SMAD2_HUMAN
ID SMAD2_HUMAN Reviewed; 467 AA.
AC Q15796;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 237.
DE RecName: Full=Mothers against decapentaplegic homolog 2;
DE Short=MAD homolog 2;
DE Short=Mothers against DPP homolog 2;
DE AltName: Full=JV18-1;
DE AltName: Full=Mad-related protein 2;
DE Short=hMAD-2;
DE AltName: Full=SMAD family member 2;
DE Short=SMAD 2;
DE Short=Smad2;
DE Short=hSMAD2;
GN Name=SMAD2; Synonyms=MADH2, MADR2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT 344-GLU--GLN-358
RP DEL.
RX PubMed=8673135; DOI=10.1038/ng0796-347;
RA Riggins G.J., Thiagalingam S., Rosenblum E., Weinstein C.L., Kern S.E.,
RA Hamilton S.R., Willson J.K.V., Markowitz S.D., Kinzler K.W.,
RA Vogelstein B.V.;
RT "Mad-related genes in the human.";
RL Nat. Genet. 13:347-349(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RC TISSUE=Placenta;
RX 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-beta
RT response.";
RL Nature 383:168-172(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), PHOSPHORYLATION BY TGFBR1, AND
RP VARIANTS CYS-133; ARG-440; HIS-445 AND GLU-450.
RC TISSUE=Kidney;
RX PubMed=8752209; DOI=10.1016/s0092-8674(00)80128-2;
RA Eppert K., Scherer S.W., Ozcelik H., Pirone R., Hoodless P., Kim H.,
RA Tsui L.-C., Bapat B., Gallinger S., Andrulis I.L., Thomsen G.H.,
RA Wrana J.L., Attisano L.;
RT "MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein
RT that is functionally mutated in colorectal carcinoma.";
RL Cell 86:543-552(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RX PubMed=9389648; DOI=10.1101/gad.11.23.3157;
RA Liu F., Pouponnot C., Massague J.;
RT "Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible
RT transcriptional complexes.";
RL Genes Dev. 11:3157-3167(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS LONG AND SHORT).
RX PubMed=9503010; DOI=10.1006/geno.1997.5149;
RA Takenoshita S., Mogi A., Nagashima M., Yang K., Yagi K., Hanyu A.,
RA Nagamachi Y., Miyazono K., Hagiwara K.;
RT "Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible
RT for the transforming growth factor-beta and activin signal transduction
RT pathway.";
RL Genomics 48:1-11(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG).
RC TISSUE=Kidney, Pancreas, and Spleen;
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 [7]
RP PROTEIN SEQUENCE OF 2-14 AND 170-182, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT SER-2, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Chronic myeloid leukemia cell;
RA Bienvenut W.V., von Kriegsheim A., Kolch W.;
RL Submitted (DEC-2008) to UniProtKB.
RN [8]
RP INTERACTION WITH TGFBR1, PHOSPHORYLATION AT SER-464; SER-465 AND SER-467,
RP AND MUTAGENESIS OF SER-464; SER-465 AND SER-467.
RX PubMed=8980228; DOI=10.1016/s0092-8674(00)81817-6;
RA Macias-Silva M., Abdollah S., Hoodless P.A., Pirone R., Attisano L.,
RA Wrana J.L.;
RT "MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is
RT required for nuclear accumulation and signaling.";
RL Cell 87:1215-1224(1996).
RN [9]
RP INTERACTION WITH ZFYVE9, AND SUBCELLULAR LOCATION.
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 receptor.";
RL Cell 95:779-791(1998).
RN [10]
RP SUBUNIT, AND INTERACTION WITH SMAD4.
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 receptors.";
RL EMBO J. 17:4056-4065(1998).
RN [11]
RP ALTERNATIVE SPLICING (ISOFORMS LONG AND SHORT).
RX PubMed=9873005; DOI=10.1074/jbc.274.2.703;
RA Yagi K., Goto D., Hamamoto T., Takenoshita S., Kato M., Miyazono K.;
RT "Alternatively spliced variant of Smad2 lacking exon 3. Comparison with
RT wild-type Smad2 and Smad3.";
RL J. Biol. Chem. 274:703-709(1999).
RN [12]
RP PHOSPHORYLATION AT SER-465 AND SER-467.
RX PubMed=9136927; DOI=10.1101/gad.11.8.984;
RA Kretzschmar M., Liu F., Hata A., Doody J., Massague J.;
RT "The TGF-beta family mediator Smad1 is phosphorylated directly and
RT activated functionally by the BMP receptor kinase.";
RL Genes Dev. 11:984-995(1997).
RN [13]
RP PHOSPHORYLATION AT SER-465 AND SER-467 BY TGFBR1.
RX PubMed=9346908; DOI=10.1074/jbc.272.44.27678;
RA Abdollah S., Macias-Silva M., Tsukazaki T., Hayashi H., Attisano L.,
RA Wrana J.L.;
RT "TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for
RT Smad2-Smad4 complex formation and signaling.";
RL J. Biol. Chem. 272:27678-27685(1997).
RN [14]
RP INTERACTION WITH FOXH1.
RC TISSUE=Colon adenocarcinoma;
RX PubMed=9702198; DOI=10.1016/s1097-2765(00)80120-3;
RA Zhou S., Zawel L., Lengauer C., Kinzler K.W., Vogelstein B.;
RT "Characterization of human FAST-1, a TGF beta and activin signal
RT transducer.";
RL Mol. Cell 2:121-127(1998).
RN [15]
RP INTERACTION WITH ACVR1B, AND FUNCTION.
