RBCC Red Blood Cell Collection

SMAD2 (MADH2, MADR2) [Confidence: low (only semi-automatic identification from reviews)]
Mothers against decapentaplegic homolog 2; MAD homolog 2; Mothers against DPP homolog 2 (JV18-1; Mad-related protein 2; hMAD-2; SMAD family member 2; SMAD 2; Smad2; hSMAD2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q15796
ID SMAD2_HUMAN Reviewed; 467 AA.
AC Q15796;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 164.
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;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANT
RP 344-GLU--GLN-358 DEL.
RX 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 [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-
RT beta response.";
RL Nature 383:168-172(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), PHOSPHORYLATION BY TGFBR1,
RP AND 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
RT protein that is functionally mutated in colorectal carcinoma.";
RL Cell 86:543-552(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG).
RX PubMed=9389648;
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
RT responsible for the transforming growth factor-beta and activin signal
RT transduction 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
RT project: 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
RP METHIONINE, ACETYLATION AT SER-2, AND 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 BY TGFBR1, AND MUTAGENESIS OF
RP 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
RT is 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
RT receptor.";
RL Cell 95:779-791(1998).
RN [10]
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 [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
RT with 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;
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/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 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 [17]
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 [18]
RP INTERACTION WITH SMURF2, 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
RT that targets SnoN for degradation.";
RL Nat. Cell Biol. 3:587-595(2001).
RN [19]
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
RT of plasminogen activator inhibitor-1 in human mesangial cells through
RT a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at
RT serine-240.";
RL Biochem. J. 362:643-649(2002).
RN [20]
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-
RT regulated kinase.";
RL J. Biol. Chem. 277:41361-41368(2002).
RN [21]
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
RT and Smad3 and antagonizes transforming growth factor-beta signaling.";
RL Hum. Mol. Genet. 14:437-445(2005).
RN [22]
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 [23]
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 [24]
RP INTERACTION WITH PPM1A, DEPHOSPHORYLATION, FUNCTION, SUBCELLULAR
RP LOCATION, 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
RT signaling.";
RL Cell 125:915-928(2006).
RN [25]
RP IDENTIFICATION IN A COMPLEX WITH SMAD3 AND TRIM33, AND INTERACTION
RP WITH 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 [26]
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 [27]
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 [28]
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
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 [29]
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 [30]
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.,
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 [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-8, AND MASS
RP SPECTROMETRY.
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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [32]
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 [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, 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 [34]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
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 [35]
RP INTERACTION WITH RANBP3, SUBCELLULAR LOCATION, FUNCTION, AND
RP MUTAGENESIS OF 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
RT of TGF-beta signaling.";
RL Dev. Cell 16:345-357(2009).
RN [36]
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.,
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 [37]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT THR-8; SER-458 AND SER-460, AND MASS SPECTROMETRY.
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.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [38]
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 [39]
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
RT the TGF-beta signal molecule Smad2.";
RL Cell Biol. Int. 35:1153-1157(2011).
RN [40]
RP UBIQUITINATION, DEUBIQUITINATION BY USP15, DNA-BINDING, AND
RP INTERACTION WITH USP15.
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 [41]
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
RT growth factor-? pathway.";
RL Cell. Signal. 24:1999-2006(2012).
RN [42]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
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.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [43]
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
RT regulates Pr-Set7/Set8-mediated cellular migration.";
RL Mol. Cell 49:1147-1158(2013).
RN [44]
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 [45]
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
