SMAD4_HUMAN
ID SMAD4_HUMAN Reviewed; 552 AA.
AC Q13485; A8K405;
DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 238.
DE RecName: Full=Mothers against decapentaplegic homolog 4;
DE Short=MAD homolog 4;
DE Short=Mothers against DPP homolog 4;
DE AltName: Full=Deletion target in pancreatic carcinoma 4;
DE AltName: Full=SMAD family member 4;
DE Short=SMAD 4;
DE Short=Smad4;
DE Short=hSMAD4;
GN Name=SMAD4; Synonyms=DPC4, MADH4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT PANCREATIC CARCINOMA
RP HIS-493.
RC TISSUE=Fetal brain;
RX PubMed=8553070; DOI=10.1126/science.271.5247.350;
RA Hahn S.A., Schutte M., Shamsul Hoque A.T.M., Moskaluk C.A., da Costa L.T.,
RA Rozenblum E., Weinstein C.L., Fischer A., Yeo C.J., Hruban R.H., Kern S.E.;
RT "DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.";
RL Science 271:350-353(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=8774881; DOI=10.1038/383168a0;
RA Zhang Y., Feng X.-H., Wu R.-Y., Derynck R.;
RT "Receptor-associated Mad homologues synergize as effectors of the TGF-beta
RT response.";
RL Nature 383:168-172(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9098646; DOI=10.1097/00019606-199704000-00003;
RA Moskaluk C.A., Hruban R.H., Schutte M., Lietman A.S., Smyrk T., Fusaro L.,
RA Fusaro R., Lynch J., Yeo C.J., Jackson C.E., Lynch H.T., Kern S.E.;
RT "Genomic sequencing of DPC4 in the analysis of familial pancreatic
RT carcinoma.";
RL Diagn. Mol. Pathol. 6:85-90(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION.
RX PubMed=9389648; DOI=10.1101/gad.11.23.3157;
RA Liu F., Pouponnot C., Massague J.;
RT "Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible
RT transcriptional complexes.";
RL Genes Dev. 11:3157-3167(1997).
RN [8]
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 receptors.";
RL EMBO J. 17:4056-4065(1998).
RN [9]
RP INTERACTION WITH CITED1.
RX PubMed=9707553; DOI=10.1073/pnas.95.17.9785;
RA Shioda T., Lechleider R.J., Dunwoodie S.L., Li H., Yahata T.,
RA de Caestecker M.P., Fenner M.H., Roberts A.B., Isselbacher K.J.;
RT "Transcriptional activating activity of Smad4: roles of SMAD hetero-
RT oligomerization and enhancement by an associating transactivator.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:9785-9790(1998).
RN [10]
RP INTERACTION WITH ZNF423.
RX PubMed=10660046; DOI=10.1016/s0092-8674(00)81561-5;
RA Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A.,
RA Massague J.;
RT "OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-
RT Smad and Olf signaling pathways.";
RL Cell 100:229-240(2000).
RN [11]
RP CHARACTERIZATION OF SAD DOMAIN.
RX PubMed=10636916; DOI=10.1074/jbc.275.3.2115;
RA de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S., Hill C.S.,
RA Shioda T., Roberts A.B., Lechleider R.J.;
RT "The Smad4 activation domain (SAD) is a proline-rich, p300-dependent
RT transcriptional activation domain.";
RL J. Biol. Chem. 275:2115-2122(2000).
RN [12]
RP IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11/LKB1 AND STK11IP, AND
RP INTERACTION WITH STK11/LKB1 AND STK11IP.
RX PubMed=11741830; DOI=10.1093/hmg/10.25.2869;
RA Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M.,
RA Ashworth A.;
RT "LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers
RT syndrome kinase LKB1.";
RL Hum. Mol. Genet. 10:2869-2877(2001).
RN [13]
RP INTERACTION WITH COPS5.
RX PubMed=11818334; DOI=10.1093/embo-reports/kvf024;
RA Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X.;
RT "Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.";
RL EMBO Rep. 3:171-176(2002).
RN [14]
RP INTERACTION WITH ZNF8.
RX PubMed=12370310; DOI=10.1128/mcb.22.21.7633-7644.2002;
RA Jiao K., Zhou Y., Hogan B.L.M.;
RT "Identification of mZnf8, a mouse Kruppel-like transcriptional repressor,
RT as a novel nuclear interaction partner of Smad1.";
RL Mol. Cell. Biol. 22:7633-7644(2002).
RN [15]
RP INTERACTION WITH VPS39.
RX PubMed=12941698; DOI=10.1093/emboj/cdg428;
RA Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M., Karpova T.S.,
RA McNally J.G., Roberts A.B.;
RT "TLP, a novel modulator of TGF-beta signaling, has opposite effects on
RT Smad2- and Smad3-dependent signaling.";
RL EMBO J. 22:4465-4477(2003).
RN [16]
RP INTERACTION WITH DACH1.
RX PubMed=14525983; DOI=10.1074/jbc.m310021200;
RA Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K.,
RA Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G.;
RT "DACH1 inhibits transforming growth factor-beta signaling through binding
RT Smad4.";
RL J. Biol. Chem. 278:51673-51684(2003).
RN [17]
RP INTERACTION WITH DLX1.
RX PubMed=14671321; DOI=10.1073/pnas.2536757100;
RA Chiba S., Takeshita K., Imai Y., Kumano K., Kurokawa M., Masuda S.,
RA Shimizu K., Nakamura S., Ruddle F.H., Hirai H.;
RT "Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway
RT from activin A in hematopoietic cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:15577-15582(2003).
RN [18]
RP INTERACTION WITH ZNF521.
RX PubMed=14630787; DOI=10.1182/blood-2003-07-2388;
RA Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N.,
RA De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M.,
RA Morrone G., Venuta S.;
RT "Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse
RT Evi3, is highly expressed in primitive human hematopoietic cells.";
RL Blood 103:2062-2070(2004).