RX PubMed=9892009; DOI=10.1210/mend.13.1.0218;
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 TGIF1.
RX PubMed=10835638; DOI=10.1038/76074;
RA Gripp K.W., Wotton D., Edwards M.C., Roessler E., Ades L., Meinecke P.,
RA Richieri-Costa A., Zackai E.H., Massague J., Muenke M., Elledge S.J.;
RT "Mutations in TGIF cause holoprosencephaly and link NODAL signalling to
RT human neural axis determination.";
RL Nat. Genet. 25:205-208(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 beta
RT receptors to the Smad pathway.";
RL EMBO J. 20:2789-2801(2001).
RN [18]
RP INTERACTION WITH SNW1.
RX PubMed=11278756; DOI=10.1074/jbc.m010815200;
RA Leong G.M., Subramaniam N., Figueroa J., Flanagan J.L., Hayman M.J.,
RA Eisman J.A., Kouzmenko A.P.;
RT "Ski-interacting protein interacts with Smad proteins to augment
RT transforming growth factor-beta-dependent transcription.";
RL J. Biol. Chem. 276:18243-18248(2001).
RN [19]
RP INTERACTION WITH SMURF2 AND SNON, AND MUTAGENESIS OF 221-PRO--TYR-225.
RX PubMed=11389444; DOI=10.1038/35078562;
RA Bonni S., Wang H.R., Causing C.G., Kavsak P., Stroschein S.L., Luo K.,
RA Wrana J.L.;
RT "TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that
RT targets SnoN for degradation.";
RL Nat. Cell Biol. 3:587-595(2001).
RN [20]
RP PHOSPHORYLATION AT SER-240.
RX PubMed=11879191; DOI=10.1042/0264-6021:3620643;
RA Abdel-Wahab N., Wicks S.J., Mason R.M., Chantry A.;
RT "Decorin suppresses transforming growth factor-beta-induced expression of
RT plasminogen activator inhibitor-1 in human mesangial cells through a
RT mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-
RT 240.";
RL Biochem. J. 362:643-649(2002).
RN [21]
RP PHOSPHORYLATION AT THR-8; THR-220; SER-245; SER-250 AND SER-255.
RX PubMed=12193595; DOI=10.1074/jbc.m204597200;
RA Funaba M., Zimmerman C.M., Mathews L.S.;
RT "Modulation of Smad2-mediated signaling by extracellular signal-regulated
RT kinase.";
RL J. Biol. Chem. 277:41361-41368(2002).
RN [22]
RP 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 and
RT Smad3 and antagonizes transforming growth factor-beta signaling.";
RL Hum. Mol. Genet. 14:437-445(2005).
RN [23]
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., Zhou S.,
RA Luo K.;
RT "The integral inner nuclear membrane protein MAN1 physically interacts with
RT the R-Smad proteins to repress signaling by the transforming growth
RT factor-{beta} superfamily of cytokines.";
RL J. Biol. Chem. 280:15992-16001(2005).
RN [24]
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-18,
RT specifically expressed in neuronal tissues.";
RL Lab. Invest. 85:1330-1341(2005).
RN [25]
RP INTERACTION WITH PPM1A, DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF VAL-398; SER-465 AND SER-467.
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 signaling.";
RL Cell 125:915-928(2006).
RN [26]
RP IDENTIFICATION IN A COMPLEX WITH SMAD3 AND TRIM33, AND INTERACTION WITH
RP 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., Massague J.;
RT "Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the
RT TGFbeta pathway.";
RL Cell 125:929-941(2006).
RN [27]
RP ACETYLATION AT LYS-19, AND MUTAGENESIS OF LYS-19 AND LYS-20.
RX PubMed=17074756; DOI=10.1074/jbc.m607868200;
RA Simonsson M., Kanduri M., Gronroos E., Heldin C.H., Ericsson J.;
RT "The DNA binding activities of Smad2 and Smad3 are regulated by
RT coactivator-mediated acetylation.";
RL J. Biol. Chem. 281:39870-39880(2006).
RN [28]
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., Song H.,
RA 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 [29]
RP FUNCTION, PHOSPHORYLATION BY PDPK1, AND 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 growth
RT factor-beta-induced signaling in a kinase-dependent manner through physical
RT interaction with Smad proteins.";
RL J. Biol. Chem. 282:12272-12289(2007).
RN [30]
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 signaling.";
RL Mol. Cell. Neurosci. 34:603-611(2007).
RN [31]
RP ACETYLATION, AND FUNCTION.
RX PubMed=16862174; DOI=10.1038/sj.onc.1209826;
RA Inoue Y., Itoh Y., Abe K., Okamoto T., Daitoku H., Fukamizu A., Onozaki K.,
RA Hayashi H.;
RT "Smad3 is acetylated by p300/CBP to regulate its transactivation
RT activity.";
RL Oncogene 26:500-508(2007).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [33]
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 [34]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [35]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [36]
RP INTERACTION WITH RANBP3, SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF
RP 465-SER--SER-467.
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 of
RT TGF-beta signaling.";
RL Dev. Cell 16:345-357(2009).
RN [37]
RP INTERACTION WITH PRDM16.
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., Morishita K.,
RA Yuki K., Hanyu A., Miyazawa K., Inazawa J., Miyazono K., Imamura T.;
RT "SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal
RT in gastric cancer cells.";
RL J. Biol. Chem. 284:3334-3344(2009).
RN [38]
RP SUBCELLULAR LOCATION.
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 [39]
RP INTERACTION WITH PMEPA1, AND MUTAGENESIS OF TRP-368.