RT transforming growth factor-beta activated cells.";
RL Cytokine Growth Factor Rev. 10:187-199(1999).
RN [46]
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 [47]
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 [48]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 261-456 IN COMPLEX WITH
RP ZFYVE9, 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 [49]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 270-466 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 [50]
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.,
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).
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 SMAD2/SMAD4 complex, activates transcription. May
CC act as a tumor suppressor in colorectal carcinoma. Positively
CC regulates PDPK1 kinase activity by stimulating its dissociation
CC from the 14-3-3 protein YWHAQ which acts as a negative regulator.
CC -!- SUBUNIT: Momomer; the absence of TGF-beta. Heterodimer; in the
CC presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in
CC the nucleus to form the transactivation complex SMAD2/SMAD4.
CC Interacts with AIP1, HGS, PML and WWP1 (By similarity). Interacts
CC with NEDD4L in response to TGF-beta (By similarity). Found in a
CC complex with SMAD3 and TRIM33 upon addition of TGF-beta. Interacts
CC with ACVR1B, SMAD3 and TRIM33. Interacts (via the MH2 domain) with
CC ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with
CC FOXH1, homeobox protein TGIF, PEBP2-alpha subunit, CREB-binding
CC protein (CBP), EP300, SKI and SNW1. Interacts with SNON; when
CC phosphorylated at Ser-465/467. Interacts with SKOR1 and SKOR2.
CC Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3.
CC Interacts with RBPMS. Interacts with WWP1. Interacts
CC (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3
CC (via its C-terminal R domain); the interaction results in the
CC export of dephosphorylated SMAD3 out of the nucleus and
CC termination ot the TGF-beta signaling. Interacts with PDPK1 (via
CC PH domain). Interacts with DAB2; the interactions are enhanced
CC upon TGF-beta stimulation. Interacts with USP15. Interacts with
CC PPP5C. Interacts with ZNF580.
CC -!- INTERACTION:
CC P05060:CHGB; NbExp=2; IntAct=EBI-1040141, EBI-712619;
CC P98082:DAB2; NbExp=4; IntAct=EBI-1040141, EBI-1171238;
CC Q9BZ29:DOCK9; NbExp=3; IntAct=EBI-1040141, EBI-2695893;
CC Q9NYA4:MTMR4; NbExp=3; IntAct=EBI-1040141, EBI-1052346;
CC P07197:NEFM; NbExp=3; IntAct=EBI-1040141, EBI-1105035;
CC Q8TAK6:OLIG1; NbExp=2; IntAct=EBI-1040141, EBI-3867416;
CC P35813:PPM1A; NbExp=2; IntAct=EBI-1040141, EBI-989143;
CC Q9H6Z4:RANBP3; NbExp=2; IntAct=EBI-1040141, EBI-992681;
CC P61586:RHOA; NbExp=2; IntAct=EBI-1040141, EBI-446668;
CC P84022:SMAD3; NbExp=2; IntAct=EBI-1040141, EBI-347161;
CC Q13485:SMAD4; NbExp=18; IntAct=EBI-1040141, EBI-347263;
CC Q9HAU4:SMURF2; NbExp=5; IntAct=EBI-1040141, EBI-396727;
CC Q13573:SNW1; NbExp=3; IntAct=EBI-1040141, EBI-632715;
CC Q9H3D4:TP63; NbExp=3; IntAct=EBI-1040141, EBI-2337775;
CC Q9UPN9:TRIM33; NbExp=6; IntAct=EBI-1040141, EBI-2214398;
CC O00308:WWP2; NbExp=4; IntAct=EBI-1040141, EBI-743923;
CC Q96KR1:ZFR; NbExp=2; IntAct=EBI-1040141, EBI-2513582;
CC O95405:ZFYVE9; NbExp=2; IntAct=EBI-1040141, EBI-296817;
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. On
CC dephosphorylation by phosphatase PPM1A, released from the
CC SMAD2/SMAD4 complex, and exported out of the nucleus by
CC interaction with RANBP1.
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.
CC -!- PTM: Phosphorylated on one or several of Thr-220, Ser-245, Ser-
CC 250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-
CC 465/467 by TGF-beta and activin type 1 receptor kinases. TGF-beta-
CC induced Ser-465/467 phosphorylation declines progressively in a
CC SETD8-dependent manner. Able to interact with SMURF2 when
CC phosphorylated on Ser-465/467, recruiting other proteins, such as
CC SNON, for degradation. In response to decorin, the naturally
CC occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-
CC 240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which
CC increases transcriptional activity and stability, and is blocked
CC by calmodulin. Phosphorylated by PDPK1.
CC -!- PTM: In response to TGF-beta, ubiquitinated by NEDD4L; which
CC promotes its degradation (By similarity). Monoubiquitinated,
CC leading to prevent DNA-binding. Deubiquitination by USP15
CC alleviates inhibition and promotes activation of TGF-beta target
CC genes.
CC -!- PTM: Acetylated on Lys-19 by coactivators in response to TGF-beta
CC signaling, which increases transcriptional activity. Isoform
CC short: Acetylation increases DNA binding activity in vitro and
CC enhances its association with target promoters in vivo.
CC Acetylation in the nucleus by EP300 is enhanced by TGF-beta.
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 -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SMAD2ID370.html";
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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 PIR; S71797; S71797.
DR RefSeq; NP_001003652.1; NM_001003652.3.
DR RefSeq; NP_005892.1; NM_005901.5.
DR RefSeq; XP_005258316.1; XM_005258259.1.
DR RefSeq; XP_005258317.1; XM_005258260.1.
DR UniGene; Hs.12253; -.
DR UniGene; Hs.705764; -.
DR UniGene; Hs.741342; -.
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=270-466.
DR PDB; 2LB3; NMR; -; B=217-224.
DR PDBsum; 1DEV; -.
DR PDBsum; 1KHX; -.
DR PDBsum; 1U7V; -.
DR PDBsum; 2LB3; -.
DR ProteinModelPortal; Q15796; -.