RN [19]
RP INTERACTION WITH TRIM33.
RX PubMed=15820681; DOI=10.1016/j.cell.2005.01.033;
RA Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M.,
RA Piccolo S.;
RT "Germ-layer specification and control of cell growth by Ectodermin, a Smad4
RT ubiquitin ligase.";
RL Cell 121:87-99(2005).
RN [20]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=15799969; DOI=10.1074/jbc.m500362200;
RA Chen H.B., Rud J.G., Lin K., Xu L.;
RT "Nuclear targeting of transforming growth factor-beta-activated Smad
RT complexes.";
RL J. Biol. Chem. 280:21329-21336(2005).
RN [21]
RP INTERACTION WITH ZMIZ1.
RX PubMed=16777850; DOI=10.1074/jbc.m508365200;
RA Li X., Thyssen G., Beliakoff J., Sun Z.;
RT "The novel PIAS-like protein hZimp10 enhances Smad transcriptional
RT activity.";
RL J. Biol. Chem. 281:23748-23756(2006).
RN [22]
RP INTERACTION WITH RBPMS.
RX PubMed=17099224; DOI=10.1093/nar/gkl914;
RA Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., Song H.,
RA Ye Q.;
RT "Potentiation of Smad-mediated transcriptional activation by the RNA-
RT binding protein RBPMS.";
RL Nucleic Acids Res. 34:6314-6326(2006).
RN [23]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, AND INTERACTION
RP WITH PDPK1.
RX PubMed=17327236; DOI=10.1074/jbc.m609279200;
RA Seong H.A., Jung H., Kim K.T., Ha H.;
RT "3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth
RT factor-beta-induced signaling in a kinase-dependent manner through physical
RT interaction with Smad proteins.";
RL J. Biol. Chem. 282:12272-12289(2007).
RN [24]
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 [25]
RP INTERACTION WITH USP9X, UBIQUITINATION, AND MUTAGENESIS OF LYS-519.
RX PubMed=19135894; DOI=10.1016/j.cell.2008.10.051;
RA Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L., Adorno M.,
RA Martello G., Stinchfield M.J., Soligo S., Morsut L., Inui M., Moro S.,
RA Modena N., Argenton F., Newfeld S.J., Piccolo S.;
RT "FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
RT controls Smad4 monoubiquitination.";
RL Cell 136:123-135(2009).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-37; LYS-428 AND LYS-507, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP POSSIBLE INVOLVEMENT IN PULMONARY HYPERTENSION, AND VARIANT SER-13.
RX PubMed=21898662; DOI=10.1002/humu.21605;
RA Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M.,
RA Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M., Gibbs J.S.,
RA Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B., Coulet F., Soubrier F.,
RA Humbert M., Morrell N.W., Trembath R.C., Machado R.D.;
RT "Molecular genetic characterization of SMAD signaling molecules in
RT pulmonary arterial hypertension.";
RL Hum. Mutat. 32:1385-1389(2011).
RN [29]
RP INTERACTION WITH ZNF451, IDENTIFICATION IN A COMPLEX WITH ZNF451; SMAD3 AND
RP SMAD2, AND SUBUNIT.
RX PubMed=24324267; DOI=10.1074/jbc.m113.526905;
RA Feng Y., Wu H., Xu Y., Zhang Z., Liu T., Lin X., Feng X.H.;
RT "Zinc finger protein 451 is a novel Smad corepressor in transforming growth
RT factor-beta signaling.";
RL J. Biol. Chem. 289:2072-2083(2014).
RN [30]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [31]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25218447; DOI=10.1038/nsmb.2890;
RA Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M.,
RA Vertegaal A.C.;
RT "Uncovering global SUMOylation signaling networks in a site-specific
RT manner.";
RL Nat. Struct. Mol. Biol. 21:927-936(2014).
RN [32]
RP INTERACTION WITH CREB3L1.
RX PubMed=25310401; DOI=10.1371/journal.pone.0108528;
RA Chen Q., Lee C.E., Denard B., Ye J.;
RT "Sustained induction of collagen synthesis by TGF-beta requires regulated
RT intramembrane proteolysis of CREB3L1.";
RL PLoS ONE 9:E108528-E108528(2014).
RN [33]
RP FUNCTION, INTERACTION WITH CREBBP; EP300; HDAC1 AND ZBTB7A, AND REGION.
RX PubMed=25514493; DOI=10.1016/j.bbagrm.2014.12.008;
RA Yang Y., Cui J., Xue F., Zhang C., Mei Z., Wang Y., Bi M., Shan D.,
RA Meredith A., Li H., Xu Z.Q.;
RT "Pokemon (FBI-1) interacts with Smad4 to repress TGF-beta-induced
RT transcriptional responses.";
RL Biochim. Biophys. Acta 1849:270-281(2015).
RN [34]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25755297; DOI=10.1074/mcp.o114.044792;
RA Xiao Z., Chang J.G., Hendriks I.A., Sigurdsson J.O., Olsen J.V.,
RA Vertegaal A.C.;
RT "System-wide analysis of SUMOylation dynamics in response to replication
RT stress reveals novel small ubiquitin-like modified target proteins and
RT acceptor lysines relevant for genome stability.";
RL Mol. Cell. Proteomics 14:1419-1434(2015).
RN [35]
RP INTERACTION WITH NUP93 AND IPO7.
