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Mothers against decapentaplegic homolog 4 (MAD homolog 4) (Mothers against DPP homolog 4) (Deletion target in pancreatic carcinoma 4) (SMAD family member 4) (SMAD 4) (Smad4) (hSMAD4)

 SMAD4_HUMAN             Reviewed;         552 AA.
Q13485; A8K405;
04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
01-NOV-1996, sequence version 1.
22-NOV-2017, entry version 204.
RecName: Full=Mothers against decapentaplegic homolog 4;
Short=MAD homolog 4;
Short=Mothers against DPP homolog 4;
AltName: Full=Deletion target in pancreatic carcinoma 4;
AltName: Full=SMAD family member 4;
Short=SMAD 4;
Short=Smad4;
Short=hSMAD4;
Name=SMAD4; Synonyms=DPC4, MADH4;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT PANCREATIC
CARCINOMA HIS-493.
TISSUE=Fetal brain;
PubMed=8553070; DOI=10.1126/science.271.5247.350;
Hahn S.A., Schutte M., Shamsul Hoque A.T.M., Moskaluk C.A.,
da Costa L.T., Rozenblum E., Weinstein C.L., Fischer A., Yeo C.J.,
Hruban R.H., Kern S.E.;
"DPC4, a candidate tumor suppressor gene at human chromosome
18q21.1.";
Science 271:350-353(1996).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
TISSUE=Placenta;
PubMed=8774881; DOI=10.1038/383168a0;
Zhang Y., Feng X.-H., Wu R.-Y., Derynck R.;
"Receptor-associated Mad homologues synergize as effectors of the TGF-
beta response.";
Nature 383:168-172(1996).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=9098646; DOI=10.1097/00019606-199704000-00003;
Moskaluk C.A., Hruban R.H., Schutte M., Lietman A.S., Smyrk T.,
Fusaro L., Fusaro R., Lynch J., Yeo C.J., Jackson C.E., Lynch H.T.,
Kern S.E.;
"Genomic sequencing of DPC4 in the analysis of familial pancreatic
carcinoma.";
Diagn. Mol. Pathol. 6:85-90(1997).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Muscle;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
FUNCTION.
PubMed=9389648; DOI=10.1101/gad.11.23.3157;
Liu F., Pouponnot C., Massague J.;
"Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible
transcriptional complexes.";
Genes Dev. 11:3157-3167(1997).
[8]
SUBUNIT.
PubMed=9670020; DOI=10.1093/emboj/17.14.4056;
Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K.;
"Smad proteins exist as monomers in vivo and undergo homo- and hetero-
oligomerization upon activation by serine/threonine kinase
receptors.";
EMBO J. 17:4056-4065(1998).
[9]
INTERACTION WITH CITED1.
PubMed=9707553; DOI=10.1073/pnas.95.17.9785;
Shioda T., Lechleider R.J., Dunwoodie S.L., Li H., Yahata T.,
de Caestecker M.P., Fenner M.H., Roberts A.B., Isselbacher K.J.;
"Transcriptional activating activity of Smad4: roles of SMAD hetero-
oligomerization and enhancement by an associating transactivator.";
Proc. Natl. Acad. Sci. U.S.A. 95:9785-9790(1998).
[10]
INTERACTION WITH ZNF423.
PubMed=10660046; DOI=10.1016/S0092-8674(00)81561-5;
Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A.,
Massague J.;
"OAZ uses distinct DNA- and protein-binding zinc fingers in separate
BMP-Smad and Olf signaling pathways.";
Cell 100:229-240(2000).
[11]
CHARACTERIZATION OF SAD DOMAIN.
PubMed=10636916; DOI=10.1074/jbc.275.3.2115;
de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S.,
Hill C.S., Shioda T., Roberts A.B., Lechleider R.J.;
"The Smad4 activation domain (SAD) is a proline-rich, p300-dependent
transcriptional activation domain.";
J. Biol. Chem. 275:2115-2122(2000).
[12]
IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11/LKB1 AND
STK11IP, AND INTERACTION WITH STK11/LKB1 AND STK11IP.
PubMed=11741830; DOI=10.1093/hmg/10.25.2869;
Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M.,
Ashworth A.;
"LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers
syndrome kinase LKB1.";
Hum. Mol. Genet. 10:2869-2877(2001).
[13]
INTERACTION WITH COPS5.
PubMed=11818334; DOI=10.1093/embo-reports/kvf024;
Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X.;
"Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.";
EMBO Rep. 3:171-176(2002).
[14]
INTERACTION WITH ZNF8.
PubMed=12370310; DOI=10.1128/MCB.22.21.7633-7644.2002;
Jiao K., Zhou Y., Hogan B.L.M.;
"Identification of mZnf8, a mouse Kruppel-like transcriptional
repressor, as a novel nuclear interaction partner of Smad1.";
Mol. Cell. Biol. 22:7633-7644(2002).
[15]
INTERACTION WITH VPS39.
PubMed=12941698; DOI=10.1093/emboj/cdg428;
Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M.,
Karpova T.S., McNally J.G., Roberts A.B.;
"TLP, a novel modulator of TGF-beta signaling, has opposite effects on
Smad2- and Smad3-dependent signaling.";
EMBO J. 22:4465-4477(2003).
[16]
INTERACTION WITH DACH1.
PubMed=14525983; DOI=10.1074/jbc.M310021200;
Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K.,
Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G.;
"DACH1 inhibits transforming growth factor-beta signaling through
binding Smad4.";
J. Biol. Chem. 278:51673-51684(2003).
[17]
INTERACTION WITH DLX1.
PubMed=14671321; DOI=10.1073/pnas.2536757100;
Chiba S., Takeshita K., Imai Y., Kumano K., Kurokawa M., Masuda S.,
Shimizu K., Nakamura S., Ruddle F.H., Hirai H.;
"Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling
pathway from activin A in hematopoietic cells.";
Proc. Natl. Acad. Sci. U.S.A. 100:15577-15582(2003).