DR SMR; Q15796; 7-172, 265-467.
DR DIP; DIP-29716N; -.
DR IntAct; Q15796; 207.
DR MINT; MINT-5006109; -.
DR STRING; 9606.ENSP00000262160; -.
DR PhosphoSite; Q15796; -.
DR DMDM; 13633914; -.
DR PaxDb; Q15796; -.
DR PRIDE; Q15796; -.
DR DNASU; 4087; -.
DR Ensembl; ENST00000262160; ENSP00000262160; ENSG00000175387.
DR Ensembl; ENST00000356825; ENSP00000349282; ENSG00000175387.
DR Ensembl; ENST00000402690; ENSP00000384449; ENSG00000175387.
DR Ensembl; ENST00000586040; ENSP00000466193; ENSG00000175387.
DR GeneID; 4087; -.
DR KEGG; hsa:4087; -.
DR UCSC; uc002lcy.4; human.
DR CTD; 4087; -.
DR GeneCards; GC18M045357; -.
DR HGNC; HGNC:6768; SMAD2.
DR HPA; CAB025507; -.
DR MIM; 601366; gene.
DR neXtProt; NX_Q15796; -.
DR PharmGKB; PA134959722; -.
DR eggNOG; NOG320700; -.
DR HOGENOM; HOG000286018; -.
DR HOVERGEN; HBG053353; -.
DR InParanoid; Q15796; -.
DR KO; K04500; -.
DR OMA; MNQSMDT; -.
DR OrthoDB; EOG7W1540; -.
DR PhylomeDB; Q15796; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_71; Gene Expression.
DR SignaLink; Q15796; -.
DR ChiTaRS; SMAD2; human.
DR EvolutionaryTrace; Q15796; -.
DR GeneWiki; Mothers_against_decapentaplegic_homolog_2; -.
DR GenomeRNAi; 4087; -.
DR NextBio; 16020; -.
DR PRO; PR:Q15796; -.
DR ArrayExpress; Q15796; -.
DR Bgee; Q15796; -.
DR CleanEx; HS_SMAD2; -.
DR Genevestigator; Q15796; -.
DR GO; GO:0032444; C:activin responsive factor complex; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
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:0009952; P:anterior/posterior pattern specification; ISS:UniProtKB.
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:0048589; P:developmental growth; IEA:Ensembl.
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: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 proliferation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:Reactome.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038092; P:nodal signaling pathway; IMP:BHF-UCL.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0060021; P:palate development; ISS:BHF-UCL.
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: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 from RNA polymerase II promoter; ISS:UniProtKB.
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:0070723; P:response to cholesterol; IDA:BHF-UCL.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
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:0007352; P:zygotic specification of dorsal/ventral axis; IMP:BHF-UCL.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD_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; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 2.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; DNA-binding; Metal-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 467 Mothers against decapentaplegic homolog
FT 2.
FT /FTId=PRO_0000090852.
FT DOMAIN 10 176 MH1.
FT DOMAIN 274 467 MH2.
FT MOTIF 221 225 PY-motif.
FT METAL 74 74 Zinc (By similarity).
FT METAL 149 149 Zinc (By similarity).
FT METAL 161 161 Zinc (By similarity).
FT METAL 166 166 Zinc (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 8 8 Phosphothreonine; by MAPK3.
FT MOD_RES 19 19 N6-acetyllysine.
FT MOD_RES 220 220 Phosphothreonine (Probable).
FT MOD_RES 240 240 Phosphoserine; by CAMK2.
FT MOD_RES 245 245 Phosphoserine (Probable).
FT MOD_RES 250 250 Phosphoserine (Probable).
FT MOD_RES 255 255 Phosphoserine (Probable).
FT MOD_RES 458 458 Phosphoserine.
FT MOD_RES 460 460 Phosphoserine.
FT MOD_RES 464 464 Phosphoserine.
FT MOD_RES 465 465 Phosphoserine; by TGFBR1.
FT MOD_RES 467 467 Phosphoserine; by TGFBR1.
FT VAR_SEQ 79 108 Missing (in isoform Short).
FT /FTId=VSP_006178.
FT VARIANT 133 133 R -> C (in a colorectal carcinoma
FT sample).
FT /FTId=VAR_011375.
FT VARIANT 300 300 D -> V (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036473.
FT VARIANT 344 358 Missing (in a colorectal carcinoma
FT sample).
FT /FTId=VAR_011376.
FT VARIANT 440 440 L -> R (in a colorectal carcinoma
FT sample).
FT /FTId=VAR_011377.
FT VARIANT 445 445 P -> H (in a colorectal carcinoma
FT sample).
FT /FTId=VAR_011378.
FT VARIANT 450 450 D -> E (in a colorectal carcinoma
FT sample).
FT /FTId=VAR_011379.
FT MUTAGEN 19 19 K->R: Loss of acetylation.
FT MUTAGEN 20 20 K->R: No effect on acetylation.
FT MUTAGEN 221 225 Missing: Loss of binding to SMURF2.
FT MUTAGEN 381 381 N->S: Loss of binding to SARA.
FT MUTAGEN 398 398 V->R: Increased binding to PPM1A.
FT MUTAGEN 464 464 S->A: Loss of phosphorylation by TGFBR1;
FT when associated with A-465 and A-467.
FT MUTAGEN 465 467 SMS->AMA: Binds RANBP3.
FT MUTAGEN 465 467 SMS->DMD: Greatly reduced RANBP2 binding.
FT MUTAGEN 465 465 S->A: No change in binding to PPM1A. Loss
FT of phosphorylation by TGFBR1; when
FT associated with A-464 and A-467.
FT MUTAGEN 465 465 S->D: No change in binding to PPM1A.
FT MUTAGEN 467 467 S->A: No change in binding to PPM1A. Loss
FT of phosphorylation by TGFBR1; when
FT associated with A-464 and A-465.
FT MUTAGEN 467 467 S->D: No change in binding to PPM1A.
FT STRAND 264 267
FT STRAND 274 281
FT STRAND 290 292
FT STRAND 294 302
FT STRAND 305 307
FT STRAND 310 312
FT HELIX 313 315
FT HELIX 323 329
FT TURN 330 334
FT STRAND 336 341
FT STRAND 344 349
FT STRAND 351 353
FT STRAND 355 358
FT HELIX 360 365
FT STRAND 374 376
FT STRAND 381 386
FT HELIX 387 397
FT HELIX 398 400
FT HELIX 402 406
FT HELIX 407 412
FT STRAND 413 419
FT STRAND 423 427
FT HELIX 431 433
FT STRAND 434 442
FT HELIX 443 453
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
//