RX PubMed=26878725; DOI=10.1038/ng.3512;
RA Braun D.A., Sadowski C.E., Kohl S., Lovric S., Astrinidis S.A., Pabst W.L.,
RA Gee H.Y., Ashraf S., Lawson J.A., Shril S., Airik M., Tan W., Schapiro D.,
RA Rao J., Choi W.I., Hermle T., Kemper M.J., Pohl M., Ozaltin F., Konrad M.,
RA Bogdanovic R., Buescher R., Helmchen U., Serdaroglu E., Lifton R.P.,
RA Antonin W., Hildebrandt F.;
RT "Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-
RT resistant nephrotic syndrome.";
RL Nat. Genet. 48:457-465(2016).
RN [36]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-113, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
RX PubMed=9214508; DOI=10.1038/40431;
RA Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P.;
RT "A structural basis for mutational inactivation of the tumour suppressor
RT Smad4.";
RL Nature 388:87-93(1997).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
RX PubMed=10647180; DOI=10.1016/s0969-2126(00)88340-9;
RA Qin B., Lam S.S., Lin K.;
RT "Crystal structure of a transcriptionally active Smad4 fragment.";
RL Structure 7:1493-1503(1999).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552 OF WILD TYPE AND MUTANTS
RP ARG-416; ARG-502 AND ARG-515 IN COMPLEX WITH SMAD3, SUBUNIT, AND
RP MUTAGENESIS OF ARG-416; ARG-502 AND ARG-515.
RX PubMed=11224571; DOI=10.1038/84995;
RA Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K.;
RT "The L3 loop and C-terminal phosphorylation jointly define Smad protein
RT trimerization.";
RL Nat. Struct. Biol. 8:248-253(2001).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 314-552 IN COMPLEX WITH SMAD2 OR
RP SMAD3, 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 [41]
RP VARIANT JPS CYS-361.
RX PubMed=9811934; DOI=10.1093/hmg/7.12.1907;
RA Houlston R., Bevan S., Williams A., Young J., Dunlop M., Rozen P., Eng C.,
RA Markie D., Woodford-Richens K., Rodriguez-Bigas M.A., Leggett B., Neale K.,
RA Phillips R., Sheridan E., Hodgson S., Iwama T., Eccles D., Bodmer W.,
RA Tomlinson I.;
RT "Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only
RT account for a minority of cases.";
RL Hum. Mol. Genet. 7:1907-1912(1998).
RN [42]
RP VARIANTS JPS GLY-330 AND ARG-352.
RX PubMed=12417513; DOI=10.1007/bf02557528;
RA Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L.,
RA Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M.,
RA Vogelstein B., Howe J.R.;
RT "Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.";
RL Ann. Surg. Oncol. 9:901-906(2002).
RN [43]
RP VARIANTS JP/HHT ARG-352 AND ASP-386.
RX PubMed=15031030; DOI=10.1016/s0140-6736(04)15732-2;
RA Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L.,
RA Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A.;
RT "A combined syndrome of juvenile polyposis and hereditary haemorrhagic
RT telangiectasia associated with mutations in MADH4 (SMAD4).";
RL Lancet 363:852-859(2004).
RN [44]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361, AND
RP INVOLVEMENT IN COLORECTAL CANCER.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [45]
RP VARIANTS MYHRS THR-500 AND VAL-500.
RX PubMed=22243968; DOI=10.1016/j.ajhg.2011.12.011;
RA Caputo V., Cianetti L., Niceta M., Carta C., Ciolfi A., Bocchinfuso G.,
RA Carrani E., Dentici M.L., Biamino E., Belligni E., Garavelli L.,
RA Boccone L., Melis D., Andria G., Gelb B.D., Stella L., Silengo M.,
RA Dallapiccola B., Tartaglia M.;
RT "A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene
RT underlies Myhre syndrome.";
RL Am. J. Hum. Genet. 90:161-169(2012).
RN [46]
RP VARIANTS MYHRS MET-500; THR-500 AND VAL-500, AND CHARACTERIZATION OF
RP VARIANT MYHRS THR-500.
RX PubMed=22158539; DOI=10.1038/ng.1016;
RA Le Goff C., Mahaut C., Abhyankar A., Le Goff W., Serre V., Afenjar A.,
RA Destree A., di Rocco M., Heron D., Jacquemont S., Marlin S., Simon M.,
RA Tolmie J., Verloes A., Casanova J.L., Munnich A., Cormier-Daire V.;
RT "Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre
RT syndrome.";
RL Nat. Genet. 44:85-88(2012).
CC -!- FUNCTION: In muscle physiology, plays a central role in the balance
CC between atrophy and hypertrophy. When recruited by MSTN, promotes
CC atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4
CC release and subsequent recruitment by the BMP pathway to promote
CC hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with
CC SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-
CC specific gene expression. Binds to SMAD binding elements (SBEs) (5'-
CC GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating
CC regions (By similarity). Common SMAD (co-SMAD) is the coactivator and
CC mediator of signal transduction by TGF-beta (transforming growth
CC factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that
CC forms in the nucleus and is required for the TGF-mediated signaling
CC (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex
CC to DNA and provides an activation function required for SMAD1 or SMAD2
CC to stimulate transcription. Component of the multimeric
CC SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site;
CC required for synergistic transcriptional activity in response to TGF-
CC beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase
CC activity by stimulating its dissociation from the 14-3-3 protein YWHAQ
CC which acts as a negative regulator. {ECO:0000250,
CC ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:25514493,
CC ECO:0000269|PubMed:9389648}.
CC -!- SUBUNIT: Monomer; in the absence of TGF-beta activation
CC (PubMed:9670020). Heterotrimer; on TGF-beta activation
CC (PubMed:15799969). Heterotrimer composed of two molecules of a C-
CC terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one
CC molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4
CC complex (PubMed:15799969, PubMed:15350224). Found in a ternary complex
CC composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with
CC SMAD1 and YY1 (By similarity). Identified in a complex that contains at
CC least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with
CC ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33.