[18]
INTERACTION WITH ZNF521.
PubMed=14630787; DOI=10.1182/blood-2003-07-2388;
Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N.,
De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M.,
Morrone G., Venuta S.;
"Early hematopoietic zinc finger protein (EHZF), the human homolog to
mouse Evi3, is highly expressed in primitive human hematopoietic
cells.";
Blood 103:2062-2070(2004).
[19]
INTERACTION WITH TRIM33.
PubMed=15820681; DOI=10.1016/j.cell.2005.01.033;
Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M.,
Rugge M., Piccolo S.;
"Germ-layer specification and control of cell growth by Ectodermin, a
Smad4 ubiquitin ligase.";
Cell 121:87-99(2005).
[20]
SUBUNIT, AND SUBCELLULAR LOCATION.
PubMed=15799969; DOI=10.1074/jbc.M500362200;
Chen H.B., Rud J.G., Lin K., Xu L.;
"Nuclear targeting of transforming growth factor-beta-activated Smad
complexes.";
J. Biol. Chem. 280:21329-21336(2005).
[21]
INTERACTION WITH RBPMS.
PubMed=17099224; DOI=10.1093/nar/gkl914;
Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J.,
Song H., Ye Q.;
"Potentiation of Smad-mediated transcriptional activation by the RNA-
binding protein RBPMS.";
Nucleic Acids Res. 34:6314-6326(2006).
[22]
FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, AND
INTERACTION WITH PDPK1.
PubMed=17327236; DOI=10.1074/jbc.M609279200;
Seong H.A., Jung H., Kim K.T., Ha H.;
"3-Phosphoinositide-dependent PDK1 negatively regulates transforming
growth factor-beta-induced signaling in a kinase-dependent manner
through physical interaction with Smad proteins.";
J. Biol. Chem. 282:12272-12289(2007).
[23]
INTERACTION WITH WWTR1.
PubMed=18568018; DOI=10.1038/ncb1748;
Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M.,
Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L.;
"TAZ controls Smad nucleocytoplasmic shuttling and regulates human
embryonic stem-cell self-renewal.";
Nat. Cell Biol. 10:837-848(2008).
[24]
INTERACTION WITH USP9X, UBIQUITINATION, AND MUTAGENESIS OF LYS-519.
PubMed=19135894; DOI=10.1016/j.cell.2008.10.051;
Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L.,
Adorno M., Martello G., Stinchfield M.J., Soligo S., Morsut L.,
Inui M., Moro S., Modena N., Argenton F., Newfeld S.J., Piccolo S.;
"FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
controls Smad4 monoubiquitination.";
Cell 136:123-135(2009).
[25]
ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-37; LYS-428 AND LYS-507, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19608861; DOI=10.1126/science.1175371;
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
Walther T.C., Olsen J.V., Mann M.;
"Lysine acetylation targets protein complexes and co-regulates major
cellular functions.";
Science 325:834-840(2009).
[26]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[27]
POSSIBLE INVOLVEMENT IN PULMONARY HYPERTENSION, AND VARIANT SER-13.
PubMed=21898662; DOI=10.1002/humu.21605;
Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M.,
Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M.,
Gibbs J.S., Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B.,
Coulet F., Soubrier F., Humbert M., Morrell N.W., Trembath R.C.,
Machado R.D.;
"Molecular genetic characterization of SMAD signaling molecules in
pulmonary arterial hypertension.";
Hum. Mutat. 32:1385-1389(2011).
[28]
INTERACTION WITH ZNF451, IDENTIFICATION IN A COMPLEX WITH ZNF451;
SMAD3 AND SMAD2, AND SUBUNIT.
PubMed=24324267; DOI=10.1074/jbc.M113.526905;
Feng Y., Wu H., Xu Y., Zhang Z., Liu T., Lin X., Feng X.H.;
"Zinc finger protein 451 is a novel Smad corepressor in transforming
growth factor-beta signaling.";
J. Biol. Chem. 289:2072-2083(2014).
[29]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[30]
SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=25218447; DOI=10.1038/nsmb.2890;
Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M.,
Vertegaal A.C.;
"Uncovering global SUMOylation signaling networks in a site-specific
manner.";
Nat. Struct. Mol. Biol. 21:927-936(2014).
[31]
INTERACTION WITH CREB3L1.
PubMed=25310401; DOI=10.1371/journal.pone.0108528;
Chen Q., Lee C.E., Denard B., Ye J.;
"Sustained induction of collagen synthesis by TGF-beta requires
regulated intramembrane proteolysis of CREB3L1.";
PLoS ONE 9:E108528-E108528(2014).
[32]
SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=25755297; DOI=10.1074/mcp.O114.044792;
Xiao Z., Chang J.G., Hendriks I.A., Sigurdsson J.O., Olsen J.V.,
Vertegaal A.C.;
"System-wide analysis of SUMOylation dynamics in response to
replication stress reveals novel small ubiquitin-like modified target
proteins and acceptor lysines relevant for genome stability.";
Mol. Cell. Proteomics 14:1419-1434(2015).
[33]
INTERACTION WITH NUP93 AND IPO7.
PubMed=26878725; DOI=10.1038/ng.3512;
Braun D.A., Sadowski C.E., Kohl S., Lovric S., Astrinidis S.A.,
Pabst W.L., Gee H.Y., Ashraf S., Lawson J.A., Shril S., Airik M.,
Tan W., Schapiro D., Rao J., Choi W.I., Hermle T., Kemper M.J.,
Pohl M., Ozaltin F., Konrad M., Bogdanovic R., Buescher R.,
Helmchen U., Serdaroglu E., Lifton R.P., Antonin W., Hildebrandt F.;
"Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-
resistant nephrotic syndrome.";
Nat. Genet. 48:457-465(2016).