MIM 601366
*RECORD*
*FIELD* NO
601366
*FIELD* TI
*601366 MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 2; SMAD2
;;MADH2;;
read moreSMA- AND MAD-RELATED PROTEIN 2 MAD, DROSOPHILA, HOMOLOG OF;;
MADR2
*FIELD* TX

CLONING

Riggins et al. (1996) identified a homolog of the Drosophila 'mothers
against decapentaplegic' (Mad) gene (also 'mothers against dpp'). The
predicted 467-amino acid polypeptide, referred to by them as JV18-1,
shows maximal homology to Mad genes at the amino and carboxy termini of
the protein, with 62% identity to Mad over 373 amino acids. Drosophila
Mad apparently acts downstream of the TGF-beta receptor (190181) to
transduce signals from the members of the TGF-beta gene family (190180).
The gene product shows 44% identity over 158 amino acids to another Mad
homolog, DPC4 (SMAD4; 600993).

Graff et al. (1996) described a family of Xenopus proteins homologous to
the Drosophila Mad and C. elegans CEM genes. MAD and MAD-related
proteins are important components of the serine/threonine kinase
receptor signal transduction pathways. Eppert et al. (1996) cloned and
characterized a member of this family, which they designated MADR2. The
gene encodes a 467-amino acid protein that contains no common structural
motifs known at that time. MADR2 shares high homology with MADR1
(601595) and significant homology with DPC4. They reported that MADR2 is
rapidly phosphorylated by activation of the TGF-beta signaling pathway.

By RT-PCR of human erythroleukemia cell mRNA using primers based on
conserved regions between the Drosophila Mad and C. elegans Sma genes,
Nakao et al. (1997) cloned a SMAD2 cDNA. Northern blot analysis of human
tissues detected ubiquitously expressed 3.4- and 2.9-kb SMAD2
transcripts. The encoded protein has a molecular mass of 58 kD by
SDS-PAGE.

Baker and Harland (1996) identified the mouse Madr2 gene using a
functional assay to clone mouse mesoderm inducers from Xenopus ectoderm.
The mouse amino acid sequence is 46% identical to the human tumor
suppressor DPC4. Madr2 was expressed widely in the mouse embryo (with
the exception of heart and the tail bud) from embryonic days 6.5 to
10.5. Madr2 was found to be confined to the nucleus in the deep anterior
cells of the second axis, whereas it was localized in the cytoplasm in
the epidermal and more posterior cells. Because Madr2 localized to the
nucleus in response to activin (see 147290) and because activin-like
phenotypes were induced by overexpression of Madr2, Baker and Harland
(1996) concluded that Madr2 is a signal transduction component that
mediates the activity of activin.

GENE FUNCTION

Macias-Silva et al. (1996) demonstrated that MADR2 and not the related
protein DPC4 transiently interacts with the TGF-beta receptor and is
directly phosphorylated by the complex on C-terminal serines.
Interaction of MADR2 with receptors and phosphorylation requires
activation of receptor I by receptor II and is mediated by the receptor
I kinase. Mutation of the phosphorylation sites generated a
dominant-negative MADR2 that blocks TGF-beta-dependent transcriptional
responses, stably associates with receptors, and fails to accumulate in
the nucleus in response to TGF-beta signaling. Thus, Macias-Silva et al.
(1996) concluded that transient association and phosphorylation of MADR2
by the TGF-beta receptor is necessary for nuclear accumulation and
initiation of signaling.