CC Associates with ZNF423 or ZNF521 in response to BMP2 leading to
CC activate transcription of BMP target genes. Interacts with USP9X.
CC Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with
CC WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2.
CC Interacts with PDPK1 (via PH domain) (By similarity). Interacts with
CC VPS39; this interaction affects heterodimer formation with SMAD3, but
CC not with SMAD2, and leads to inhibition of SMAD3-dependent
CC transcription activation. Interactions with VPS39 and SMAD2 may be
CC mutually exclusive. Interacts (via MH2 domain) with ZNF451 (via N-
CC terminal zinc-finger domains) (PubMed:24324267). Interacts with ZC3H3
CC (By similarity). Interacts weakly with ZNF8 (PubMed:12370310).
CC Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus
CC through the NPC upon BMP7 stimulation resulting in activation of SMAD4
CC signaling (PubMed:26878725). Interacts with CREB3L1, the interaction
CC takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator
CC to induce the expression of genes involved in the assembly of collagen
CC extracellular matrix (PubMed:25310401). Interacts with DLX1
CC (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and
CC stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the
CC recruitment of this transcriptional coactivator is negatively regulated
CC by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with
CC this transcriptional coactivator is negatively regulated by ZBTB7A
CC (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts
CC (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta
CC signaling pathway increases the activity of the SMAD3/SMAD4
CC transcriptional complex (PubMed:16777850).
CC {ECO:0000250|UniProtKB:O70437, ECO:0000250|UniProtKB:P97471,
CC ECO:0000269|PubMed:10660046, ECO:0000269|PubMed:11224571,
CC ECO:0000269|PubMed:11741830, ECO:0000269|PubMed:11818334,
CC ECO:0000269|PubMed:12370310, ECO:0000269|PubMed:12941698,
CC ECO:0000269|PubMed:14525983, ECO:0000269|PubMed:14630787,
CC ECO:0000269|PubMed:14671321, ECO:0000269|PubMed:15350224,
CC ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:15820681,
CC ECO:0000269|PubMed:16777850, ECO:0000269|PubMed:17099224,
CC ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:18568018,
CC ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:24324267,
CC ECO:0000269|PubMed:25310401, ECO:0000269|PubMed:25514493,
CC ECO:0000269|PubMed:26878725, ECO:0000269|PubMed:9670020,
CC ECO:0000269|PubMed:9707553}.
CC -!- INTERACTION:
CC Q13485; P05067: APP; NbExp=3; IntAct=EBI-347263, EBI-77613;
CC Q13485; Q9Y297: BTRC; NbExp=2; IntAct=EBI-347263, EBI-307461;
CC Q13485; Q9UI36: DACH1; NbExp=3; IntAct=EBI-347263, EBI-347111;
CC Q13485; Q9NPI6: DCP1A; NbExp=5; IntAct=EBI-347263, EBI-374238;
CC Q13485; Q92988: DLX4; NbExp=5; IntAct=EBI-347263, EBI-1752755;
CC Q13485; P43268-3: ETV4; NbExp=3; IntAct=EBI-347263, EBI-12130722;
CC Q13485; Q01844: EWSR1; NbExp=3; IntAct=EBI-347263, EBI-739737;
CC Q13485; O43524: FOXO3; NbExp=9; IntAct=EBI-347263, EBI-1644164;
CC Q13485; P98177: FOXO4; NbExp=2; IntAct=EBI-347263, EBI-4481939;
CC Q13485; P23769: GATA2; NbExp=5; IntAct=EBI-347263, EBI-2806671;
CC Q13485; P61968: LMO4; NbExp=8; IntAct=EBI-347263, EBI-2798728;
CC Q13485; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-347263, EBI-10271199;
CC Q13485; Q9UBE8: NLK; NbExp=6; IntAct=EBI-347263, EBI-366978;
CC Q13485; P24468: NR2F2; NbExp=4; IntAct=EBI-347263, EBI-2795198;
CC Q13485; Q8WWW0: RASSF5; NbExp=5; IntAct=EBI-347263, EBI-367390;
CC Q13485; P12755: SKI; NbExp=13; IntAct=EBI-347263, EBI-347281;
CC Q13485; P12757: SKIL; NbExp=3; IntAct=EBI-347263, EBI-2902468;
CC Q13485; Q15797: SMAD1; NbExp=12; IntAct=EBI-347263, EBI-1567153;
CC Q13485; Q15796: SMAD2; NbExp=21; IntAct=EBI-347263, EBI-1040141;
CC Q13485; P84022: SMAD3; NbExp=35; IntAct=EBI-347263, EBI-347161;
CC Q13485; Q13485: SMAD4; NbExp=3; IntAct=EBI-347263, EBI-347263;
CC Q13485; O15198: SMAD9; NbExp=4; IntAct=EBI-347263, EBI-748763;
CC Q13485; O15198-2: SMAD9; NbExp=3; IntAct=EBI-347263, EBI-12273450;
CC Q13485; P08047: SP1; NbExp=2; IntAct=EBI-347263, EBI-298336;
CC Q13485; Q08117-2: TLE5; NbExp=3; IntAct=EBI-347263, EBI-11741437;
CC Q13485; Q9UPN9: TRIM33; NbExp=6; IntAct=EBI-347263, EBI-2214398;
CC Q13485; P63279: UBE2I; NbExp=6; IntAct=EBI-347263, EBI-80168;
CC Q13485; Q93008: USP9X; NbExp=2; IntAct=EBI-347263, EBI-302524;
CC Q13485; Q15915: ZIC1; NbExp=3; IntAct=EBI-347263, EBI-11963196;
CC Q13485; P70056: foxh1; Xeno; NbExp=2; IntAct=EBI-347263, EBI-9969973;
CC Q13485; P70398: Usp9x; Xeno; NbExp=4; IntAct=EBI-347263, EBI-2214043;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15799969,
CC ECO:0000269|PubMed:17327236}. Nucleus {ECO:0000269|PubMed:15799969}.