[34]
SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=28112733; DOI=10.1038/nsmb.3366;
Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
Nielsen M.L.;
"Site-specific mapping of the human SUMO proteome reveals co-
modification with phosphorylation.";
Nat. Struct. Mol. Biol. 24:325-336(2017).
[35]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
PubMed=9214508; DOI=10.1038/40431;
Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P.;
"A structural basis for mutational inactivation of the tumour
suppressor Smad4.";
Nature 388:87-93(1997).
[36]
X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
PubMed=10647180; DOI=10.1016/S0969-2126(00)88340-9;
Qin B., Lam S.S., Lin K.;
"Crystal structure of a transcriptionally active Smad4 fragment.";
Structure 7:1493-1503(1999).
[37]
X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552 OF WILD TYPE AND
MUTANTS ARG-416; ARG-502 AND ARG-515 IN COMPLEX WITH SMAD3, SUBUNIT,
AND MUTAGENESIS OF ARG-416; ARG-502 AND ARG-515.
PubMed=11224571; DOI=10.1038/84995;
Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P.,
Lin K.;
"The L3 loop and C-terminal phosphorylation jointly define Smad
protein trimerization.";
Nat. Struct. Biol. 8:248-253(2001).
[38]
X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 314-552 IN COMPLEX WITH SMAD2
OR SMAD3, AND SUBUNIT.
PubMed=15350224; DOI=10.1016/j.molcel.2004.07.016;
Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J.,
De Caestecker M., Lin K.;
"Structural basis of heteromeric smad protein assembly in TGF-beta
signaling.";
Mol. Cell 15:813-823(2004).
[39]
VARIANT JPS CYS-361.
PubMed=9811934; DOI=10.1093/hmg/7.12.1907;
Houlston R., Bevan S., Williams A., Young J., Dunlop M., Rozen P.,
Eng C., Markie D., Woodford-Richens K., Rodriguez-Bigas M.A.,
Leggett B., Neale K., Phillips R., Sheridan E., Hodgson S., Iwama T.,
Eccles D., Bodmer W., Tomlinson I.;
"Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only
account for a minority of cases.";
Hum. Mol. Genet. 7:1907-1912(1998).
[40]
VARIANTS JPS GLY-330 AND ARG-352.
PubMed=12417513; DOI=10.1007/BF02557528;
Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L.,
Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M.,
Vogelstein B., Howe J.R.;
"Germline SMAD4 or BMPR1A mutations and phenotype of juvenile
polyposis.";
Ann. Surg. Oncol. 9:901-906(2002).
[41]
VARIANTS JP/HHT ARG-352 AND ASP-386.
PubMed=15031030; DOI=10.1016/S0140-6736(04)15732-2;
Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L.,
Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A.;
"A combined syndrome of juvenile polyposis and hereditary haemorrhagic
telangiectasia associated with mutations in MADH4 (SMAD4).";
Lancet 363:852-859(2004).
[42]
VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361, AND
INVOLVEMENT IN COLORECTAL CANCER.
PubMed=16959974; DOI=10.1126/science.1133427;
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
Vogelstein B., Kinzler K.W., Velculescu V.E.;
"The consensus coding sequences of human breast and colorectal
cancers.";
Science 314:268-274(2006).
[43]
VARIANTS MYHRS THR-500 AND VAL-500.
PubMed=22243968; DOI=10.1016/j.ajhg.2011.12.011;
Caputo V., Cianetti L., Niceta M., Carta C., Ciolfi A.,
Bocchinfuso G., Carrani E., Dentici M.L., Biamino E., Belligni E.,
Garavelli L., Boccone L., Melis D., Andria G., Gelb B.D., Stella L.,
Silengo M., Dallapiccola B., Tartaglia M.;
"A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene
underlies Myhre syndrome.";
Am. J. Hum. Genet. 90:161-169(2012).
[44]
VARIANTS MYHRS MET-500; THR-500 AND VAL-500, AND CHARACTERIZATION OF
VARIANT MYHRS THR-500.
PubMed=22158539; DOI=10.1038/ng.1016;
Le Goff C., Mahaut C., Abhyankar A., Le Goff W., Serre V., Afenjar A.,
Destree A., di Rocco M., Heron D., Jacquemont S., Marlin S., Simon M.,
Tolmie J., Verloes A., Casanova J.L., Munnich A., Cormier-Daire V.;
"Mutations at a single codon in Mad homology 2 domain of SMAD4 cause
Myhre syndrome.";
Nat. Genet. 44:85-88(2012).
-!- FUNCTION: In muscle physiology, plays a central role in the
balance between atrophy and hypertrophy. When recruited by MSTN,
promotes atrophy response via phosphorylated SMAD2/4. MSTN
decrease causes SMAD4 release and subsequent recruitment by the
BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8.
Acts synergistically with SMAD1 and YY1 in bone morphogenetic
protein (BMP)-mediated cardiac-specific gene expression. Binds to
SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response
element (BMPRE) of cardiac activating regions (By similarity).
Common SMAD (co-SMAD) is the coactivator and mediator of signal
transduction by TGF-beta (transforming growth factor). Component
of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the
nucleus and is required for the TGF-mediated signaling. Promotes
binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an
activation function required for SMAD1 or SMAD2 to stimulate
transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS
complex which forms at the AP1 promoter site; required for
synergistic transcriptional activity in response to TGF-beta. May
act as a tumor suppressor. Positively regulates PDPK1 kinase
activity by stimulating its dissociation from the 14-3-3 protein
YWHAQ which acts as a negative regulator. {ECO:0000250,
ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9389648}.
-!- SUBUNIT: Found in a complex with SMAD1 and YY1 (By similarity).