SMAD proteins mediate TGF-beta signaling to regulate cell growth and
differentiation. Stroschein et al. (1999) identified SnoN (165340) as a
component of the SMAD pathway. They proposed a model of regulation of
TGF-beta signaling by SnoN in which SnoN maintains the repressed state
of TGF-beta target genes in the absence of ligand and participates in
the negative feedback regulation of TGF-beta signaling. In the absence
of TGF-beta, SnoN binds to the nuclear SMAD4 (DPC4) and represses
TGF-beta-responsive promoter activity through recruitment of a nuclear
repressor complex. TGF-beta induces activation and nuclear translocation
of SMAD2, SMAD3 (603109), and SMAD4. SMAD3 causes degradation of SnoN,
allowing a SMAD2/SMAD4 complex to activate TGF-beta target genes. To
initiate a negative feedback mechanism that permits a precise and timely
regulation of TGF-beta signaling, TGF-beta also induces an increased
expression of SnoN at a later stage, which in turn binds to SMAD
heteromeric complexes and shuts off TGF-beta signaling.

SMADs mediate activin, TGF-beta, and BMP signaling from receptors to
nuclei. According to the current model, activated activin/TGF-beta
receptors phosphorylate the carboxyl-terminal serines of SMAD2 and SMAD3
(SSMS-COOH); phosphorylated SMAD2/SMAD3 oligomerizes with SMAD4,
translocates to the nucleus, and modulates transcription of defined
genes. To test key features of this model, Funaba and Mathews (2000)
explored the construction of constitutively active SMAD2 mutants. To
mimic phosphorylated SMAD2, they made 2 SMAD2 mutants with acidic amino
acid substitutions of carboxyl-terminal serines: SMAD2-2E and SMAD2-3E.
The mutants enhanced basal transcriptional activity in a mink lung
epithelial cell line, L17. In a SMAD4-deficient cell line, SMAD2-2E did
not affect basal signaling; suggesting that the constitutively active
SMAD2 mutant also requires SMAD4 for function. Funaba and Mathews (2000)
concluded that SMAD2 phosphorylation results in both tighter binding to
SMAD4 and increased nuclear concentration; those changes may be
responsible for transcriptional activation by SMAD2.

You and Kruse (2002) studied corneal myofibroblast differentiation and
signal transduction induced by the TGFB family members activin A
(147290) and bone morphogenetic protein-7 (BMP7; 112267). They found
that activin A induced phosphorylation of SMAD2, and BMP7 induced SMAD1
(601595), both of which were inhibited by follistatin (136470).
Transfection with antisense SMAD2/SMAD3 prevented activin-induced
expression and accumulation of alpha-smooth muscle actin. The authors
concluded that TGFB proteins have different functions in the cornea.
Activin A and TGFB1, but not BMP7, are regulators of keratocyte
differentiation and might play a role during myofibroblast
transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be
important in the regulation of muscle-specific genes.

Oft et al. (2002) found that activation of Smad2 induced migration of
mouse squamous carcinoma cells, but that elevated levels of H-ras
(190020) were required for nuclear accumulation of Smad2. Elevated
levels of both were required for induction of spindle-cell
transformation and metastasis.

SMAD2 is released from cytoplasmic retention by TGFB receptor-mediated
phosphorylation and accumulates in the nucleus, where it associates with
cofactors to regulate transcription. Xu et al. (2002) uncovered direct
interactions of SMAD2 with the nucleoporins NUP214 (114350) and NUP153
(603948). These interactions mediate constitutive nucleocytoplasmic
shuttling of SMAD2. NUP214 and NUP153 compete with the cytoplasmic
retention factor SARA (603755) and the nuclear SMAD2 partner FAST1
(603621) for binding to a hydrophobic corridor on the MH2 surface of
SMAD2. TGFB receptor-mediated phosphorylation stimulates nuclear
accumulation of SMAD2 by modifying its affinity for SARA and SMAD4 but
not for NUP214 or NUP153. Thus, by directly contacting the nuclear pore
complex, SMAD2 undergoes constant shuttling, providing a dynamic pool
that is competitively drawn by cytoplasmic and nuclear signal
transduction partners.

TGFB stimulation leads to phosphorylation and activation of SMAD2 and
SMAD3, which form complexes with SMAD4 that accumulate in the nucleus
and regulate transcription of target genes. Inman et al. (2002)
demonstrated that following TGFB stimulation of epithelial cells,
receptors remain active for at least 3 to 4 hours, and continuous
receptor activity is required to maintain active SMADs in the nucleus
and for TGFB-induced transcription. Continuous nucleocytoplasmic
shuttling of the SMADs during active TGFB signaling provides the
mechanism whereby the intracellular transducers of the signal
continuously monitor receptor activity. These data explain how, at all
times, the concentration of active SMADs in the nucleus is directly
dictated by the levels of activated receptors in the cytoplasm.

Using Xenopus embryo explants, whole zebrafish embryos, and mammalian
cell lines, Batut et al. (2007) showed that phosphorylation and nuclear
accumulation of Smad2 required an intact microtubule network and the
ATPase activity of the kinesin motor. Smad2 interacted directly with the
kinesin-1 light chain subunit (KLC2), and interfering with kinesin
activity in Xenopus and zebrafish embryos phenocopied loss of Nodal
(601265) signaling.

