhanced upon TGF-beta stimulation. Interacts CC with USP15. CC -!- INTERACTION: CC P60709:ACTB; NbExp=3; IntAct=EBI-347161, EBI-353944; CC Q9H2X0:CHRD; NbExp=2; IntAct=EBI-347161, EBI-947551; CC P98082:DAB2; NbExp=3; IntAct=EBI-347161, EBI-1171238; CC Q9BZ29:DOCK9; NbExp=3; IntAct=EBI-347161, EBI-2695893; CC Q99836:MYD88; NbExp=3; IntAct=EBI-347161, EBI-447677; CC Q16822:PCK2; NbExp=2; IntAct=EBI-347161, EBI-2825219; CC Q9BZL4:PPP1R12C; NbExp=2; IntAct=EBI-347161, EBI-721802; CC P24158:PRTN3; NbExp=2; IntAct=EBI-347161, EBI-465028; CC Q96EP0:RNF31; NbExp=2; IntAct=EBI-347161, EBI-948111; CC Q9BYW2:SETD2; NbExp=2; IntAct=EBI-347161, EBI-945869; CC Q15796:SMAD2; NbExp=2; IntAct=EBI-347161, EBI-1040141; CC Q13485:SMAD4; NbExp=9; IntAct=EBI-347161, EBI-347263; CC Q13501:SQSTM1; NbExp=3; IntAct=EBI-347161, EBI-307104; CC Q12772:SREBF2; NbExp=3; IntAct=EBI-347161, EBI-465059; CC Q05066:SRY; NbExp=3; IntAct=EBI-347161, EBI-464987; CC Q9Y3Q8:TSC22D4; NbExp=2; IntAct=EBI-347161, EBI-739485; CC Q93009:USP7; NbExp=2; IntAct=EBI-347161, EBI-302474; CC O00308:WWP2; NbExp=4; IntAct=EBI-347161, EBI-743923; CC Q5D1E8:ZC3H12A; NbExp=2; IntAct=EBI-347161, EBI-747793; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytoplasmic and CC nuclear in the absence of TGF-beta. On TGF-beta stimulation, CC migrates to the nucleus when complexed with SMAD4. Through the CC action of the phosphatase PPM1A, released from the SMAD2/SMAD4 CC complex, and exported out of the nucleus by interaction with CC RANBP1. Co-localizes with LEMD3 at the nucleus inner membrane. CC MAPK-mediated phosphorylation appears to have no effect on nuclear CC import. PDPK1 prevents its nuclear translocation in response to CC TGF-beta. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P84022-1; Sequence=Displayed; CC Name=2; CC IsoId=P84022-2; Sequence=VSP_042900; CC Note=No experimental confirmation available; CC Name=3; CC IsoId=P84022-3; Sequence=VSP_043793; CC -!- DOMAIN: The MH1 domain is required for DNA binding. Also binds CC zinc ions which are necessary for the DNA binding. CC -!- DOMAIN: The MH2 domain is required for both homomeric and CC heteromeric interactions and for transcriptional regulation. CC Sufficient for nuclear import. CC -!- DOMAIN: The linker region is required for the TGFbeta-mediated CC transcriptional activity and acts synergistically with the MH2 CC domain. CC -!- PTM: Phosphorylated on serine and threonine residues. Enhanced CC phosphorylation in the linker region on Thr-179, Ser-204 and Ser- CC 208 on EGF AND TGF-beta treatment. Ser-208 is the main site of CC MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs CC in a cell-cycle dependent manner and inhibits both the CC transcriptional activity and antiproliferative functions of SMAD3. CC This phosphorylation is inhibited by flavopiridol. Maximum CC phosphorylation at the G(1)/S junction. Also phosphorylated on CC serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. CC 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 CC the 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 CC nuclear export and terminates TGF-beta-mediated signaling. CC Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand- CC dependent ubiquitination and subsequent proteasome degradation, CC thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated CC by PDPK1. CC -!- PTM: Acetylation in the nucleus by EP300 in the MH2 domain CC regulates positively its transcriptional activity and is enhanced CC by TGF-beta. CC -!- PTM: Ubiquitinated. Monoubiquitinated, leading to prevent DNA- CC binding. Deubiquitination by USP15 alleviates inhibition and CC promotes activation of TGF-beta target genes. CC -!- DISEASE: Defects in SMAD3 may be a cause of colorectal cancer CC (CRC) [MIM:114500]. CC -!