Interacts with CITED2 (By similarity). Monomer; in the absence of
TGF-beta activation. Heterodimer; on TGF-beta activation. Composed
of two molecules of a C-terminally phosphorylated R-SMAD molecule,
SMAD2 or SMAD3, and one molecule of SMAD4 to form the
transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a
ternary complex composed of SMAD4, STK11/LKB1 and STK11IP.
Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP
and TRIM33. Interacts with ZNF423; the interaction takes place in
response to BMP2 leading to activation of transcription of BMP
target genes. Interacts with ZNF521; the interaction takes place
in response to BMP2 leading to activation of transcription of BMP
target genes. Interacts with USP9X. Interacts (via the MH1 and MH2
domains) with RBPMS. Interacts with WWTR1 (via coiled-coil
domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS
which forms at the AP1 promoter site; required for synergistic
transcriptional activity in response to TGF-beta. Interacts with
CITED1. Interacts with PDPK1 (via PH domain) (By similarity).
Interacts with VPS39; this interaction affects heterodimer
formation with SMAD3, but not with SMAD2, and leads to inhibition
of SMAD3-dependent transcription activation. Interactions with
VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3
(By similarity). Interacts (via MH2 domain) with ZNF451 (via N-
terminal zinc-finger domains) (PubMed:24324267). Identified in a
complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4
(PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310).
Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus
through the NPC upon BMP7 stimulation resulting in activation of
SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the
interaction takes place upon TGFB1 induction and SMAD4 acts as
CREB3L1 coactivator to induce the expression of genes involved in
the assembly of collagen extracellular matrix (PubMed:25310401).
Interacts with DLX1 (PubMed:14671321).
{ECO:0000250|UniProtKB:O70437, ECO:0000250|UniProtKB:P97471,
ECO:0000269|PubMed:10660046, ECO:0000269|PubMed:11224571,
ECO:0000269|PubMed:11741830, ECO:0000269|PubMed:11818334,
ECO:0000269|PubMed:12370310, ECO:0000269|PubMed:12941698,
ECO:0000269|PubMed:14525983, ECO:0000269|PubMed:14630787,
ECO:0000269|PubMed:14671321, ECO:0000269|PubMed:15350224,
ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:15820681,
ECO:0000269|PubMed:17099224, ECO:0000269|PubMed:17327236,
ECO:0000269|PubMed:18568018, ECO:0000269|PubMed:19135894,
ECO:0000269|PubMed:24324267, ECO:0000269|PubMed:25310401,
ECO:0000269|PubMed:26878725, ECO:0000269|PubMed:9670020,
ECO:0000269|PubMed:9707553}.
-!- INTERACTION:
Self; NbExp=3; IntAct=EBI-347263, EBI-347263;
P31749:AKT1; NbExp=2; IntAct=EBI-347263, EBI-296087;
Q9UI36:DACH1; NbExp=3; IntAct=EBI-347263, EBI-347111;
Q9NPI6:DCP1A; NbExp=4; IntAct=EBI-347263, EBI-374238;
Q92988:DLX4; NbExp=5; IntAct=EBI-347263, EBI-1752755;
P70056:foxh1 (xeno); NbExp=2; IntAct=EBI-347263, EBI-9969973;
O43524:FOXO3; NbExp=9; IntAct=EBI-347263, EBI-1644164;
P98177:FOXO4; NbExp=2; IntAct=EBI-347263, EBI-4481939;
P23769:GATA2; NbExp=2; IntAct=EBI-347263, EBI-2806671;
P61968:LMO4; NbExp=5; IntAct=EBI-347263, EBI-2798728;
Q9UBE8:NLK; NbExp=6; IntAct=EBI-347263, EBI-366978;
P24468:NR2F2; NbExp=4; IntAct=EBI-347263, EBI-2795198;
Q8WWW0:RASSF5; NbExp=3; IntAct=EBI-347263, EBI-367390;
P12755:SKI; NbExp=13; IntAct=EBI-347263, EBI-347281;
P12757:SKIL; NbExp=3; IntAct=EBI-347263, EBI-2902468;
Q15797:SMAD1; NbExp=9; IntAct=EBI-347263, EBI-1567153;
Q15796:SMAD2; NbExp=20; IntAct=EBI-347263, EBI-1040141;
P84022:SMAD3; NbExp=24; IntAct=EBI-347263, EBI-347161;
O15198-2:SMAD9; NbExp=4; IntAct=EBI-347263, EBI-12273450;
P08047:SP1; NbExp=2; IntAct=EBI-347263, EBI-298336;
Q9UPN9:TRIM33; NbExp=6; IntAct=EBI-347263, EBI-2214398;
P63279:UBE2I; NbExp=4; IntAct=EBI-347263, EBI-80168;
Q93008:USP9X; NbExp=2; IntAct=EBI-347263, EBI-302524;
P70398:Usp9x (xeno); NbExp=4; IntAct=EBI-347263, EBI-2214043;
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15799969,
ECO:0000269|PubMed:17327236}. Nucleus
{ECO:0000269|PubMed:15799969}. Note=Cytoplasmic in the absence of
ligand. Migrates to the nucleus when complexed with R-SMAD
(PubMed:15799969). PDPK1 prevents its nuclear translocation in
response to TGF-beta (PubMed:17327236).
{ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236}.
-!- DOMAIN: The MH1 domain is required for DNA binding.
-!- DOMAIN: The MH2 domain is required for both homomeric and
heteromeric interactions and for transcriptional regulation.
Sufficient for nuclear import.
-!- PTM: Phosphorylated by PDPK1. {ECO:0000269|PubMed:17327236}.
-!- PTM: Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase
TRIM33. Monoubiquitination hampers its ability to form a stable
complex with activated SMAD2/3 resulting in inhibition of TGF-
beta/BMP signaling cascade. Deubiquitination by USP9X restores its
competence to mediate TGF-beta signaling.
{ECO:0000269|PubMed:19135894}.