Davis et al. (2008) demonstrated that induction of a contractile
phenotype in human vascular smooth muscle cells by TGF-beta (190180) and
BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610),
which in turn acts as a negative regulator of smooth muscle contractile
genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid
increase in expression of mature miR21 through a posttranscriptional
step, promoting the processing of primary transcripts of miR21
(pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (see
608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1, SMAD2,
SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a
complex with the RNA helicase p68 (DDX5; 180630), a component of the
Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not
required for this process. Thus, Davis et al. (2008) concluded that
regulation of microRNA biogenesis by ligand-specific SMAD proteins is
critical for control of the vascular smooth muscle cell phenotype and
potentially for SMAD4-independent responses mediated by the TGF-beta and
BMP signaling pathways.

BIOCHEMICAL FEATURES

- Crystal Structure

Wu et al. (2000) determined the crystal structure of a SMAD2 MH2 domain
in complex with the SMAD-binding domain of SARA at 2.2-angstrom
resolution.

Wu et al. (2001) determined the crystal structure of a phosphorylated
SMAD2 at 1.8-angstrom resolution. The structure revealed the formation
of a homotrimer mediated by the C-terminal phosphoserine residues. The
phosphoserine-binding surface on the MH2 domain, which is frequently
targeted for inactivation in cancers, is highly conserved among the
comediator SMADs (Co-SMADs) and receptor-regulated SMADs (R-SMADs). This
finding, together with mutagenesis data, pinpointed a functional
interface between SMAD2 and SMAD4. In addition, the
phosphoserine-binding surface on the MH2 domain coincides with the
surface on R-SMADs that is required for docking interactions with the
serine-phosphorylated receptor kinases. These observations defined a
bifunctional role for the MH2 domain as a
phosphoserine-X-phosphoserine-binding module in receptor ser/thr kinase
signaling pathways.

GENE STRUCTURE

Takenoshita et al. (1998) determined the structure of the human MADH2
gene and characterized the 5-prime and 3-prime ends of MADH2 mRNAs. The
MADH2 gene contains 12 exons, the first 2 (1a and 1b) of which are
alternatively spliced such that they are used singly or in combination.
In addition, RT-PCR showed that the fourth exon (exon 3), which encodes
30 amino acids, is spliced out in about 10% of MADH2 transcripts. The
authors found that MADH2 mRNAs are transcribed from 2 different
promoters located in 1 CpG island. The 3-prime ends of MADH2 mRNAs are
heterogeneous, and Takenoshita et al. (1998) identified several
polyadenylation signals.

MAPPING

Eppert et al. (1996) mapped the MADR2 gene close to DPC4 at 18q21, a
region which is frequently deleted in colorectal cancers. Riggins et al.
(1996) mapped the human MADH2 gene to 18q21. Nakao et al. (1997) refined
the localization of the SMAD2 gene to 18q21.1, approximately 3 Mb
proximal to DPC4, by fluorescence in situ hybridization.

MOLECULAR GENETICS

- Somatic Mutation in Colorectal Cancer

In a screen of 66 sporadic colorectal carcinomas, Eppert et al. (1996)
identified 4 missense mutations in MADR2, 2 of which were associated
with loss of heterozygosity (LOH) in 1 allele. These mutations were
associated with loss of protein expression or loss of TGF-beta-regulated
phosphorylation. Eppert et al. (1996) proposed that MADR2 is a tumor
suppressor gene and that mutations acquired in colorectal cancer may
function to disrupt TGF-beta signaling.

Riggins et al. (1996) evaluated JV18-1 in a panel of 18 colorectal
cancer cell lines, each containing allelic loss of the minimally lost
region on chromosome 18q. RT-PCR studies revealed JV18-1 expression in
normal colon, normal brain, and in 17 of 18 colorectal tumors. They
identified 1 tumor in which there was a homozygous deletion of JV18-1
sequences. The deletion in this tumor did not extend proximally to
include D18S535 or distally to DPC4. In another tumor, a smaller protein
encoded by JV18-1 was present. The protein was shorter because of a
deletion extending from codons 345 to 358. This deletion was somatic in
origin. Riggins et al. (1996) concluded that this gene family may be
important in the suppression of neoplasia, since its members transduce
growth inhibitory signals from TGF-beta.

By PCR-SSCP analysis of the entire coding region of the SMAD2 gene using
intron-based primers, Takenoshita et al. (1998) screened genomic DNA
sequences of colorectal cancers for mutations of the SMAD2 gene.
Although no mutations were found within any exon of SMAD2, 2 of 60
sporadic colorectal cancers displayed deletions in the polypyrimidine
tract preceding exon 4. Deletions of this region were also detected in
colon cancer cell lines, and were clustered within cells exhibiting
microsatellite instability. Deletions in the polypyrimidine tract had no
effect on the splicing of the SMAD2 gene in these cases; however, the
polypyrimidine tract in the splicing acceptor site may be a target for
mutations in mismatch repair-deficient tumors.