RX PubMed=20129061; DOI=10.1016/j.molcel.2009.10.028;
RA Watanabe Y., Itoh S., Goto T., Ohnishi E., Inamitsu M., Itoh F., Satoh K.,
RA Wiercinska E., Yang W., Shi L., Tanaka A., Nakano N., Mommaas A.M.,
RA Shibuya H., Ten Dijke P., Kato M.;
RT "TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad
RT proteins from active participation in TGF-beta signaling.";
RL Mol. Cell 37:123-134(2010).
RN [40]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT THR-8; SER-458 AND SER-460, CLEAVAGE OF INITIATOR METHIONINE
RP [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [41]
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., Buerckstuemmer T.,
RA 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 [42]
RP INTERACTION WITH ZNF580, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=21599657; DOI=10.1042/cbi20110050;
RA Luo Y., Hu W., Xu R., Hou B., Zhang L., Zhang W.;
RT "ZNF580, a novel C2H2 zinc-finger transcription factor, interacts with the
RT TGF-beta signal molecule Smad2.";
RL Cell Biol. Int. 35:1153-1157(2011).
RN [43]
RP UBIQUITINATION, DEUBIQUITINATION BY USP15, DNA-BINDING, AND INTERACTION
RP WITH USP15.
RX PubMed=21947082; DOI=10.1038/ncb2346;
RA Inui M., Manfrin A., Mamidi A., Martello G., Morsut L., Soligo S., Enzo E.,
RA 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 [44]
RP INTERACTION WITH PPP5C, AND SUBCELLULAR LOCATION.
RX PubMed=22781750; DOI=10.1016/j.cellsig.2012.07.003;
RA Bruce D.L., Macartney T., Yong W., Shou W., Sapkota G.P.;
RT "Protein phosphatase 5 modulates SMAD3 function in the transforming growth
RT factor-beta pathway.";
RL Cell. Signal. 24:1999-2006(2012).
RN [45]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [46]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8 AND SER-458, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [48]
RP PHOSPHORYLATION AT SER-465 AND SER-467.
RX PubMed=23478445; DOI=10.1016/j.molcel.2013.02.003;
RA Abbas T., Mueller A.C., Shibata E., Keaton M., Rossi M., Dutta A.;
RT "CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-
RT Set7/Set8-mediated cellular migration.";
RL Mol. Cell 49:1147-1158(2013).
RN [49]
RP INTERACTION WITH ZNF451, AND IDENTIFICATION IN A COMPLEX WITH ZNF451; SMAD3
RP AND SMAD4.
RX PubMed=24324267; DOI=10.1074/jbc.m113.526905;
RA Feng Y., Wu H., Xu Y., Zhang Z., Liu T., Lin X., Feng X.H.;
RT "Zinc finger protein 451 is a novel Smad corepressor in transforming growth
RT factor-beta signaling.";
RL J. Biol. Chem. 289:2072-2083(2014).
RN [50]
RP INTERACTION WITH LDLRAD4.
RX PubMed=24627487; DOI=10.1074/jbc.m114.558981;
RA Nakano N., Maeyama K., Sakata N., Itoh F., Akatsu R., Nakata M., Katsu Y.,
RA Ikeno S., Togawa Y., Vo Nguyen T.T., Watanabe Y., Kato M., Itoh S.;
RT "C18 ORF1, a novel negative regulator of transforming growth factor-beta
RT signaling.";
RL J. Biol. Chem. 289:12680-12692(2014).
RN [51]
RP REVIEW.
RX PubMed=9759503; DOI=10.1146/annurev.biochem.67.1.753;
RA Massague J.;
RT "TGF-beta signal transduction.";
RL Annu. Rev. Biochem. 67:753-791(1998).
RN [52]
RP REVIEW.
RX PubMed=10647776; DOI=10.1016/s1359-6101(99)00012-x;
RA Verschueren K., Huylebroeck D.;
RT "Remarkable versatility of Smad proteins in the nucleus of transforming
RT growth factor-beta activated cells.";
RL Cytokine Growth Factor Rev. 10:187-199(1999).
RN [53]
RP REVIEW.
RX PubMed=10708948; DOI=10.1016/s1359-6101(99)00024-6;
RA Wrana J.L., Attisano L.;
RT "The Smad pathway.";
RL Cytokine Growth Factor Rev. 11:5-13(2000).
RN [54]
RP REVIEW.
RX PubMed=10708949; DOI=10.1016/s1359-6101(99)00025-8;
RA Miyazono K.;
RT "TGF-beta signaling by Smad proteins.";
RL Cytokine Growth Factor Rev. 11:15-22(2000).
RN [55]
RP INTERACTION WITH ZFHX3.
RX PubMed=25105025; DOI=10.1155/2014/970346;
RA Sakata N., Kaneko S., Ikeno S., Miura Y., Nakabayashi H., Dong X.Y.,
RA Dong J.T., Tamaoki T., Nakano N., Itoh S.;
RT "TGF-beta signaling cooperates with AT motif-binding factor-1 for
RT repression of the alpha -fetoprotein promoter.";
RL J. Signal Transduct. 2014:970346-970346(2014).
RN [56]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 261-456 IN COMPLEX WITH ZFYVE9,
RP INTERACTION WITH SARA, AND MUTAGENESIS OF ASN-381.
RX PubMed=10615055; DOI=10.1126/science.287.5450.92;
RA Wu G., Chen Y.-G., Ozdamar B., Gyuricza C.A., Chong P.A., Wrana J.L.,
RA Massague J., Shi Y.;
RT "Structural basis of Smad2 recognition by the Smad anchor for receptor
RT activation.";
RL Science 287:92-97(2000).