-!- DISEASE: Pancreatic cancer (PNCA) [MIM:260350]: A malignant
neoplasm of the pancreas. Tumors can arise from both the exocrine
and endocrine portions of the pancreas, but 95% of them develop
from the exocrine portion, including the ductal epithelium, acinar
cells, connective tissue, and lymphatic tissue.
{ECO:0000269|PubMed:8553070}. Note=The gene represented in this
entry may be involved in disease pathogenesis.
-!- DISEASE: Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal
dominant gastrointestinal hamartomatous polyposis syndrome in
which patients are at risk for developing gastrointestinal
cancers. The lesions are typified by a smooth histological
appearance, predominant stroma, cystic spaces and lack of a smooth
muscle core. Multiple juvenile polyps usually occur in a number of
Mendelian disorders. Sometimes, these polyps occur without
associated features as in JPS; here, polyps tend to occur in the
large bowel and are associated with an increased risk of colon and
other gastrointestinal cancers. {ECO:0000269|PubMed:12417513,
ECO:0000269|PubMed:9811934}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Juvenile polyposis/hereditary hemorrhagic telangiectasia
syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists
of the coexistence of juvenile polyposis (JIP) and hereditary
hemorrhagic telangiectasia (HHT) [MIM:187300] in a single
individual. JIP and HHT are autosomal dominant disorders with
distinct and non-overlapping clinical features. The former, an
inherited gastrointestinal malignancy predisposition, is caused by
mutations in SMAD4 or BMPR1A, and the latter is a vascular
malformation disorder caused by mutations in ENG or ACVRL1. All
four genes encode proteins involved in the transforming-growth-
factor-signaling pathway. Although there are reports of patients
and families with phenotypes of both disorders combined, the
genetic etiology of this association is unknown.
{ECO:0000269|PubMed:15031030}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
characterized by malignant lesions arising from the inner wall of
the large intestine (the colon) and the rectum. Genetic
alterations are often associated with progression from
premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
factors for cancer of the colon and rectum include colon polyps,
long-standing ulcerative colitis, and genetic family history.
{ECO:0000269|PubMed:16959974}. Note=The disease may be caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Note=SMAD4 variants may be associated with susceptibility
to pulmonary hypertension, a disorder characterized by plexiform
lesions of proliferating endothelial cells in pulmonary
arterioles. The lesions lead to elevated pulmonary arterial
pression, right ventricular failure, and death. The disease can
occur from infancy throughout life and it has a mean age at onset
of 36 years. Penetrance is reduced. Although familial pulmonary
hypertension is rare, cases secondary to known etiologies are more
common and include those associated with the appetite-suppressant
drugs. {ECO:0000269|PubMed:21898662}.
-!- DISEASE: Myhre syndrome (MYHRS) [MIM:139210]: A syndrome
characterized by pre- and postnatal growth deficiency, mental
retardation, generalized muscle hypertrophy and striking muscular
build, decreased joint mobility, cryptorchidism, and unusual
facies. Dysmorphic facial features include microcephaly, midface
hypoplasia, prognathism, and blepharophimosis. Typical skeletal
anomalies are short stature, square body shape, broad ribs, iliac
hypoplasia, brachydactyly, flattened vertebrae, and thickened
calvaria. Other features, such as congenital heart disease, may
also occur. {ECO:0000269|PubMed:22158539,
ECO:0000269|PubMed:22243968}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/SMAD4ID371.html";
-!- WEB RESOURCE: Name=Mendelian genes SMAD family member 4 (SMAD4);
Note=Leiden Open Variation Database (LOVD);
URL="http://www.lovd.nl/SMAD4";
-----------------------------------------------------------------------
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EMBL; AF045447; AAC03051.1; -; Genomic_DNA.
EMBL; AF045438; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045439; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045440; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045441; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045442; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045443; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045444; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045445; AAC03051.1; JOINED; Genomic_DNA.
EMBL; AF045446; AAC03051.1; JOINED; Genomic_DNA.
EMBL; U44378; AAA91041.1; -; mRNA.
EMBL; AK290770; BAF83459.1; -; mRNA.
EMBL; CH471096; EAW62985.1; -; Genomic_DNA.
EMBL; BC002379; AAH02379.1; -; mRNA.
CCDS; CCDS11950.1; -.
PIR; S71811; S71811.
RefSeq; NP_005350.1; NM_005359.5.
UniGene; Hs.75862; -.
PDB; 1DD1; X-ray; 2.62 A; A/B/C=285-552.
PDB; 1G88; X-ray; 3.00 A; A/B/C=285-552.
PDB; 1MR1; X-ray; 2.85 A; A/B=319-552.
PDB; 1U7F; X-ray; 2.60 A; B=314-552.
PDB; 1U7V; X-ray; 2.70 A; B=314-549.
PDB; 1YGS; X-ray; 2.10 A; A=319-552.
PDB; 5C4V; X-ray; 2.60 A; A/C/E=314-549.
PDB; 5UWU; X-ray; 2.24 A; D=133-149.
PDBsum; 1DD1; -.
PDBsum; 1G88; -.
PDBsum; 1MR1; -.
PDBsum; 1U7F; -.
PDBsum; 1U7V; -.
PDBsum; 1YGS; -.
PDBsum; 5C4V; -.
PDBsum; 5UWU; -.
DisProt; DP00464; -.
ProteinModelPortal; Q13485; -.
SMR; Q13485; -.
BioGrid; 110264; 223.
CORUM; Q13485; -.
DIP; DIP-31512N; -.
IntAct; Q13485; 122.
MINT; MINT-244037; -.
STRING; 9606.ENSP00000341551; -.
iPTMnet; Q13485; -.
PhosphoSitePlus; Q13485; -.
BioMuta; SMAD4; -.
DMDM; 13959561; -.
EPD; Q13485; -.
