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 27-MAR-2024, entry version 247. 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 TSC22D1. RX PubMed=15881652; DOI=10.1007/s11010-005-3456-7; RA Choi S.J., Moon J.H., Ahn Y.W., Ahn J.H., Kim D.U., Han T.H.; RT "Tsc-22 enhances TGF-beta signaling by associating with Smad4 and induces RT erythroid cell differentiation."; RL Mol. Cell. Biochem. 271:23-28(2005). RN [22] 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 [23] 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 [24] 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 [25] 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 [26] 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 [27] 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 [28] 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 [29] 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 [30] 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 [31] 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 [32] 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 [33] 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 [34] 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 [35] 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 [36] 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 [37] 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 [38] 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 [39] 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 [40] 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-496; 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 [41] 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 [42] 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 [43] 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 [44] 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 [45] 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 [46] 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 [47] 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 a CREB3L1 CC coactivator to induce the expression of genes involved in the assembly CC of collagen 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). Interacts (via N-terminus) CC with TSC22D1 (PubMed:15881652). {ECO:0000250|UniProtKB:O70437, CC ECO:0000250|UniProtKB:P97471, ECO:0000269|PubMed:10660046, CC ECO:0000269|PubMed:11224571, ECO:0000269|PubMed:11741830, CC ECO:0000269|PubMed:11818334, ECO:0000269|PubMed:12370310, CC ECO:0000269|PubMed:12941698, ECO:0000269|PubMed:14525983, CC ECO:0000269|PubMed:14630787, ECO:0000269|PubMed:14671321, CC ECO:0000269|PubMed:15350224, ECO:0000269|PubMed:15799969, CC ECO:0000269|PubMed:15820681, ECO:0000269|PubMed:15881652, 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=22; 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]: An autosomal dominant CC syndrome characterized by pre- and postnatal growth deficiency, CC intellectual disability, generalized muscle hypertrophy and striking CC muscular build, decreased joint mobility, cryptorchidism, and unusual CC facies. Dysmorphic facial features include microcephaly, midface CC hypoplasia, prognathism, and blepharophimosis. Typical skeletal CC anomalies are short stature, square body shape, broad ribs, iliac CC hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. CC Other features, such as congenital heart disease, may also occur. CC {ECO:0000269|PubMed:22158539, ECO:0000269|PubMed:22243968}. Note=The CC disease is caused by variants affecting the gene represented in this CC 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="https://atlasgeneticsoncology.org/gene/371/SMAD4"; 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"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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; 522. 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 GlyCosmos; Q13485; 5 sites, 1 glycan. DR GlyGen; Q13485; 9 sites, 1 O-linked glycan (9 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; 9606-ENSP00000341551; -. DR PeptideAtlas; Q13485; -. DR ProteomicsDB; 59479; -. DR Pumba; Q13485; -. DR Antibodypedia; 3711; 1272 antibodies from 45 providers. DR DNASU; 4089; -. DR Ensembl; ENST00000342988.8; ENSP00000341551.3; ENSG00000141646.16. DR Ensembl; ENST00000398417.6; ENSP00000381452.1; ENSG00000141646.16. DR Ensembl; ENST00000588860.6; ENSP00000465878.2; ENSG00000141646.16. DR Ensembl; ENST00000589076.6; ENSP00000466934.2; ENSG00000141646.16. DR Ensembl; ENST00000589941.2; ENSP00000465874.2; ENSG00000141646.16. DR Ensembl; ENST00000590061.2; ENSP00000464772.2; ENSG00000141646.16. 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 AGR; HGNC:6770; -. 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; 5395671at2759; -. 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 Reactome; R-HSA-9733709; Cardiogenesis. DR Reactome; R-HSA-9735871; SARS-CoV-1 targets host intracellular signalling and regulatory pathways. DR Reactome; R-HSA-9754189; Germ layer formation at gastrulation. DR Reactome; R-HSA-9823730; Formation of definitive endoderm. DR SignaLink; Q13485; -. DR SIGNOR; Q13485; -. DR BioGRID-ORCS; 4089; 81 hits in 1216 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 198 other cell types or tissues. DR ExpressionAtlas; Q13485; baseline and differential. 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:0003700; F:DNA-binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO: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:0043565; F:sequence-specific DNA binding; IDA:BHF-UCL. 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:0001222; F:transcription corepressor binding; IPI:HGNC-UCL. DR GO; GO:0032924; P:activin receptor signaling pathway; NAS:ComplexPortal. DR GO; GO:0030325; P:adrenal gland development; 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:0014898; P:cardiac muscle hypertrophy in response to stress; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl. 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:0071560; P:cellular response to transforming growth factor beta stimulus; IMP:BHF-UCL. DR GO; GO:0048589; P:developmental growth; IEA:Ensembl. DR GO; GO:0006351; P:DNA-templated transcription; IDA:ComplexPortal. 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:0010631; P:epithelial cell migration; IMP:BHF-UCL. DR GO; GO:0001837; P:epithelial to mesenchymal transition; IMP:BHF-UCL. 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:0097191; P:extrinsic apoptotic signaling pathway; IMP:BHF-UCL. 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:0006879; P:intracellular iron ion homeostasis; 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:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:BHF-UCL. 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: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:0045892; P:negative regulation of DNA-templated transcription; IDA:BHF-UCL. 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:0072134; P:nephrogenic mesenchyme morphogenesis; IEA:Ensembl. DR GO; GO:0014033; P:neural crest cell differentiation; IEA:Ensembl. DR GO; GO:0048665; P:neuron fate specification; IMP:BHF-UCL. 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: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:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:BHF-UCL. DR GO; GO:1901203; P:positive regulation of extracellular matrix assembly; IMP:BHF-UCL. DR GO; GO:0046881; P:positive regulation of follicle-stimulating hormone secretion; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP: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: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:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0006355; P:regulation of DNA-templated transcription; NAS:ComplexPortal. DR GO; GO:0051797; P:regulation of hair follicle development; IEA:Ensembl. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. 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: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: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 CDD; cd10492; MH1_SMAD_4; 1. DR CDD; cd10498; MH2_SMAD_4; 1. DR DisProt; DP00464; -. DR Gene3D; 2.60.200.10; -; 1. DR Gene3D; 3.90.520.10; SMAD MH1 domain; 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:SF63; MOTHERS AGAINST DECAPENTAPLEGIC HOMOLOG 4; 1. DR PANTHER; PTHR13703; SMAD; 1. DR Pfam; PF03165; MH1; 1. DR Pfam; PF03166; MH2; 1. DR SMART; SM00523; DWA; 1. DR SMART; SM00524; DWB; 1. DR SUPFAM; SSF56366; SMAD MH1 domain; 1. DR SUPFAM; SSF49879; SMAD/FHA domain; 1. DR PROSITE; PS51075; MH1; 1. DR PROSITE; PS51076; MH2; 1. DR Genevisible; Q13485; HS. 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 44..69 FT /note="Required for interaction with TSC22D1" FT /evidence="ECO:0000269|PubMed:15881652" 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; uncertain 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 //