CC Note=Cytoplasmic in the absence of ligand. Migrates to the nucleus when
CC complexed with R-SMAD (PubMed:15799969). PDPK1 prevents its nuclear
CC translocation in response to TGF-beta (PubMed:17327236).
CC {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236}.
CC -!- DOMAIN: The MH1 domain is required for DNA binding.
CC -!- DOMAIN: The MH2 domain is required for both homomeric and heteromeric
CC interactions and for transcriptional regulation. Sufficient for nuclear
CC import.
CC -!- PTM: Phosphorylated by PDPK1. {ECO:0000269|PubMed:17327236}.
CC -!- PTM: Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase
CC TRIM33. Monoubiquitination hampers its ability to form a stable complex
CC with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP
CC signaling cascade. Deubiquitination by USP9X restores its competence to
CC mediate TGF-beta signaling. {ECO:0000269|PubMed:19135894}.
CC -!- DISEASE: Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of
CC the pancreas. Tumors can arise from both the exocrine and endocrine
CC portions of the pancreas, but 95% of them develop from the exocrine
CC portion, including the ductal epithelium, acinar cells, connective
CC tissue, and lymphatic tissue. {ECO:0000269|PubMed:8553070}. Note=The
CC gene represented in this entry may be involved in disease pathogenesis.
CC -!- DISEASE: Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal
CC dominant gastrointestinal hamartomatous polyposis syndrome in which
CC patients are at risk for developing gastrointestinal cancers. The
CC lesions are typified by a smooth histological appearance, predominant
CC stroma, cystic spaces and lack of a smooth muscle core. Multiple
CC juvenile polyps usually occur in a number of Mendelian disorders.
CC Sometimes, these polyps occur without associated features as in JPS;
CC here, polyps tend to occur in the large bowel and are associated with
CC an increased risk of colon and other gastrointestinal cancers.
CC {ECO:0000269|PubMed:12417513, ECO:0000269|PubMed:9811934}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Juvenile polyposis/hereditary hemorrhagic telangiectasia
CC syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of
CC the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic
CC telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT
CC are autosomal dominant disorders with distinct and non-overlapping
CC clinical features. The former, an inherited gastrointestinal malignancy
CC predisposition, is caused by mutations in SMAD4 or BMPR1A, and the
CC latter is a vascular malformation disorder caused by mutations in ENG
CC or ACVRL1. All four genes encode proteins involved in the transforming-
CC growth-factor-signaling pathway. Although there are reports of patients
CC and families with phenotypes of both disorders combined, the genetic
CC etiology of this association is unknown. {ECO:0000269|PubMed:15031030}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of the
CC large intestine (the colon) and the rectum. Genetic alterations are
CC often associated with progression from premalignant lesion (adenoma) to
CC invasive adenocarcinoma. Risk factors for cancer of the colon and
CC rectum include colon polyps, long-standing ulcerative colitis, and
CC genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease
CC may be caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Note=SMAD4 variants may be associated with susceptibility to
CC pulmonary hypertension, a disorder characterized by plexiform lesions
CC of proliferating endothelial cells in pulmonary arterioles. The lesions
CC lead to elevated pulmonary arterial pression, right ventricular
CC failure, and death. The disease can occur from infancy throughout life
CC and it has a mean age at onset of 36 years. Penetrance is reduced.
CC Although familial pulmonary hypertension is rare, cases secondary to
CC known etiologies are more common and include those associated with the
CC appetite-suppressant drugs. {ECO:0000269|PubMed:21898662}.
CC -!- DISEASE: Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized
CC by pre- and postnatal growth deficiency, intellectual disability,
CC generalized muscle hypertrophy and striking muscular build, decreased
CC joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial
CC features include microcephaly, midface hypoplasia, prognathism, and
CC blepharophimosis. Typical skeletal anomalies are short stature, square
CC body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened
CC vertebrae, and thickened calvaria. Other features, such as congenital
CC heart disease, may also occur. {ECO:0000269|PubMed:22158539,
CC ECO:0000269|PubMed:22243968}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SMAD4ID371.html";
CC -!- WEB RESOURCE: Name=Mendelian genes SMAD family member 4 (SMAD4);
CC Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/SMAD4";
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DR EMBL; AF045447; AAC03051.1; -; Genomic_DNA.
DR EMBL; AF045438; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045439; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045440; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045441; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045442; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045443; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045444; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045445; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; AF045446; AAC03051.1; JOINED; Genomic_DNA.
DR EMBL; U44378; AAA91041.1; -; mRNA.
DR EMBL; AK290770; BAF83459.1; -; mRNA.
DR EMBL; CH471096; EAW62985.1; -; Genomic_DNA.
DR EMBL; BC002379; AAH02379.1; -; mRNA.
DR CCDS; CCDS11950.1; -.
DR PIR; S71811; S71811.
DR RefSeq; NP_005350.1; NM_005359.5.
DR PDB; 1DD1; X-ray; 2.62 A; A/B/C=285-552.
DR PDB; 1G88; X-ray; 3.00 A; A/B/C=285-552.
DR PDB; 1MR1; X-ray; 2.85 A; A/B=319-552.
DR PDB; 1U7F; X-ray; 2.60 A; B=314-552.
DR PDB; 1U7V; X-ray; 2.70 A; B=314-549.
DR PDB; 1YGS; X-ray; 2.10 A; A=319-552.
DR PDB; 5C4V; X-ray; 2.60 A; A/C/E=314-549.
DR PDB; 5MEY; X-ray; 2.05 A; A=10-140.
DR PDB; 5MEZ; X-ray; 2.98 A; A/B=10-140.