- DISEASE: Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 CC (LDS3) [MIM:613795]. An aortic aneurysm syndrome with widespread CC systemic involvement. The disorder is characterized by the triad CC of arterial tortuosity and aneurysms, hypertelorism, and bifid CC uvula or cleft palate. Patients with LDS3 also manifest early- CC onset osteoarthritis. They lack craniosynostosis and mental CC retardation. Note=SMAD3 mutations have been reported to be also CC associated with thoracic aortic aneurysms and dissection (TAAD) CC (PubMed:21778426). This phenotype is distinguised from LDS3 by CC having aneurysms restricted to thoracic aorta. As individuals CC carrying these mutations also exhibit aneurysms of other arteries, CC including abdominal aorta, iliac, and/or intracranial arteries CC (PubMed:21778426), they have been classified as LDS3 by the OMIM CC resource. CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. CC -!- SIMILARITY: Contains 1 MH1 (MAD homology 1) domain. CC -!- SIMILARITY: Contains 1 MH2 (MAD homology 2) domain. 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; U68019; AAB80960.1; -; mRNA. DR EMBL; U76622; AAB18967.1; -; mRNA. DR EMBL; AB004930; BAA22032.1; -; Genomic_DNA. DR EMBL; AF025300; AAL68976.1; -; Genomic_DNA. DR EMBL; AF025293; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025294; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025295; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025296; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025297; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025298; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AF025299; AAL68976.1; JOINED; Genomic_DNA. DR EMBL; AK290881; BAF83570.1; -; mRNA. DR EMBL; AK298139; BAH12731.1; -; mRNA. DR EMBL; AK316017; BAH14388.1; -; mRNA. DR EMBL; AC012568; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC087482; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471082; EAW77788.1; -; Genomic_DNA. DR EMBL; BC050743; AAH50743.1; -; mRNA. DR IPI; IPI00024305; -. DR IPI; IPI00922698; -. DR PIR; S71798; S71798. DR RefSeq; NP_001138574.1; NM_001145102.1. DR RefSeq; NP_001138575.1; NM_001145103.1. DR RefSeq; NP_005893.1; NM_005902.3. DR UniGene; Hs.727986; -. DR PDB; 1MHD; X-ray; 2.80 A; A/B=1-132. DR PDB; 1MJS; X-ray; 1.91 A; A=229-425. DR PDB; 1MK2; X-ray; 2.74 A; A=220-425. DR PDB; 1OZJ; X-ray; 2.40 A; A/B=1-144. DR PDB; 1U7F; X-ray; 2.60 A; A/C=228-424. DR PDB; 2LAJ; NMR; -; B=202-211. DR PDB; 2LB2; NMR; -; B=178-189. DR PDBsum; 1MHD; -. DR PDBsum; 1MJS; -. DR PDBsum; 1MK2; -. DR PDBsum; 1OZJ; -. DR PDBsum; 1U7F; -. DR PDBsum; 2LAJ; -. DR PDBsum; 2LB2; -. DR ProteinModelPortal; P84022; -. DR SMR; P84022; 7-132, 228-425. DR DIP; DIP-29720N; -. DR IntAct; P84022; 107. DR MINT; MINT-193987; -. DR STRING; P84022; -. DR PhosphoSite; P84022; -. DR DMDM; 51338669; -. DR PaxDb; P84022; -. DR PRIDE; P84022; -. DR DNASU; 4088; -. DR Ensembl; ENST00000327367; ENSP00000332973; ENSG00000166949. DR Ensembl; ENST00000439724; ENSP00000401133; ENSG00000166949. DR Ensembl; ENST00000535241; ENSP00000441856; ENSG00000166949. DR Ensembl; ENST00000540846; ENSP00000437757; ENSG00000166949. DR GeneID; 4088; -. DR KEGG; hsa:4088; -. DR UCSC; uc002aqj.3; human. DR CTD; 4088; -. DR GeneCards; GC15P067358; -. DR HGNC; HGNC:6769; SMAD3. DR HPA; CAB008094; -. DR MIM; 114500; phenotype. DR MIM; 603109; gene. DR MIM; 613795; phenotype. DR neXtProt; NX_P84022; -. DR Orphanet; 284984; Aneurysm - osteoarthritis syndrome. DR PharmGKB; PA30526; -. DR eggNOG; NOG320700; -. DR HOGENOM; HOG000286018; -. DR HOVERGEN; HBG053353; -. DR InParanoid; P84022; -. DR KO; K04500; -. DR OMA; HTEIPSE; -. DR OrthoDB; EOG48PMK5; -. DR PhylomeDB; P84022; -. DR Pathway_Interaction_DB; hif1_tfpathway; HIF-1-alpha transcription factor network. DR Pathway_Interaction_DB; smad2_3pathway; Regulation of cytoplasmic and nuclear SMAD2/3 signaling. DR Pathway_Interaction_DB; smad2_3nuclearpathway; Regulation of nuclear SMAD2/3 signaling. DR Pathway_Interaction_DB; telomerasepathway; Regulation of Telomerase. DR Pathway_Interaction_DB; tgfbrpathway; TGF-beta receptor signaling. DR Reactome; REACT_111045; Developmental Biology. DR Reactome; REACT_111102; Signal Transduction. DR Reactome; REACT_71; Gene Expression. DR ChEMBL; CHEMBL1293258; -. DR EvolutionaryTrace; P84022; -. DR GenomeRNAi; 4088; -. DR NextBio; 16026; -. DR ArrayExpress; P84022; -. DR Bgee; P84022; -. DR CleanEx; HS_SMAD3; -. DR Genevestigator; P84022; -. DR GermOnline; ENSG00000166949; Homo sapiens. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005637; C:nuclear inner membrane; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005886; C:plasma membrane; IEA:Compara. DR GO; GO:0043235; C:receptor complex; IMP:BHF-UCL. DR GO; GO:0071141; C:SMAD protein complex; IDA:UniProtKB. DR GO; GO:0005667; C:transcription factor complex; IEA:Compara. DR GO; GO:0031490; F:chromatin DNA binding; IEA:Compara. DR GO; GO:0000987; F:core promoter proximal region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Compara. DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0030618; F:transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity; IDA:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:BHF-UCL. DR GO; GO:0008633; P:activation of pro-apoptotic gene products; IEA:Compara. DR GO; GO:0007050; P:cell cycle arrest; IMP:BHF-UCL. DR GO; GO:0045216; P:cell-cell junction organization; IMP:BHF-UCL. DR GO; GO:0048589; P:developmental growth; IEA:Compara. DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Compara. DR GO; GO:0048617; P:embryonic foregut morphogenesis; IEA:Compara. DR GO; GO:0009880; P:embryonic pattern specification; IEA:Compara. DR GO; GO:0007492; P:endoderm development; IEA:Compara. DR GO; GO:0019049; P:evasion or tolerance of host defenses by virus; IDA:BHF-UCL. DR GO; GO:0001947; P:heart looping; IEA:Compara. DR GO; GO:0006955; P:immune response; IMP:BHF-UCL. DR GO; GO:0002520; P:immune system development; IEA:Compara. DR GO; GO:0001701; P:in utero embryonic development; IEA:Compara. DR GO; GO:0006917; P:induction of apoptosis; IMP:BHF-UCL. DR GO; GO:0070306; P:lens fiber cell differentiation; IEA:Compara. DR GO; GO:0001889; P:liver development; IEA:Compara. DR GO; GO:0001707; P:mesoderm formation; IEA:Compara. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Compara. DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL. DR GO; GO:0050728; P:negative regulation of inflammatory response; IEA:Compara. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IMP:BHF-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Compara. DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; IEA:Compara. DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:BHF-UCL. DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL. DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome. DR GO; GO:0061045; P:negative regulation of wound healing; IEA:Compara. DR GO; GO:0038092; P:nodal signaling pathway; IMP:BHF-UCL. DR GO; GO:0002076; P:osteoblast development; IEA:Compara. DR GO; GO:0048340; P:paraxial mesoderm morphogenesis; IEA:Compara. DR GO; GO:0060039; P:pericardium development; IEA:Compara. DR GO; GO:0010694; P:positive regulation of alkaline phosphatase activity; IEA:Compara. DR GO; GO:0030501; P:positive regulation of bone mineralization; IEA:Compara. DR GO; GO:0090263; P:positive regulation of canonical Wnt receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0035413; P:positive regulation of catenin import into nucleus; IMP:BHF-UCL. DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Compara. DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; IEA:Compara. DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; IDA:BHF-UCL. DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IEA:Compara. DR GO; GO:1901313; P:positive regulation of gene expression involved in extracellular matrix organization; IMP:BHF-UCL. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Compara. DR GO; GO:0050927; P:positive regulation of positive chemotaxis; IEA:Compara. DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IEA:Compara. DR GO; GO:0042993; P:positive regulation of transcription factor import into nucleus; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB. DR GO; GO:0032916; P:positive regulation of transforming growth factor beta3 production; IEA:Compara. DR GO; GO:0031053; P:primary miRNA processing; TAS:BHF-UCL. DR GO; GO:0050821; P:protein stabilization; IMP:BHF-UCL. DR GO; GO:0051098; P:regulation of binding; IEA:Compara. DR GO; GO:0050678; P:regulation of epithelial cell proliferation; IEA:Compara. DR GO; GO:0050776; P:regulation of immune response; IEA:Compara. DR GO; GO:0016202; P:regulation of striated muscle tissue development; IEA:Compara. DR GO; GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL. DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:Compara. DR GO; GO:0001666; P:response to hypoxia; IMP:BHF-UCL. DR GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL. DR GO; GO:0001756; P:somitogenesis; IEA:Compara. DR GO; GO:0042110; P:T cell activation; IEA:Compara. DR GO; GO:0030878; P:thyroid gland development; IEA:Compara. DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome. DR GO; GO:0060290; P:transdifferentiation; IEA:Compara. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0006810; P:transport; IDA:BHF-UCL. DR GO; GO:0001657; P:ureteric bud development; IEA:Compara. DR GO; GO:0042060; P:wound healing; TAS:BHF-UCL. DR Gene3D; 3.90.520.10; MAD_MH1; 1. DR Gene3D; 2.60.200.10; MH2_Dwarfin-type; 1. DR InterPro; IPR013790; Dwarfin. DR InterPro; IPR003619; MAD_homology1_Dwarfin-type. DR InterPro; IPR013019; MAD_homology_MH1. DR InterPro; IPR017855; SMAD_dom-like. DR InterPro; IPR001132; SMAD_dom_Dwarfin-type. DR InterPro; IPR008984; SMAD_FHA_domain. 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; SSF56366; MAD_MH1; 1. DR SUPFAM; SSF49879; SMAD_FHA; 1. DR PROSITE; PS51075; MH1; 1. DR PROSITE; PS51076; MH2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Aortic aneurysm; KW Complete proteome; Cytoplasm; Disease mutation; DNA-binding; KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; Polymorphism; KW Reference proteome; Transcription; Transcription regulation; KW Ubl conjugation; Zinc. FT CHAIN 1 425 Mothers against decapentaplegic homolog FT 3. FT /FTId=PRO_0000090856. FT DOMAIN 10 136 MH1. FT DOMAIN 232 425 MH2. FT REGION 137 231 Linker. FT REGION 271 324 Sufficient for interaction with XPO4. FT METAL 64 64 Zinc. FT METAL 109 109 Zinc. FT METAL 121 121 Zinc. FT METAL 126 126 Zinc. FT SITE 40 40 Required for trimerization. FT SITE 41 41 Required for interaction with DNA and JUN FT and for functional cooperation with JUN. FT MOD_RES 8 8 Phosphothreonine; by CDK2 and CDK4. FT MOD_RES 179 179 Phosphothreonine; by CDK2, CDK4 and MAPK. FT MOD_RES 204 204 Phosphoserine; by GSK3 and MAPK. FT MOD_RES 208 208 Phosphoserine; by MAPK. FT MOD_RES 213 213 Phosphoserine; by CDK2 and CDK4. FT MOD_RES 378 378 N6-acetyllysine. FT MOD_RES 416 416 Phosphoserine. FT MOD_RES 418 418 Phosphoserine; by CK1. FT MOD_RES 422 422 Phosphoserine; by TGFBR1 (By similarity). FT MOD_RES 423 423 Phosphoserine; by TGFBR1 (By similarity). FT MOD_RES 425 425 Phosphoserine; by TGFBR1 (By similarity). FT CROSSLNK 33 33 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin) FT (Probable). FT CROSSLNK 81 81 Glycyl lysine isopeptide (Lys-Gly) FT (interchain with G-Cter in ubiquitin) FT (Probable). FT VAR_SEQ 1 105 Missing (in isoform 3). FT /FTId=VSP_043793. FT VAR_SEQ 1 68 MSSILPFTPPIVKRLLGWKKGEQNGQEEKWCEKAVKSLVKK FT LKKTGQLDELEKAITTQNVNTKCITIP -> MSCLHPRQTW FT KGAALVHRKAWWMG (in isoform 2). FT /FTId=VSP_042900. FT VARIANT 112 112 A -> V (in LDS3). FT /FTId=VAR_067051. FT VARIANT 170 170 I -> V (in dbSNP:rs35874463). FT /FTId=VAR_052021. FT VARIANT 239 239 E -> K (in LDS3). FT /FTId=VAR_067047. FT VARIANT 261 261 T -> I (in LDS3). FT /FTId=VAR_065578. FT VARIANT 279 279 R -> K (in LDS3). FT /FTId=VAR_067048. FT VARIANT 287 287 R -> W (in LDS3). FT /FTId=VAR_065579. FT VARIANT 393 393 P -> L (in a colorectal cancer sample; FT somatic