Takagi et al. (1998) carried out mutation analyses of the SMAD2 gene on
cDNA sampled from 36 primary colorectal cancer specimens. Only 1
missense mutation (2.8%), producing an amino acid substitution in the
highly conserved region, and 2 homozygous deletions (5.5%) of the total
coding region of SMAD2 gene were detected. They concluded that the SMAD2
gene may play a role as a candidate tumor suppressor gene in a small
fraction of colorectal cancers. Even in combination with changes in
SMAD4, the observed frequency was not sufficient to account for all
18q21 deletions in colorectal cancers. Thus, another tumor suppressor
gene, such as DCC (120470), discovered as the first tumor suppressor
candidate in the region, may exist in the 18q21 region where LOH is
often seen.

Using cDNA, Roth et al. (2000) conducted mutation analysis of the SMAD2,
SMAD3, and SMAD4 genes in 14 Finnish kindreds with hereditary
nonpolyposis colon cancer (see 120435). They found no mutations.

ANIMAL MODEL

Waldrip et al. (1998) studied the effect of Smad2 in mouse embryonic
development by targeted disruption of the mouse Smad2 gene using
embryonic stem cell technology. They found that Smad2 function was not
required for mesoderm production per se, but, rather unexpectedly, in
the absence of Smad2, the entire epiblast adopts a mesodermal fate
giving rise to a normal yolk sac and fetal blood cells. In contrast,
Smad2 mutant mouse embryos entirely lacked tissues of the embryonic germ
layers. Waldrip et al. (1998) concluded that Smad2 signals serve to
restrict the site of primitive streak formation and establish
anterior-posterior identity within the epiblast. Chimera experiments
demonstrated that these essential activities are contributed by the
extraembryonic tissues. Thus, the extraembryonic tissues play critical
roles in establishing the body plan during early mouse development.

NOMENCLATURE

Derynck et al. (1996) proposed a revised nomenclature for the
Mad-related products and genes that are implicated in signal
transduction by members of the TGF-beta family. As the root symbol they
proposed SMAD, which is a merger of Sma (the gene in C. elegans) and
Mad. SMAD serves to differentiate these proteins from unrelated gene
products previously called MAD (see 600021). JV18.1 became SMAD2 in
their nomenclature.

*FIELD* AV
.0001
VARIANT OF UNKNOWN SIGNIFICANCE
SMAD2, IVS6, G-A, +1

This variant is classified as a variant of unknown significance because
its contribution to heterotaxy (see 306955) has not been confirmed.

In a patient with dextrocardia, unbalanced complete atrioventricular
canal defect, and pulmonary stenosis, Zaidi et al. (2013) identified a
heterozygous de novo splice site mutation in intron 6 of the SMAD2 gene
(p.IVS6+1G-A). The patient also had unbalanced double-outlet right
ventricle, dextroposition of the great arteries, atrial septal defect,
and asplenia. Height and weight were at the 95th and 10th percentile,
respectively. Neurologic development was normal. The patient was
identified in a cohort of 362 parent-child trios comprising a child with
severe congenital heart disease and no first-degree relative with
identified structural heart disease.

.0002
VARIANT OF UNKNOWN SIGNIFICANCE
SMAD2, TRP244CYS

This variant is classified as a variant of unknown significance because
its contribution to heterotaxy (see 306955) has not been confirmed.

In a patient with dextrocardia, unbalanced right-dominant complete
atrioventricular canal defect, and pulmonary stenosis, Zaidi et al.
(2013) identified a heterozygous de novo missense mutation in the SMAD2
gene (trp244 to cys; W244C). The patient also had left superior vena
cava to left atrium, partial anomalous pulmonary venous return,
double-outlet right ventricle, abnormal nose, foot syndactyly, and gut
malrotation. Height and weight were at the 50th percentile for each.
Information on neurodevelopment was not available. The patient was
identified in a cohort of 362 parent-child trios comprising a child with
severe congenital heart disease and no first-degree relative with
identified structural heart disease.