RN [57]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 270-466 IN COMPLEX WITH SMAD4, AND
RP 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 [58]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-300.
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., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular
CC signal transducer and transcriptional modulator activated by TGF-beta
CC (transforming growth factor) and activin type 1 receptor kinases. Binds
CC the TRE element in the promoter region of many genes that are regulated
CC by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates
CC transcription. May act as a tumor suppressor in colorectal carcinoma.
CC Positively regulates PDPK1 kinase activity by stimulating its
CC dissociation from the 14-3-3 protein YWHAQ which acts as a negative
CC regulator. {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174,
CC ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19289081,
CC ECO:0000269|PubMed:9892009}.
CC -!- SUBUNIT: Monomer; in the absence of TGF-beta (PubMed:9670020).
CC Heterodimer; in the presence of TGF-beta (PubMed:9670020). Forms a
CC heterodimer with co-SMAD, SMAD4, in the nucleus to form the
CC transactivation complex SMAD2/SMAD4 (PubMed:9670020, PubMed:24324267,
CC PubMed:15350224). Found in a complex with SMAD3 and TRIM33 upon
CC addition of TGF-beta (PubMed:16751102). Identified in a complex that
CC contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267).
CC Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the
CC SMAD4 co-SMAD (PubMed:10615055). Interacts with TAZ/WWRT1
CC (PubMed:18568018). Interacts with FOXH1 (PubMed:9702198). Interacts
CC with SNW1 (PubMed:11278756). Interacts with CREB-binding protein (CBP)
CC and EP300 (PubMed:16862174). Interacts with SNON (PubMed:11389444).
CC Interacts with ALK4/ACVR1B (PubMed:9892009, PubMed:10615055). Interacts
CC with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078).
CC Interacts with PRDM16 (PubMed:19049980). Interacts (via MH2 domain)
CC with LEMD3 (PubMed:15601644, PubMed:15647271). Interacts with RBPMS
CC (PubMed:17099224). Interacts with WWP1. Interacts (dephosphorylated
CC form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R
CC domain); the interaction results in the export of dephosphorylated
CC SMAD3 out of the nucleus and termination of the TGF-beta signaling
CC (PubMed:19289081). Interacts with PDPK1 (via PH domain)
CC (PubMed:17327236). Interacts with DAB2; the interactions are enhanced
CC upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15
CC (PubMed:21947082). Interacts with PPP5C (PubMed:22781750). Interacts
CC with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487).
CC Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif)
CC (PubMed:20129061). Interacts with ZFHX3 (PubMed:25105025). Interacts
CC with ZNF451 (PubMed:24324267). Interacts with SMURF2 when
CC phosphorylated on Ser-465/467 (PubMed:11389444). Interacts with PPM1A
CC (PubMed:16751101). Interacts with TGF-beta (PubMed:8980228). Interacts
CC with TGFBR1 (PubMed:9865696). Interacts with TGIF (PubMed:10835638).
CC Interacts with SMAD3 and TRIM33 (PubMed:16751102). Interacts with
CC ZNF580 (PubMed:21599657). Interacts with NEDD4L in response to TGF-beta
CC (By similarity). Interacts with HGS (By similarity). Interacts with
CC AIP1 (By similarity). Interacts with WWP1 (By similarity). Interacts
CC with PML (By similarity). Interacts weakly with ZNF8 (By similarity).
CC Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer
CC of the transcriptional responses by mediating ubiquitination and
CC degradation of SMAD2 inhibitors (By similarity). Interacts with YAP1
CC (when phosphorylated at 'Ser-127') (By similarity).
CC {ECO:0000250|UniProtKB:Q62432, ECO:0000269|PubMed:10615055,
CC ECO:0000269|PubMed:10835638, ECO:0000269|PubMed:11278756,
CC ECO:0000269|PubMed:11387212, ECO:0000269|PubMed:11389444,
CC ECO:0000269|PubMed:15350224, ECO:0000269|PubMed:15601644,
CC ECO:0000269|PubMed:15647271, ECO:0000269|PubMed:16200078,
CC ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16751102,
CC ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17099224,
CC ECO:0000269|PubMed:17292623, ECO:0000269|PubMed:17327236,
CC ECO:0000269|PubMed:18568018, ECO:0000269|PubMed:19049980,
CC ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:20129061,
CC ECO:0000269|PubMed:21599657, ECO:0000269|PubMed:21947082,
CC ECO:0000269|PubMed:22781750, ECO:0000269|PubMed:24324267,
CC ECO:0000269|PubMed:24627487, ECO:0000269|PubMed:25105025,
CC ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9670020,
CC ECO:0000269|PubMed:9702198, ECO:0000269|PubMed:9865696,
CC ECO:0000269|PubMed:9892009}.