DR PDB; 5MF0; X-ray; 3.03 A; A/B=10-140.
DR PDB; 5UWU; X-ray; 2.24 A; D=133-149.
DR PDB; 6YIC; X-ray; 1.60 A; P=398-406.
DR PDBsum; 1DD1; -.
DR PDBsum; 1G88; -.
DR PDBsum; 1MR1; -.
DR PDBsum; 1U7F; -.
DR PDBsum; 1U7V; -.
DR PDBsum; 1YGS; -.
DR PDBsum; 5C4V; -.
DR PDBsum; 5MEY; -.
DR PDBsum; 5MEZ; -.
DR PDBsum; 5MF0; -.
DR PDBsum; 5UWU; -.
DR PDBsum; 6YIC; -.
DR AlphaFoldDB; Q13485; -.
DR SASBDB; Q13485; -.
DR SMR; Q13485; -.
DR BioGRID; 110264; 503.
DR ComplexPortal; CPX-1; SMAD2-SMAD3-SMAD4 complex.
DR ComplexPortal; CPX-3208; SMAD2-SMAD4 complex.
DR ComplexPortal; CPX-3252; SMAD3-SMAD4 complex.
DR ComplexPortal; CPX-54; SMAD1-SMAD4 complex.
DR CORUM; Q13485; -.
DR DIP; DIP-31512N; -.
DR IntAct; Q13485; 128.
DR MINT; Q13485; -.
DR STRING; 9606.ENSP00000341551; -.
DR GlyGen; Q13485; 5 sites, 1 O-linked glycan (5 sites).
DR iPTMnet; Q13485; -.
DR MetOSite; Q13485; -.
DR PhosphoSitePlus; Q13485; -.
DR SwissPalm; Q13485; -.
DR BioMuta; SMAD4; -.
DR DMDM; 13959561; -.
DR CPTAC; CPTAC-1268; -.
DR CPTAC; CPTAC-1269; -.
DR EPD; Q13485; -.
DR jPOST; Q13485; -.
DR MassIVE; Q13485; -.
DR MaxQB; Q13485; -.
DR PaxDb; Q13485; -.
DR PeptideAtlas; Q13485; -.
DR PRIDE; Q13485; -.
DR ProteomicsDB; 59479; -.
DR Antibodypedia; 3711; 1102 antibodies from 45 providers.
DR DNASU; 4089; -.
DR Ensembl; ENST00000342988.8; ENSP00000341551.3; ENSG00000141646.15.
DR Ensembl; ENST00000398417.6; ENSP00000381452.1; ENSG00000141646.15.
DR GeneID; 4089; -.
DR KEGG; hsa:4089; -.
DR MANE-Select; ENST00000342988.8; ENSP00000341551.3; NM_005359.6; NP_005350.1.
DR UCSC; uc010xdp.3; human.
DR CTD; 4089; -.
DR DisGeNET; 4089; -.
DR GeneCards; SMAD4; -.
DR GeneReviews; SMAD4; -.
DR HGNC; HGNC:6770; SMAD4.
DR HPA; ENSG00000141646; Low tissue specificity.
DR MalaCards; SMAD4; -.
DR MIM; 114500; phenotype.
DR MIM; 139210; phenotype.
DR MIM; 174900; phenotype.
DR MIM; 175050; phenotype.
DR MIM; 260350; phenotype.
DR MIM; 600993; gene.
DR neXtProt; NX_Q13485; -.
DR OpenTargets; ENSG00000141646; -.
DR Orphanet; 1333; Familial pancreatic carcinoma.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR Orphanet; 329971; Generalized juvenile polyposis/juvenile polyposis coli.
DR Orphanet; 774; Hereditary hemorrhagic telangiectasia.
DR Orphanet; 2588; Myhre syndrome.
DR PharmGKB; PA30527; -.
DR VEuPathDB; HostDB:ENSG00000141646; -.
DR eggNOG; KOG3701; Eukaryota.
DR GeneTree; ENSGT00940000157435; -.
DR InParanoid; Q13485; -.
DR OMA; CWIEVQI; -.
DR OrthoDB; 905048at2759; -.
DR PhylomeDB; Q13485; -.
DR TreeFam; TF314923; -.
DR PathwayCommons; Q13485; -.
DR Reactome; R-HSA-1181150; Signaling by NODAL.
DR Reactome; R-HSA-1502540; Signaling by Activin.
DR Reactome; R-HSA-201451; Signaling by BMP.
DR Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs.
DR Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-HSA-2173796; SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
DR Reactome; R-HSA-3311021; SMAD4 MH2 Domain Mutants in Cancer.
DR Reactome; R-HSA-3315487; SMAD2/3 MH2 Domain Mutants in Cancer.
DR Reactome; R-HSA-452723; Transcriptional regulation of pluripotent stem cells.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-8941326; RUNX2 regulates bone development.
DR Reactome; R-HSA-8941855; RUNX3 regulates CDKN1A transcription.
DR Reactome; R-HSA-8952158; RUNX3 regulates BCL2L11 (BIM) transcription.
DR Reactome; R-HSA-9615017; FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes.
DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes.
DR SignaLink; Q13485; -.
DR SIGNOR; Q13485; -.
DR BioGRID-ORCS; 4089; 75 hits in 1117 CRISPR screens.
DR ChiTaRS; SMAD4; human.
DR EvolutionaryTrace; Q13485; -.
DR GeneWiki; Mothers_against_decapentaplegic_homolog_4; -.
DR GenomeRNAi; 4089; -.
DR Pharos; Q13485; Tbio.
DR PRO; PR:Q13485; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q13485; protein.
DR Bgee; ENSG00000141646; Expressed in ventricular zone and 196 other tissues.
DR ExpressionAtlas; Q13485; baseline and differential.