MaxQB; Q13485; -.
PaxDb; Q13485; -.
PeptideAtlas; Q13485; -.
PRIDE; Q13485; -.
DNASU; 4089; -.
Ensembl; ENST00000342988; ENSP00000341551; ENSG00000141646.
Ensembl; ENST00000398417; ENSP00000381452; ENSG00000141646.
GeneID; 4089; -.
KEGG; hsa:4089; -.
UCSC; uc010xdp.3; human.
CTD; 4089; -.
DisGeNET; 4089; -.
EuPathDB; HostDB:ENSG00000141646.13; -.
GeneCards; SMAD4; -.
GeneReviews; SMAD4; -.
HGNC; HGNC:6770; SMAD4.
HPA; HPA019154; -.
MalaCards; SMAD4; -.
MIM; 114500; phenotype.
MIM; 139210; phenotype.
MIM; 174900; phenotype.
MIM; 175050; phenotype.
MIM; 260350; phenotype.
MIM; 600993; gene.
neXtProt; NX_Q13485; -.
OpenTargets; ENSG00000141646; -.
Orphanet; 1333; Familial pancreatic carcinoma.
Orphanet; 329971; Generalized juvenile polyposis/juvenile polyposis coli.
Orphanet; 774; Hereditary hemorrhagic telangiectasia.
Orphanet; 2588; Myhre syndrome.
PharmGKB; PA30527; -.
eggNOG; KOG3701; Eukaryota.
eggNOG; ENOG410XQKU; LUCA.
GeneTree; ENSGT00760000119091; -.
HOGENOM; HOG000286019; -.
HOVERGEN; HBG053353; -.
InParanoid; Q13485; -.
KO; K04501; -.
OMA; DIGTIQH; -.
OrthoDB; EOG091G05Z9; -.
PhylomeDB; Q13485; -.
TreeFam; TF314923; -.
Reactome; R-HSA-1181150; Signaling by NODAL.
Reactome; R-HSA-1502540; Signaling by Activin.
Reactome; R-HSA-201451; Signaling by BMP.
Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs.
Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
Reactome; R-HSA-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
Reactome; R-HSA-3311021; SMAD4 MH2 Domain Mutants in Cancer.
Reactome; R-HSA-3315487; SMAD2/3 MH2 Domain Mutants in Cancer.
Reactome; R-HSA-452723; Transcriptional regulation of pluripotent stem cells.
Reactome; R-HSA-5689880; Ub-specific processing proteases.
Reactome; R-HSA-8941326; RUNX2 regulates bone development.
Reactome; R-HSA-8941855; RUNX3 regulates CDKN1A transcription.
Reactome; R-HSA-8952158; RUNX3 regulates BCL2L11 (BIM) transcription.
SignaLink; Q13485; -.
SIGNOR; Q13485; -.
ChiTaRS; SMAD4; human.
EvolutionaryTrace; Q13485; -.
GeneWiki; Mothers_against_decapentaplegic_homolog_4; -.
GenomeRNAi; 4089; -.
PRO; PR:Q13485; -.
Proteomes; UP000005640; Chromosome 18.
Bgee; ENSG00000141646; -.
CleanEx; HS_SMAD4; -.
ExpressionAtlas; Q13485; baseline and differential.
Genevisible; Q13485; HS.
GO; GO:0032444; C:activin responsive factor complex; IDA:BHF-UCL.
GO; GO:0005813; C:centrosome; IDA:HPA.
GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0000790; C:nuclear chromatin; IDA:BHF-UCL.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
GO; GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
GO; GO:0005667; C:transcription factor complex; IDA:BHF-UCL.
GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
GO; GO:0005518; F:collagen binding; IEA:Ensembl.
GO; GO:0000987; F:core promoter proximal region sequence-specific DNA binding; IDA:UniProtKB.
GO; GO:0070411; F:I-SMAD binding; IPI:BHF-UCL.
GO; GO:0042802; F:identical protein binding; IMP:CAFA.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0046982; F:protein heterodimerization activity; IEA:Ensembl.
GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
GO; GO:0070412; F:R-SMAD binding; IPI:BHF-UCL.
GO; GO:0000978; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding; IDA:NTNU_SB.
GO; GO:0001085; F:RNA polymerase II transcription factor binding; IEA:Ensembl.
GO; GO:0043199; F:sulfate binding; IMP:CAFA.
GO; GO:0001076; F:transcription factor activity, RNA polymerase II transcription factor binding; IEA:Ensembl.
GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:BHF-UCL.
GO; GO:0001077; F:transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding; IDA:NTNU_SB.
GO; GO:0030616; F:transforming growth factor beta receptor, common-partner cytoplasmic mediator activity; IDA:BHF-UCL.
GO; GO:0036302; P:atrioventricular canal development; IEA:Ensembl.
GO; GO:0003190; P:atrioventricular valve formation; IEA:Ensembl.
GO; GO:0007411; P:axon guidance; IEA:Ensembl.
GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
GO; GO:0003360; P:brainstem development; IEA:Ensembl.
GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IEA:Ensembl.
GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
GO; GO:0006879; P:cellular iron ion homeostasis; ISS:BHF-UCL.
GO; GO:0071773; P:cellular response to BMP stimulus; NAS:BHF-UCL.
GO; GO:0048589; P:developmental growth; IEA:Ensembl.
GO; GO:0042733; P:embryonic digit morphogenesis; IEA:Ensembl.
GO; GO:0060956; P:endocardial cell differentiation; IEA:Ensembl.
GO; GO:0007492; P:endoderm development; IEA:Ensembl.
GO; GO:0042118; P:endothelial cell activation; IEA:Ensembl.
GO; GO:0003198; P:epithelial to mesenchymal transition involved in endocardial cushion formation; IEA:Ensembl.