CC -!- INTERACTION:
CC Q15796; Q12955: ANK3; NbExp=2; IntAct=EBI-1040141, EBI-2691178;
CC Q15796; P05060: CHGB; NbExp=2; IntAct=EBI-1040141, EBI-712619;
CC Q15796; O15111: CHUK; NbExp=2; IntAct=EBI-1040141, EBI-81249;
CC Q15796; P98082: DAB2; NbExp=4; IntAct=EBI-1040141, EBI-1171238;
CC Q15796; Q9BZ29: DOCK9; NbExp=3; IntAct=EBI-1040141, EBI-2695893;
CC Q15796; O75593: FOXH1; NbExp=4; IntAct=EBI-1040141, EBI-1759806;
CC Q15796; P05412: JUN; NbExp=3; IntAct=EBI-1040141, EBI-852823;
CC Q15796; Q9NYA4: MTMR4; NbExp=2; IntAct=EBI-1040141, EBI-1052346;
CC Q15796; P07197: NEFM; NbExp=3; IntAct=EBI-1040141, EBI-1105035;
CC Q15796; Q8TAK6: OLIG1; NbExp=2; IntAct=EBI-1040141, EBI-3867416;
CC Q15796; P35813: PPM1A; NbExp=2; IntAct=EBI-1040141, EBI-989143;
CC Q15796; Q9H6Z4: RANBP3; NbExp=2; IntAct=EBI-1040141, EBI-992681;
CC Q15796; P61586: RHOA; NbExp=2; IntAct=EBI-1040141, EBI-446668;
CC Q15796; P12755: SKI; NbExp=10; IntAct=EBI-1040141, EBI-347281;
CC Q15796; P84022: SMAD3; NbExp=2; IntAct=EBI-1040141, EBI-347161;
CC Q15796; Q13485: SMAD4; NbExp=21; IntAct=EBI-1040141, EBI-347263;
CC Q15796; Q9HAU4: SMURF2; NbExp=6; IntAct=EBI-1040141, EBI-396727;
CC Q15796; Q13573: SNW1; NbExp=3; IntAct=EBI-1040141, EBI-632715;
CC Q15796; P04637: TP53; NbExp=7; IntAct=EBI-1040141, EBI-366083;
CC Q15796; Q9H3D4: TP63; NbExp=3; IntAct=EBI-1040141, EBI-2337775;
CC Q15796; Q9UPN9: TRIM33; NbExp=6; IntAct=EBI-1040141, EBI-2214398;
CC Q15796; O00308: WWP2; NbExp=4; IntAct=EBI-1040141, EBI-743923;
CC Q15796; Q96KR1: ZFR; NbExp=2; IntAct=EBI-1040141, EBI-2513582;
CC Q15796; O95405: ZFYVE9; NbExp=6; IntAct=EBI-1040141, EBI-296817;
CC Q15796; P70056: foxh1; Xeno; NbExp=4; IntAct=EBI-1040141, EBI-9969973;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16751101,
CC ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499,
CC ECO:0000269|PubMed:9865696}. Nucleus {ECO:0000269|PubMed:16751101,
CC ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499,
CC ECO:0000269|PubMed:21599657, ECO:0000269|PubMed:22781750,
CC ECO:0000269|PubMed:9865696}. Note=Cytoplasmic and nuclear in the
CC absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus
CC when complexed with SMAD4 (PubMed:9865696, PubMed:21145499). On
CC dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4
CC complex, and exported out of the nucleus by interaction with RANBP1
CC (PubMed:16751101, PubMed:19289081). Localized mainly to the nucleus in
CC the early stages of embryo development with expression becoming evident
CC in the cytoplasm at the blastocyst and epiblast stages (By similarity).
CC {ECO:0000250|UniProtKB:Q62432, ECO:0000269|PubMed:16751101,
CC ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499,
CC ECO:0000269|PubMed:9865696}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=Q15796-1; Sequence=Displayed;
CC Name=Short; Synonyms=Smad2Deltaexon3;
CC IsoId=Q15796-2; Sequence=VSP_006178;
CC -!- TISSUE SPECIFICITY: Expressed at high levels in skeletal muscle,
CC endothelial cells, heart and placenta. {ECO:0000269|PubMed:21599657}.
CC -!- PTM: Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and
CC Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF-
CC beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467
CC phosphorylation declines progressively in a KMT5A-dependent manner.
CC Able to interact with SMURF2 when phosphorylated on Ser-465/467,
CC recruiting other proteins, such as SNON, for degradation. In response
CC to decorin, the naturally occurring inhibitor of TGF-beta signaling,
CC phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF
CC stimulation; which increases transcriptional activity and stability,
CC and is blocked by calmodulin. Phosphorylated by PDPK1.
CC {ECO:0000269|PubMed:11879191, ECO:0000269|PubMed:12193595,
CC ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:23478445,
CC ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228,
CC ECO:0000269|PubMed:9136927, ECO:0000269|PubMed:9346908}.
CC -!- PTM: In response to TGF-beta, ubiquitinated by NEDD4L; which promotes
CC its degradation. Monoubiquitinated, leading to prevent DNA-binding (By
CC similarity). Deubiquitination by USP15 alleviates inhibition and
CC promotes activation of TGF-beta target genes (PubMed:21947082).
CC Ubiquitinated by RNF111, leading to its degradation: only SMAD2
CC proteins that are 'in use' are targeted by RNF111, RNF111 playing a key
CC role in activating SMAD2 and regulating its turnover (By similarity).
CC {ECO:0000250|UniProtKB:Q62432, ECO:0000269|PubMed:21947082}.
CC -!- PTM: Acetylated on Lys-19 by coactivators in response to TGF-beta
CC signaling, which increases transcriptional activity. Isoform short:
CC Acetylation increases DNA binding activity in vitro and enhances its
CC association with target promoters in vivo. Acetylation in the nucleus
CC by EP300 is enhanced by TGF-beta. {ECO:0000269|PubMed:16862174,
CC ECO:0000269|PubMed:17074756, ECO:0000269|Ref.7}.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SMAD2ID370.html";
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; U59911; AAC50789.1; -; mRNA.
DR EMBL; U68018; AAB17087.1; -; mRNA.