mutation). FT /FTId=VAR_036474. FT MUTAGEN 8 8 T->V: Reduced phosphorylation, increased FT transcriptional and antiproliferative FT activities. Further increase in FT transcriptional and antiproliferative FT activities; when associated with V-179 FT and A-213. FT MUTAGEN 33 33 K->R: Slightly decreased FT monoubiquitination. FT MUTAGEN 40 40 K->A: Little effect on interaction with FT DNA or JUN. Abolishes interaction with FT DNA and JUN; when associated with A-41; FT A-43 and A-44. FT MUTAGEN 41 41 K->A: Greatly reduced interaction with FT DNA and JUN. Abolishes interaction with FT DNA and JUN; when associated with A-40; FT A-44 and A-43. FT MUTAGEN 43 43 K->A: Little effect on interaction with FT DNA or JUN. Abolishes interaction with FT DNA and JUN; when associated with A-40; FT A-41 and A-44. FT MUTAGEN 44 44 K->A: Little effect on interaction with FT DNA or JUN. Abolishes interaction with FT JUN; when associated with A-40; A-41 and FT A-43. FT MUTAGEN 53 53 K->R: Slightly decreased FT monoubiquitination. FT MUTAGEN 74 74 R->D: Reduced interaction with JUN. Loss FT of transcriptional activity and FT cooperation with JUN. FT MUTAGEN 81 81 K->R: Decreased monoubiquitination. FT MUTAGEN 179 179 T->V: Reduced phosphorylation, increased FT transcriptional and increased FT antiproliferative activities. Further FT increase in transcriptional and FT antiproliferative activities; when FT associated with V-8 and A-213. FT MUTAGEN 204 204 S->A: Increased transcriptional activity. FT Further increased transcriptional FT activity; when associated with S-208. FT MUTAGEN 208 208 S->A: Increased transcriptional activity. FT Further increased transcriptional FT activity; when associated with S-208. FT MUTAGEN 213 213 S->A: Reduced phosphorylation. Increased FT transcriptional and antiproliferative FT activities. Further increase in FT transcriptional and antiproliferative FT activities; when associated with V-8 and FT V-179. FT MUTAGEN 333 333 K->R: No effect on acetylation. FT Completely abolishes acetylation and 97% FT reduction in transcriptional activity; FT when associated with R-341; R-378 and R- FT 409. FT MUTAGEN 341 341 K->R: No effect on acetylation. FT Completely abolishes acetylation and 97% FT reduction in transcriptional activity; FT when associated with R-333; R-378 and R- FT 409. FT MUTAGEN 378 378 K->Q: Increased transcriptional activity. FT No further increase in transcriptional FT activity with EP300. FT MUTAGEN 378 378 K->R: Greatly reduced acetylation and 85% FT reduction in transcriptional activity. FT Completely abolishes acetylation and 97% FT reduction in transcriptional activity; FT when associated with R-333; R-341 and R- FT 409. FT MUTAGEN 409 409 K->R: No effect on acetylation. FT Completely abolishes acetylation and 97% FT reduction in transcriptional activity; FT when associated with R-333; R-341 and R- FT 378. FT MUTAGEN 418 418 S->A: Increased constitutive activity. FT MUTAGEN 418 418 S->D: Decreased activity. FT MUTAGEN 422 425 SSVS->AAVA: Does not abolish protein FT nuclear export. Abolishes almost FT completely acetylation. FT MUTAGEN 422 425 SSVS->EEVE: Forms heterotrimers. FT MUTAGEN 422 425 SSVS->RRVR: Diminishes cargo protein FT export. FT CONFLICT 178 178 E -> EVGTWAAQAGL (in Ref. 3; BAA22032). FT HELIX 10 16 FT HELIX 25 44 FT HELIX 48 57 FT STRAND 60 62 FT STRAND 66 68 FT STRAND 75 77 FT STRAND 80 82 FT HELIX 84 92 FT HELIX 100 102 FT STRAND 103 105 FT HELIX 113 115 FT STRAND 118 121 FT HELIX 124 126 FT STRAND 127 129 FT STRAND 221 225 FT STRAND 231 239 FT STRAND 242 250 FT STRAND 252 258 FT STRAND 268 270 FT HELIX 271 273 FT HELIX 281 290 FT STRAND 294 299 FT STRAND 302 307 FT STRAND 309 311 FT STRAND 313 316 FT HELIX 318 321 FT HELIX 323 325 FT STRAND 332 334 FT STRAND 339 343 FT HELIX 345 358 FT HELIX 360 364 FT HELIX 365 370 FT STRAND 371 377 FT STRAND 384 386 FT HELIX 389 391 FT STRAND 392 400 FT HELIX 401 413 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 //