GO; GO:0061040; P:female gonad morphogenesis; IEA:Ensembl.
GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
GO; GO:0001702; P:gastrulation with mouth forming second; IEA:Ensembl.
GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:BHF-UCL.
GO; GO:0035556; P:intracellular signal transduction; IMP:CACAO.
GO; GO:0003220; P:left ventricular cardiac muscle tissue morphogenesis; ISS:BHF-UCL.
GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
GO; GO:0072133; P:metanephric mesenchyme morphogenesis; IEA:Ensembl.
GO; GO:0010614; P:negative regulation of cardiac muscle hypertrophy; ISS:BHF-UCL.
GO; GO:1905305; P:negative regulation of cardiac myofibril assembly; ISS:BHF-UCL.
GO; GO:0060548; P:negative regulation of cell death; IEA:Ensembl.
GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL.
GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; ISS:BHF-UCL.
GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:BHF-UCL.
GO; GO:0072134; P:nephrogenic mesenchyme morphogenesis; IEA:Ensembl.
GO; GO:0014033; P:neural crest cell differentiation; IEA:Ensembl.
GO; GO:0048663; P:neuron fate commitment; IEA:Ensembl.
GO; GO:0003148; P:outflow tract septum morphogenesis; ISS:BHF-UCL.
GO; GO:0001541; P:ovarian follicle development; IEA:Ensembl.
GO; GO:0060021; P:palate development; ISS:BHF-UCL.
GO; GO:0030513; P:positive regulation of BMP signaling pathway; IMP:BHF-UCL.
GO; GO:0003251; P:positive regulation of cell proliferation involved in heart valve morphogenesis; IEA:Ensembl.
GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:BHF-UCL.
GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IEA:Ensembl.
GO; GO:0051571; P:positive regulation of histone H3-K4 methylation; ISS:BHF-UCL.
GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; ISS:BHF-UCL.
GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; IEA:Ensembl.
GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISS:BHF-UCL.
GO; GO:0060391; P:positive regulation of SMAD protein import into nucleus; ISS:BHF-UCL.
GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
GO; GO:1901522; P:positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus; TAS:BHF-UCL.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
GO; GO:0016579; P:protein deubiquitination; TAS:Reactome.
GO; GO:0070207; P:protein homotrimerization; IMP:CAFA.
GO; GO:0051098; P:regulation of binding; IEA:Ensembl.
GO; GO:0051797; P:regulation of hair follicle development; IEA:Ensembl.
GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL.
GO; GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL.
GO; GO:0001666; P:response to hypoxia; IMP:BHF-UCL.
GO; GO:0071559; P:response to transforming growth factor beta; IDA:UniProtKB.
GO; GO:0048733; P:sebaceous gland development; IEA:Ensembl.
GO; GO:0072520; P:seminiferous tubule development; IEA:Ensembl.
GO; GO:0007338; P:single fertilization; IEA:Ensembl.
GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
GO; GO:0060395; P:SMAD protein signal transduction; IDA:BHF-UCL.
GO; GO:0035019; P:somatic stem cell population maintenance; TAS:Reactome.
GO; GO:0032525; P:somite rostral/caudal axis specification; IEA:Ensembl.
GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
GO; GO:0060065; P:uterus development; IEA:Ensembl.
GO; GO:0060412; P:ventricular septum morphogenesis; ISS:BHF-UCL.
Gene3D; 2.60.200.10; -; 1.
Gene3D; 3.90.520.10; -; 1.
InterPro; IPR013790; Dwarfin.
InterPro; IPR003619; MAD_homology1_Dwarfin-type.
InterPro; IPR013019; MAD_homology_MH1.
InterPro; IPR017855; SMAD-like_dom_sf.
InterPro; IPR001132; SMAD_dom_Dwarfin-type.
InterPro; IPR008984; SMAD_FHA_dom_sf.
InterPro; IPR036578; SMAD_MH1_sf.
PANTHER; PTHR13703; PTHR13703; 1.
Pfam; PF03165; MH1; 1.
Pfam; PF03166; MH2; 1.
SMART; SM00523; DWA; 1.
SMART; SM00524; DWB; 1.
SUPFAM; SSF49879; SSF49879; 1.
SUPFAM; SSF56366; SSF56366; 1.
PROSITE; PS51075; MH1; 1.
PROSITE; PS51076; MH2; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Complete proteome; Cytoplasm;
Disease mutation; DNA-binding; Isopeptide bond; Metal-binding;
Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
Transcription; Transcription regulation; Ubl conjugation; Zinc.
CHAIN 1 552 Mothers against decapentaplegic homolog
4.
/FTId=PRO_0000090861.
DOMAIN 18 142 MH1. {ECO:0000255|PROSITE-
ProRule:PRU00438}.
DOMAIN 323 552 MH2. {ECO:0000255|PROSITE-
ProRule:PRU00439}.
REGION 275 320 SAD.
COMPBIAS 451 466 Poly-Ala.
METAL 71 71 Zinc. {ECO:0000250}.
METAL 115 115 Zinc. {ECO:0000250}.
METAL 127 127 Zinc. {ECO:0000250}.
METAL 132 132 Zinc. {ECO:0000250}.
SITE 515 515 Necessary for heterotrimerization.
MOD_RES 37 37 N6-acetyllysine.
{ECO:0000244|PubMed:19608861}.
MOD_RES 428 428 N6-acetyllysine.
{ECO:0000244|PubMed:19608861}.
MOD_RES 507 507 N6-acetyllysine.
{ECO:0000244|PubMed:19608861}.
CROSSLNK 113 113 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO2).
{ECO:0000244|PubMed:25218447,
ECO:0000244|PubMed:25755297,
ECO:0000244|PubMed:28112733}.
CROSSLNK 519 519 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000269|PubMed:19135894}.