DR EMBL; U65019; AAB17054.1; -; mRNA.
DR EMBL; AF027964; AAC51918.1; -; mRNA.
DR EMBL; U78733; AAC39657.1; -; Genomic_DNA.
DR EMBL; U78727; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; U78728; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; U78729; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; U78730; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; U78731; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; U78732; AAC39657.1; JOINED; Genomic_DNA.
DR EMBL; BC014840; AAH14840.1; -; mRNA.
DR EMBL; BC025699; AAH25699.1; -; mRNA.
DR CCDS; CCDS11934.1; -. [Q15796-1]
DR PIR; S71797; S71797.
DR RefSeq; NP_001003652.1; NM_001003652.3. [Q15796-1]
DR RefSeq; NP_005892.1; NM_005901.5. [Q15796-1]
DR RefSeq; XP_005258316.1; XM_005258259.3. [Q15796-1]
DR RefSeq; XP_006722514.1; XM_006722451.3. [Q15796-1]
DR RefSeq; XP_016881234.1; XM_017025745.1. [Q15796-1]
DR RefSeq; XP_016881235.1; XM_017025746.1. [Q15796-2]
DR PDB; 1DEV; X-ray; 2.20 A; A/C=261-456.
DR PDB; 1KHX; X-ray; 1.80 A; A=241-467.
DR PDB; 1U7V; X-ray; 2.70 A; A/C=270-467.
DR PDB; 2LB3; NMR; -; B=217-224.
DR PDB; 5XOD; X-ray; 1.85 A; A=262-458.
DR PDB; 5ZOJ; X-ray; 2.79 A; A/B/C=262-458.
DR PDB; 6M64; X-ray; 1.45 A; A/C/E=262-464.
DR PDB; 6YIA; X-ray; 1.30 A; P=459-467.
DR PDB; 6ZVQ; X-ray; 2.03 A; A=241-467.
DR PDB; 7CO1; X-ray; 3.30 A; A/C/E=262-467.
DR PDBsum; 1DEV; -.
DR PDBsum; 1KHX; -.
DR PDBsum; 1U7V; -.
DR PDBsum; 2LB3; -.
DR PDBsum; 5XOD; -.
DR PDBsum; 5ZOJ; -.
DR PDBsum; 6M64; -.
DR PDBsum; 6YIA; -.
DR PDBsum; 6ZVQ; -.
DR PDBsum; 7CO1; -.
DR AlphaFoldDB; Q15796; -.
DR BMRB; Q15796; -.
DR SASBDB; Q15796; -.
DR SMR; Q15796; -.
DR BioGRID; 110262; 337.
DR ComplexPortal; CPX-1; SMAD2-SMAD3-SMAD4 complex.
DR ComplexPortal; CPX-11; SMAD2 homotrimer.
DR ComplexPortal; CPX-3208; SMAD2-SMAD4 complex.
DR CORUM; Q15796; -.
DR DIP; DIP-29716N; -.
DR IntAct; Q15796; 231.
DR MINT; Q15796; -.
DR STRING; 9606.ENSP00000262160; -.
DR ChEMBL; CHEMBL2396512; -.
DR DrugBank; DB04522; Dexfosfoserine.
DR GlyGen; Q15796; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q15796; -.
DR PhosphoSitePlus; Q15796; -.
DR BioMuta; SMAD2; -.
DR DMDM; 13633914; -.
DR EPD; Q15796; -.
DR jPOST; Q15796; -.
DR MassIVE; Q15796; -.
DR MaxQB; Q15796; -.
DR PaxDb; Q15796; -.
DR PeptideAtlas; Q15796; -.
DR PRIDE; Q15796; -.
DR ProteomicsDB; 60764; -. [Q15796-1]
DR ProteomicsDB; 60765; -. [Q15796-2]
DR ABCD; Q15796; 1 sequenced antibody.
DR Antibodypedia; 9235; 1994 antibodies from 48 providers.
DR DNASU; 4087; -.
DR Ensembl; ENST00000262160.11; ENSP00000262160.6; ENSG00000175387.16. [Q15796-1]
DR Ensembl; ENST00000356825.8; ENSP00000349282.4; ENSG00000175387.16. [Q15796-2]
DR Ensembl; ENST00000402690.6; ENSP00000384449.1; ENSG00000175387.16. [Q15796-1]
DR Ensembl; ENST00000586040.5; ENSP00000466193.1; ENSG00000175387.16. [Q15796-2]
DR GeneID; 4087; -.
DR KEGG; hsa:4087; -.
DR MANE-Select; ENST00000262160.11; ENSP00000262160.6; NM_005901.6; NP_005892.1.
DR UCSC; uc010xdc.4; human. [Q15796-1]
DR CTD; 4087; -.
DR DisGeNET; 4087; -.
DR GeneCards; SMAD2; -.
DR GeneReviews; SMAD2; -.
DR HGNC; HGNC:6768; SMAD2.
DR HPA; ENSG00000175387; Low tissue specificity.
DR MIM; 601366; gene.
DR neXtProt; NX_Q15796; -.
DR OpenTargets; ENSG00000175387; -.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR PharmGKB; PA134959722; -.
DR VEuPathDB; HostDB:ENSG00000175387; -.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000153499; -.
DR HOGENOM; CLU_026736_0_2_1; -.
DR InParanoid; Q15796; -.
DR OMA; TNMCTIR; -.
DR PhylomeDB; Q15796; -.
DR TreeFam; TF314923; -.
DR PathwayCommons; Q15796; -.
DR Reactome; R-HSA-1181150; Signaling by NODAL.