DR Genevisible; Q13485; HS.
DR GO; GO:0032444; C:activin responsive factor complex; IDA:BHF-UCL.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0071144; C:heteromeric SMAD protein complex; IPI:ComplexPortal.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0071141; C:SMAD protein complex; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IDA:BHF-UCL.
DR GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR GO; GO:0005518; F:collagen binding; IEA:Ensembl.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:GO_Central.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0031005; F:filamin binding; IEA:Ensembl.
DR GO; GO:0070411; F:I-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
DR GO; GO:0070412; F:R-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IEA:Ensembl.
DR GO; GO:0043199; F:sulfate binding; IMP:CAFA.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:BHF-UCL.
DR GO; GO:0001223; F:transcription coactivator binding; IPI:UniProtKB.
DR GO; GO:0032924; P:activin receptor signaling pathway; IC:ComplexPortal.
DR GO; GO:0030325; P:adrenal gland development; IEA:Ensembl.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0036302; P:atrioventricular canal development; ISS:BHF-UCL.
DR GO; GO:0003190; P:atrioventricular valve formation; ISS:BHF-UCL.
DR GO; GO:0007411; P:axon guidance; IEA:Ensembl.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0003360; P:brainstem development; IEA:Ensembl.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IEA:Ensembl.
DR GO; GO:0003161; P:cardiac conduction system development; NAS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0006879; P:cellular iron ion homeostasis; ISS:BHF-UCL.
DR GO; GO:0071773; P:cellular response to BMP stimulus; NAS:BHF-UCL.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0048589; P:developmental growth; IEA:Ensembl.
DR GO; GO:0042733; P:embryonic digit morphogenesis; IEA:Ensembl.
DR GO; GO:0060956; P:endocardial cell differentiation; ISS:BHF-UCL.
DR GO; GO:0042118; P:endothelial cell activation; IEA:Ensembl.
DR GO; GO:0003198; P:epithelial to mesenchymal transition involved in endocardial cushion formation; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0061040; P:female gonad morphogenesis; IEA:Ensembl.
DR GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
DR GO; GO:0001702; P:gastrulation with mouth forming second; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:BHF-UCL.
DR GO; GO:0035556; P:intracellular signal transduction; IMP:CACAO.
DR GO; GO:0003220; P:left ventricular cardiac muscle tissue morphogenesis; ISS:BHF-UCL.
DR GO; GO:0048382; P:mesendoderm development; IEA:Ensembl.
DR GO; GO:0072133; P:metanephric mesenchyme morphogenesis; IEA:Ensembl.
DR GO; GO:0010614; P:negative regulation of cardiac muscle hypertrophy; ISS:BHF-UCL.
DR GO; GO:1905305; P:negative regulation of cardiac myofibril assembly; ISS:BHF-UCL.
DR GO; GO:0060548; P:negative regulation of cell death; IEA:Ensembl.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR GO; GO:0072134; P:nephrogenic mesenchyme morphogenesis; IEA:Ensembl.
DR GO; GO:0014033; P:neural crest cell differentiation; IEA:Ensembl.
DR GO; GO:0048663; P:neuron fate commitment; IEA:Ensembl.
DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0003148; P:outflow tract septum morphogenesis; ISS:BHF-UCL.
DR GO; GO:0001541; P:ovarian follicle development; IEA:Ensembl.
DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IMP:BHF-UCL.
DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0003251; P:positive regulation of cell proliferation involved in heart valve morphogenesis; ISS:BHF-UCL.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:BHF-UCL.
DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IEA:Ensembl.
DR GO; GO:0051571; P:positive regulation of histone H3-K4 methylation; ISS:BHF-UCL.
DR GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; ISS:BHF-UCL.
DR GO; GO:0033686; P:positive regulation of luteinizing hormone secretion; IEA:Ensembl.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IEA:Ensembl.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; ISS:BHF-UCL.
DR GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:GO_Central.
DR GO; GO:1901522; P:positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus; TAS:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0051098; P:regulation of binding; IEA:Ensembl.
DR GO; GO:0051797; P:regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL.
DR GO; GO:0001666; P:response to hypoxia; IMP:BHF-UCL.
DR GO; GO:0071559; P:response to transforming growth factor beta; IDA:UniProtKB.
DR GO; GO:0048733; P:sebaceous gland development; IEA:Ensembl.
DR GO; GO:0062009; P:secondary palate development; ISS:BHF-UCL.
DR GO; GO:0072520; P:seminiferous tubule development; IEA:Ensembl.
DR GO; GO:0007338; P:single fertilization; IEA:Ensembl.
DR GO; GO:0007183; P:SMAD protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0032525; P:somite rostral/caudal axis specification; IEA:Ensembl.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-templated; IDA:ComplexPortal.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0060065; P:uterus development; IEA:Ensembl.
DR GO; GO:0060412; P:ventricular septum morphogenesis; ISS:BHF-UCL.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR DisProt; DP00464; -.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR IDEAL; IID00132; -.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR001132; SMAD_dom_Dwarfin-type.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036578; SMAD_MH1_sf.
DR PANTHER; PTHR13703; PTHR13703; 1.
DR Pfam; PF03165; MH1; 1.
DR Pfam; PF03166; MH2; 1.
DR SMART; SM00523; DWA; 1.
DR SMART; SM00524; DWB; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 1.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Disease variant; DNA-binding;
KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc.