VARIANT 13 13 N -> S (rare variant; found in a patient
with pulmonary hypertension; unknown
pathological significance;
dbSNP:rs281875323).
{ECO:0000269|PubMed:21898662}.
/FTId=VAR_066870.
VARIANT 130 130 P -> S (in a colorectal cancer sample;
somatic mutation).
{ECO:0000269|PubMed:16959974}.
/FTId=VAR_036475.
VARIANT 330 330 E -> G (in JPS; dbSNP:rs281875324).
{ECO:0000269|PubMed:12417513}.
/FTId=VAR_022833.
VARIANT 351 351 D -> N (in a colorectal cancer sample;
somatic mutation).
{ECO:0000269|PubMed:16959974}.
/FTId=VAR_036476.
VARIANT 352 352 G -> R (in JP/HHT and JPS;
dbSNP:rs121912581).
{ECO:0000269|PubMed:12417513,
ECO:0000269|PubMed:15031030}.
/FTId=VAR_019571.
VARIANT 361 361 R -> C (in JPS; dbSNP:rs80338963).
{ECO:0000269|PubMed:9811934}.
/FTId=VAR_019572.
VARIANT 361 361 R -> H (in a colorectal cancer sample;
somatic mutation; dbSNP:rs377767347).
{ECO:0000269|PubMed:16959974}.
/FTId=VAR_036477.
VARIANT 386 386 G -> D (in JP/HHT; dbSNP:rs28936393).
{ECO:0000269|PubMed:15031030}.
/FTId=VAR_019573.
VARIANT 493 493 D -> H (in pancreatic carcinoma;
dbSNP:rs28936392).
{ECO:0000269|PubMed:8553070}.
/FTId=VAR_011380.
VARIANT 500 500 I -> M (in MYHRS; dbSNP:rs281875320).
{ECO:0000269|PubMed:22158539}.
/FTId=VAR_067602.
VARIANT 500 500 I -> T (in MYHRS; there is an enhanced
levels of SMAD4 protein with lower levels
of ubiquitinated SMAD4 fibroblasts
compared to controls suggesting
stabilization of the mutant protein; 8-
fold increase in phosphorylated SMAD2 and
SMAD3; 11-fold increase in phosphorylated
SMAD1, SMAD5 and SMAD8 in cell nuclei
compared to controls; dbSNP:rs281875321).
{ECO:0000269|PubMed:22158539,
ECO:0000269|PubMed:22243968}.
/FTId=VAR_067603.
VARIANT 500 500 I -> V (in MYHRS; dbSNP:rs281875322).
{ECO:0000269|PubMed:22158539,
ECO:0000269|PubMed:22243968}.
/FTId=VAR_067604.
MUTAGEN 416 416 R->S: No effect on heterotrimerization.
Partially diminished transcriptional
activation.
{ECO:0000269|PubMed:11224571}.
MUTAGEN 496 496 R->S: No effect on heterotrimerization.
Partially diminished transcriptional
activation.
MUTAGEN 502 502 R->S: No effect on heterotrimerization.
Greatly reduced transcriptional
activation.
{ECO:0000269|PubMed:11224571}.
MUTAGEN 515 515 R->S: Reduced heterotrimerization.
{ECO:0000269|PubMed:11224571}.
MUTAGEN 519 519 K->R: Abolishes ubiquitination.
{ECO:0000269|PubMed:19135894}.
HELIX 143 145 {ECO:0000244|PDB:5UWU}.
STRAND 288 291 {ECO:0000244|PDB:1DD1}.
STRAND 321 330 {ECO:0000244|PDB:1YGS}.
STRAND 333 342 {ECO:0000244|PDB:1YGS}.
STRAND 346 353 {ECO:0000244|PDB:1YGS}.
STRAND 359 363 {ECO:0000244|PDB:1YGS}.
HELIX 364 366 {ECO:0000244|PDB:1U7F}.
HELIX 374 380 {ECO:0000244|PDB:1YGS}.
TURN 381 385 {ECO:0000244|PDB:1YGS}.
STRAND 387 392 {ECO:0000244|PDB:1YGS}.
TURN 393 395 {ECO:0000244|PDB:1YGS}.
STRAND 396 401 {ECO:0000244|PDB:1YGS}.
STRAND 403 405 {ECO:0000244|PDB:1YGS}.
STRAND 407 410 {ECO:0000244|PDB:1YGS}.
HELIX 412 416 {ECO:0000244|PDB:1YGS}.
TURN 417 419 {ECO:0000244|PDB:1YGS}.
STRAND 427 429 {ECO:0000244|PDB:1YGS}.
STRAND 434 438 {ECO:0000244|PDB:1YGS}.
HELIX 440 454 {ECO:0000244|PDB:1YGS}.
TURN 455 458 {ECO:0000244|PDB:1DD1}.
HELIX 461 464 {ECO:0000244|PDB:1DD1}.
HELIX 493 497 {ECO:0000244|PDB:1YGS}.
STRAND 500 506 {ECO:0000244|PDB:1YGS}.
HELIX 518 520 {ECO:0000244|PDB:1YGS}.
STRAND 521 529 {ECO:0000244|PDB:1YGS}.
HELIX 530 541 {ECO:0000244|PDB:1YGS}.
SEQUENCE 552 AA; 60439 MW; 7EE3C4647712DA90 CRC64;
MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA
ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD
LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPSSMMVKD EYVHDFEGQP SLSTEGHSIQ
TIQHPPSNRA STETYSTPAL LAPSESNATS TANFPNIPVA STSQPASILG GSHSEGLLQI
ASGPQPGQQQ NGFTGQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH
YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV DGYVDPSGGD
RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR CLSDHAVFVQ SYYLDREAGR
APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ AATAQAAAAA QAAAVAGNIP GPGSVGGIAP
AISLSAAAGI GVDDLRRLCI LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL
HTMPIADPQP LD


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