DR Reactome; R-HSA-1502540; Signaling by Activin.
DR Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling.
DR Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs.
DR Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-HSA-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
DR Reactome; R-HSA-3304356; SMAD2/3 Phosphorylation Motif Mutants in Cancer.
DR Reactome; R-HSA-3311021; SMAD4 MH2 Domain Mutants in Cancer.
DR Reactome; R-HSA-3315487; SMAD2/3 MH2 Domain Mutants in Cancer.
DR Reactome; R-HSA-3656532; TGFBR1 KD Mutants in Cancer.
DR Reactome; R-HSA-452723; Transcriptional regulation of pluripotent stem cells.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes.
DR SignaLink; Q15796; -.
DR SIGNOR; Q15796; -.
DR BioGRID-ORCS; 4087; 16 hits in 1105 CRISPR screens.
DR ChiTaRS; SMAD2; human.
DR EvolutionaryTrace; Q15796; -.
DR GeneWiki; Mothers_against_decapentaplegic_homolog_2; -.
DR GenomeRNAi; 4087; -.
DR Pharos; Q15796; Tbio.
DR PRO; PR:Q15796; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q15796; protein.
DR Bgee; ENSG00000175387; Expressed in calcaneal tendon and 209 other tissues.
DR ExpressionAtlas; Q15796; baseline and differential.
DR Genevisible; Q15796; HS.
DR GO; GO:0032444; C:activin responsive factor complex; IDA:BHF-UCL.
DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IDA:BHF-UCL.
DR GO; GO:0071142; C:homomeric SMAD protein complex; IPI:ComplexPortal.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA.
DR GO; GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IDA:BHF-UCL.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; IC:BHF-UCL.
DR GO; GO:0070410; F:co-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
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:BHF-UCL.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0070411; F:I-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0019902; F:phosphatase binding; IPI:UniProtKB.
DR GO; GO:0070412; F:R-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IEA:Ensembl.
DR GO; GO:0046332; F:SMAD binding; IPI:UniProtKB.
DR GO; GO:0048156; F:tau protein binding; ISS:ARUK-UCL.
DR GO; GO:0005160; F:transforming growth factor beta receptor binding; IPI:BHF-UCL.
DR GO; GO:0034713; F:type I transforming growth factor beta receptor binding; IPI:BHF-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
DR GO; GO:0032924; P:activin receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0009952; P:anterior/posterior pattern specification; ISS:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0045165; P:cell fate commitment; ISS:UniProtKB.
DR GO; GO:0007182; P:common-partner SMAD protein phosphorylation; IDA:MGI.
DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl.
DR GO; GO:0048617; P:embryonic foregut morphogenesis; IEA:Ensembl.
DR GO; GO:0001706; P:endoderm formation; IEA:Ensembl.
DR GO; GO:0007369; P:gastrulation; TAS:BHF-UCL.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0030073; P:insulin secretion; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0001707; P:mesoderm formation; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:BHF-UCL.
DR GO; GO:0038092; P:nodal signaling pathway; IMP:BHF-UCL.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0031016; P:pancreas development; IEA:Ensembl.
DR GO; GO:0048340; P:paraxial mesoderm morphogenesis; ISS:UniProtKB.
DR GO; GO:0060039; P:pericardium development; IEA:Ensembl.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IMP:BHF-UCL.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:1900224; P:positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0031053; P:primary miRNA processing; TAS:BHF-UCL.
DR GO; GO:0051098; P:regulation of binding; ISS:UniProtKB.
DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0070723; P:response to cholesterol; IDA:BHF-UCL.
DR GO; GO:0009749; P:response to glucose; IEA:Ensembl.
DR GO; GO:0062009; P:secondary palate development; ISS:BHF-UCL.
DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; IEA:Ensembl.
DR GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR GO; GO:0006351; P:transcription, DNA-templated; IC:ComplexPortal.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR GO; GO:0007352; P:zygotic specification of dorsal/ventral axis; IMP:BHF-UCL.
DR DisProt; DP01319; -.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR IDEAL; IID00127; -.
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; Alternative splicing; Cytoplasm;
KW Direct protein sequencing; DNA-binding; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..467
FT /note="Mothers against decapentaplegic homolog 2"
FT /id="PRO_0000090852"
FT DOMAIN 10..176
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 274..467
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 207..251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 221..225
FT /note="PY-motif"
FT COMPBIAS 229..251
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 74
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 149
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 161
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 8
FT /note="Phosphothreonine; by MAPK3"
FT /evidence="ECO:0000269|PubMed:12193595,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 19
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:17074756"
FT MOD_RES 220
FT /note="Phosphothreonine"
FT /evidence="ECO:0000305|PubMed:12193595"
FT MOD_RES 240
FT /note="Phosphoserine; by CAMK2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
FT ECO:0000269|PubMed:11879191"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0000305|PubMed:12193595"
FT MOD_RES 250
FT /note="Phosphoserine"
FT /evidence="ECO:0000305|PubMed:12193595"
FT MOD_RES 255
FT /note="Phosphoserine"
FT /evidence="ECO:0000305|PubMed:12193595"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"
FT MOD_RES 460
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 464
FT /note="Phosphoserine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
FT ECO:0000269|PubMed:8980228"
FT MOD_RES 465
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
FT ECO:0000269|PubMed:23478445, ECO:0000269|PubMed:8980228,
FT ECO:0000269|PubMed:9136927, ECO:0000269|PubMed:9346908"
FT MOD_RES 467
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439,
FT ECO:0000269|PubMed:23478445, ECO:0000269|PubMed:8980228,
FT ECO:0000269|PubMed:9136927, ECO:0000269|PubMed:9346908"
FT VAR_SEQ 79..108
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000305"
FT /id="VSP_006178"
FT VARIANT 133
FT /note="R -> C (in a colorectal carcinoma sample)"
FT /evidence="ECO:0000269|PubMed:8752209"
FT /id="VAR_011375"
FT VARIANT 300
FT /note="D -> V (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036473"
FT VARIANT 344..358
FT /note="Missing (in a colorectal carcinoma sample)"
FT /evidence="ECO:0000269|PubMed:8673135"
FT /id="VAR_011376"
FT VARIANT 440
FT /note="L -> R (in a colorectal carcinoma sample)"
FT /evidence="ECO:0000269|PubMed:8752209"
FT /id="VAR_011377"
FT VARIANT 445
FT /note="P -> H (in a colorectal carcinoma sample)"
FT /evidence="ECO:0000269|PubMed:8752209"
FT /id="VAR_011378"
FT VARIANT 450
FT /note="D -> E (in a colorectal carcinoma sample)"
FT /evidence="ECO:0000269|PubMed:8752209"
FT /id="VAR_011379"
FT MUTAGEN 19
FT /note="K->R: Loss of acetylation."