FT CHAIN 1..552
FT /note="Mothers against decapentaplegic homolog 4"
FT /id="PRO_0000090861"
FT DOMAIN 18..142
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 323..552
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 1..322
FT /note="Mediates interaction with ZBTB7A"
FT /evidence="ECO:0000269|PubMed:25514493"
FT REGION 168..194
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 236..256
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 275..320
FT /note="SAD"
FT COMPBIAS 171..194
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 238..256
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 71
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 115
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 127
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT SITE 515
FT /note="Necessary for heterotrimerization"
FT MOD_RES 37
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 428
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 507
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT CROSSLNK 113
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:25218447,
FT ECO:0007744|PubMed:25755297, ECO:0007744|PubMed:28112733"
FT CROSSLNK 519
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:19135894"
FT VARIANT 13
FT /note="N -> S (rare variant; found in a patient with
FT pulmonary hypertension; unknown pathological significance;
FT dbSNP:rs281875323)"
FT /evidence="ECO:0000269|PubMed:21898662"
FT /id="VAR_066870"
FT VARIANT 130
FT /note="P -> S (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs1555685186)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036475"
FT VARIANT 330
FT /note="E -> G (in JPS; dbSNP:rs281875324)"
FT /evidence="ECO:0000269|PubMed:12417513"
FT /id="VAR_022833"
FT VARIANT 351
FT /note="D -> N (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs1057519739)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036476"
FT VARIANT 352
FT /note="G -> R (in JP/HHT and JPS; dbSNP:rs121912581)"
FT /evidence="ECO:0000269|PubMed:12417513,
FT ECO:0000269|PubMed:15031030"
FT /id="VAR_019571"
FT VARIANT 361
FT /note="R -> C (in JPS; dbSNP:rs80338963)"
FT /evidence="ECO:0000269|PubMed:9811934"
FT /id="VAR_019572"
FT VARIANT 361
FT /note="R -> H (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs377767347)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036477"
FT VARIANT 386
FT /note="G -> D (in JP/HHT; dbSNP:rs121912580)"
FT /evidence="ECO:0000269|PubMed:15031030"
FT /id="VAR_019573"
FT VARIANT 493
FT /note="D -> H (in pancreatic carcinoma; dbSNP:rs121912578)"
FT /evidence="ECO:0000269|PubMed:8553070"
FT /id="VAR_011380"
FT VARIANT 500
FT /note="I -> M (in MYHRS; dbSNP:rs281875320)"
FT /evidence="ECO:0000269|PubMed:22158539"
FT /id="VAR_067602"
FT VARIANT 500
FT /note="I -> T (in MYHRS; there is an enhanced levels of
FT SMAD4 protein with lower levels of ubiquitinated SMAD4
FT fibroblasts compared to controls suggesting stabilization
FT of the mutant protein; 8-fold increase in phosphorylated
FT SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1,
FT SMAD5 and SMAD8 in cell nuclei compared to controls;
FT dbSNP:rs281875321)"
FT /evidence="ECO:0000269|PubMed:22158539,
FT ECO:0000269|PubMed:22243968"
FT /id="VAR_067603"
FT VARIANT 500
FT /note="I -> V (in MYHRS; dbSNP:rs281875322)"
FT /evidence="ECO:0000269|PubMed:22158539,
FT ECO:0000269|PubMed:22243968"
FT /id="VAR_067604"
FT MUTAGEN 416
FT /note="R->S: No effect on heterotrimerization. Partially
FT diminished transcriptional activation."
FT /evidence="ECO:0000269|PubMed:11224571"
FT MUTAGEN 496
FT /note="R->S: No effect on heterotrimerization. Partially
FT diminished transcriptional activation."
FT MUTAGEN 502
FT /note="R->S: No effect on heterotrimerization. Greatly
FT reduced transcriptional activation."
FT /evidence="ECO:0000269|PubMed:11224571"
FT MUTAGEN 515
FT /note="R->S: Reduced heterotrimerization."
FT /evidence="ECO:0000269|PubMed:11224571"
FT MUTAGEN 519
FT /note="K->R: Abolishes ubiquitination."
FT /evidence="ECO:0000269|PubMed:19135894"
FT HELIX 16..24
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 29..31
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 33..47
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 51..62
FT /evidence="ECO:0007829|PDB:5MEY"
FT TURN 63..65
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 73..75
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 78..80
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 82..84
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 87..89
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 91..99
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 109..111
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 119..121
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 124..127
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 130..132
FT /evidence="ECO:0007829|PDB:5MEY"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:5MEY"
FT HELIX 143..145
FT /evidence="ECO:0007829|PDB:5UWU"
FT STRAND 288..291
FT /evidence="ECO:0007829|PDB:1DD1"
FT STRAND 321..330
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 333..342
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 346..353
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 359..363
FT /evidence="ECO:0007829|PDB:1YGS"
FT HELIX 364..366
FT /evidence="ECO:0007829|PDB:1U7F"
FT HELIX 374..380
FT /evidence="ECO:0007829|PDB:1YGS"
FT TURN 381..385
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 387..392
FT /evidence="ECO:0007829|PDB:1YGS"
FT TURN 393..395
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 396..401
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 403..405
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 407..410
FT /evidence="ECO:0007829|PDB:1YGS"
FT HELIX 412..416
FT /evidence="ECO:0007829|PDB:1YGS"
FT TURN 417..419
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 427..429
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 434..438
FT /evidence="ECO:0007829|PDB:1YGS"
FT HELIX 440..454
FT /evidence="ECO:0007829|PDB:1YGS"
FT TURN 455..458
FT /evidence="ECO:0007829|PDB:1DD1"
FT HELIX 461..464
FT /evidence="ECO:0007829|PDB:1DD1"
FT HELIX 493..497
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 500..506
FT /evidence="ECO:0007829|PDB:1YGS"
FT HELIX 518..520
FT /evidence="ECO:0007829|PDB:1YGS"
FT STRAND 521..529
FT /evidence="ECO:0007829|PDB:1YGS"
FT HELIX 530..541
FT /evidence="ECO:0007829|PDB:1YGS"
SQ 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