*FIELD* RF
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2. Batut, J.; Howell, M.; Hill, C. S.: Kinesin-mediated transport
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3. Davis, B. N.; Hilyard, A. C.; Lagna, G.; Hata, A.: SMAD proteins
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4. Derynck, R.; Gelbart, W. M.; Harland, R. M.; Heldin, C.-H.; Kern,
S. E.; Massague, J.; Melton, D. A.; Mlodzik, M.; Padgett, R. W.; Roberts,
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6. Funaba, M.; Mathews, L. S.: Identification and characterization
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7. Graff, J. M.; Bansal, A.; Melton, D. A.: Xenopus Mad proteins
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8. Inman, G. J.; Nicolas, F. J.; Hill, C. S.: Nucleocytoplasmic shuttling
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9. Macias-Silva, M.; Abdollah, S.; Hoodless, P. A.; Pirone, R.; Attisano,
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10. Nakao, A.; Roijer, E.; Imamura, T.; Souchelnytskyi, S.; Stenman,
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11. Oft, M.; Akhurst, R. J.; Balmain, A.: Metastasis is driven by
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12. Riggins, G. J.; Thiagalingam, S.; Rozenblum, E.; Weinstein, C.
L.; Kern, S. E.; Hamilton, S. R.; Willson, J. K. V.; Markowitz, S.
D.; Kinzler, K. W.; Vogelstein, B.: Mad-related genes in the human. Nature
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13. Roth, S.; Johansson, M.; Loukola, A.; Peltomaki, P.; Jarvinen,
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14. Stroschein, S. L.; Wang, W.; Zhou, S.; Zhou, Q.; Luo, K.: Negative
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15. Takagi, Y.; Koumura, H.; Futamura, M.; Aoki, S.; Ymaguchi, K.;
Kida, H.; Tanemura, H.; Shimokawa, K.; Saji, S.: Somatic alterations
of the SMAD-2 gene in human colorectal cancers. Brit. J. Cancer 78:
1152-1155, 1998.

16. Takenoshita, S.; Mogi, A.; Nagashima, M.; Yang, K.; Yagi, K.;
Hanyu, A.; Nagamachi, Y.; Miyazono, K.; Hagiwara, K.: Characterization
of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming
growth factor-beta and activin signal transduction pathway. Genomics 48:
1-11, 1998.

17. Takenoshita, S.; Tani, M.; Mogi, A.; Nagashima, M.; Nagamachi,
Y.; Bennett, W. P.; Hagiwara, K.; Harris, C. C.; Yokota, J.: Mutation
analysis of the Smad2 gene in human colon cancers using genomic DNA
and intron primers. Carcinogenesis 19: 803-807, 1998.

18. Waldrip, W. R.; Bikoff, E. K.; Hoodless, P. A.; Wrana, J. L.;
Robertson, E. J.: Smad2 signaling in extraembryonic tissues determines
anterior-posterior polarity of the early mouse embryo. Cell 92:
797-808, 1998.

19. Wu, G.; Chen, Y.-G.; Ozdamar, B.; Gyuricza, C. A.; Chong, P. A.;
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20. Wu, J.-W.; Hu, M.; Chai, J.; Seoane, J.; Huse, M.; Li, C.; Rigotti,
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21. Xu, L.; Kang, Y.; Col, S.; Massague, J.: Smad2 nucleocytoplasmic
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22. You, L.; Kruse, F. E.: Differential effect of activin A and BMP-7
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*FIELD* CN
Ada Hamosh - updated: 07/24/2013
Ada Hamosh - updated: 9/11/2008
Patricia A. Hartz - updated: 3/2/2007
Ada Hamosh - updated: 9/29/2004
Stylianos E. Antonarakis - updated: 9/11/2002
Patricia A. Hartz - updated: 8/5/2002
John A. Phillips, III - updated: 8/2/2002
Jane Kelly - updated: 7/8/2002
Matthew B. Gross - reorganized: 1/4/2002
Stylianos E. Antonarakis - updated: 1/4/2002
Michael J. Wright - updated: 1/8/2001
Patti M. Sherman - updated: 6/15/2000
Ada Hamosh - updated: 2/8/2000
Ada Hamosh - updated: 10/23/1999
Victor A. McKusick - updated: 2/3/1999
Victor A. McKusick - updated: 8/17/1998
Stylianos E. Antonarakis - updated: 5/20/1998
Rebekah S. Rasooly - updated: 4/6/1998
Ethylin Wang Jabs - updated: 11/18/1997
Victor A. McKusick - updated: 2/6/1997
Moyra Smith - updated: 12/20/1996

*FIELD* CD
Moyra Smith: 8/8/1996

*FIELD* ED
alopez: 07/24/2013
alopez: 9/11/2008
wwang: 12/28/2007
terry: 12/11/2007
mgross: 3/6/2007
terry: 3/2/2007
carol: 4/28/2005
mgross: 4/13/2005
terry: 9/29/2004
mgross: 10/7/2002
alopez: 9/16/2002
mgross: 9/11/2002
carol: 8/5/2002
cwells: 8/2/2002
mgross: 7/8/2002
mgross: 1/4/2002
alopez: 1/8/2001
mcapotos: 6/22/2000
psherman: 6/15/2000
alopez: 2/8/2000
alopez: 10/23/1999
carol: 2/11/1999
terry: 2/3/1999
dkim: 9/11/1998
carol: 8/20/1998
terry: 8/17/1998
carol: 5/20/1998
psherman: 4/6/1998
mark: 11/19/1997
jenny: 11/18/1997
terry: 2/6/1997
mark: 2/6/1997
terry: 2/6/1997
terry: 2/3/1997
mark: 12/20/1996
terry: 12/9/1996
mark: 8/15/1996
marlene: 8/9/1996
mark: 8/8/1996