FT /evidence="ECO:0000269|PubMed:17074756"
FT MUTAGEN 20
FT /note="K->R: No effect on acetylation."
FT /evidence="ECO:0000269|PubMed:17074756"
FT MUTAGEN 221..225
FT /note="Missing: Loss of binding to SMURF2."
FT /evidence="ECO:0000269|PubMed:11389444"
FT MUTAGEN 368
FT /note="W->A: Loss of interaction with PMEPA1."
FT /evidence="ECO:0000269|PubMed:20129061"
FT MUTAGEN 381
FT /note="N->S: Loss of binding to SARA."
FT /evidence="ECO:0000269|PubMed:10615055"
FT MUTAGEN 398
FT /note="V->R: Increased binding to PPM1A."
FT /evidence="ECO:0000269|PubMed:16751101"
FT MUTAGEN 464
FT /note="S->A: Loss of phosphorylation by TGFBR1; when
FT associated with A-465 and A-467."
FT /evidence="ECO:0000269|PubMed:8980228"
FT MUTAGEN 465..467
FT /note="SMS->AMA: Binds RANBP3."
FT /evidence="ECO:0000269|PubMed:19289081"
FT MUTAGEN 465..467
FT /note="SMS->DMD: Greatly reduced RANBP2 binding."
FT /evidence="ECO:0000269|PubMed:19289081"
FT MUTAGEN 465
FT /note="S->A: No change in binding to PPM1A. Loss of
FT phosphorylation by TGFBR1; when associated with A-464 and
FT A-467."
FT /evidence="ECO:0000269|PubMed:16751101,
FT ECO:0000269|PubMed:8980228"
FT MUTAGEN 465
FT /note="S->D: No change in binding to PPM1A."
FT /evidence="ECO:0000269|PubMed:16751101,
FT ECO:0000269|PubMed:8980228"
FT MUTAGEN 467
FT /note="S->A: No change in binding to PPM1A. Loss of
FT phosphorylation by TGFBR1; when associated with A-464 and
FT A-465."
FT /evidence="ECO:0000269|PubMed:16751101,
FT ECO:0000269|PubMed:8980228"
FT MUTAGEN 467
FT /note="S->D: No change in binding to PPM1A."
FT /evidence="ECO:0000269|PubMed:16751101,
FT ECO:0000269|PubMed:8980228"
FT STRAND 264..267
FT /evidence="ECO:0007829|PDB:1DEV"
FT STRAND 272..281
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 290..292
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 294..302
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 305..307
FT /evidence="ECO:0007829|PDB:1U7V"
FT STRAND 310..312
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 313..315
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 323..329
FT /evidence="ECO:0007829|PDB:6M64"
FT TURN 330..334
FT /evidence="ECO:0007829|PDB:1KHX"
FT STRAND 336..341
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 344..349
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 351..353
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 355..358
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 360..366
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 374..376
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 381..386
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 387..398
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 402..406
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 407..412
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 413..419
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 423..427
FT /evidence="ECO:0007829|PDB:1KHX"
FT HELIX 431..433
FT /evidence="ECO:0007829|PDB:6M64"
FT STRAND 434..442
FT /evidence="ECO:0007829|PDB:6M64"
FT HELIX 443..453
FT /evidence="ECO:0007829|PDB:6M64"
SQ SEQUENCE 467 AA; 52306 MW; 95406DB5FC0AA4C9 CRC64;
MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK KLKKTGRLDE
LEKAITTQNC NTKCVTIPST CSEIWGLSTP NTIDQWDTTG LYSFSEQTRS LDGRLQVSHR
KGLPHVIYCR LWRWPDLHSH HELKAIENCE YAFNLKKDEV CVNPYHYQRV ETPVLPPVLV
PRHTEILTEL PPLDDYTHSI PENTNFPAGI EPQSNYIPET PPPGYISEDG ETSDQQLNQS
MDTGSPAELS PTTLSPVNHS LDLQPVTYSE PAFWCSIAYY ELNQRVGETF HASQPSLTVD
GFTDPSNSER FCLGLLSNVN RNATVEMTRR HIGRGVRLYY IGGEVFAECL SDSAIFVQSP
NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF AALLAQSVNQ GFEAVYQLTR MCTIRMSFVK
GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD KVLTQMGSPS VRCSSMS
