PDCD4_HUMAN
ID PDCD4_HUMAN Reviewed; 469 AA.
AC Q53EL6; B2RCV4; B5ME91; O15501; Q5VZS6; Q6PJI5; Q8TAR5; Q99834;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 2.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Programmed cell death protein 4;
DE AltName: Full=Neoplastic transformation inhibitor protein;
DE AltName: Full=Nuclear antigen H731-like;
DE AltName: Full=Protein 197/15a;
GN Name=PDCD4; Synonyms=H731;
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], AND VARIANT VAL-36.
RC TISSUE=Glial tumor;
RA Matsuhashi S., Yoshinaga H., Yatsuki H., Tsugita A., Hori K.;
RT "Isolation of a novel gene from a human cell line with Pr-28 MAb which
RT recognizes a nuclear antigen involved in the cell cycle.";
RL Res. Commun. Biochem. Cell Mol. Biol. 1:109-120(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION, AND VARIANT VAL-36.
RC TISSUE=Blood;
RX PubMed=9759869;
RA Azzoni L., Zatsepina O., Abebe B., Bennett I.M., Kanakaraj P., Perussia B.;
RT "Differential transcriptional regulation of CD161 and a novel gene,
RT 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells.";
RL J. Immunol. 161:3493-3500(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT VAL-36.
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-36.
RC TISSUE=Spleen;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS VAL-36 AND
RP TYR-48.
RC TISSUE=Brain, and Skin;
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 SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=10632927; DOI=10.1046/j.1440-1827.1999.00995.x;
RA Yoshinaga H., Matsuhashi S., Fujiyama C., Masaki Z.;
RT "Novel human PDCD4 (H731) gene expressed in proliferative cells is
RT expressed in the small duct epithelial cells of the breast as revealed by
RT an anti-H731 antibody.";
RL Pathol. Int. 49:1067-1077(1999).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=12898601; DOI=10.1002/path.1378;
RA Chen Y., Knosel T., Kristiansen G., Pietas A., Garber M.E., Matsuhashi S.,
RA Ozaki I., Petersen I.;
RT "Loss of PDCD4 expression in human lung cancer correlates with tumour
RT progression and prognosis.";
RL J. Pathol. 200:640-646(2003).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [10]
RP PHOSPHORYLATION AT SER-67 AND SER-457 BY PKB, FUNCTION, MUTAGENESIS OF
RP SER-67 AND SER-457, AND SUBCELLULAR LOCATION.
RX PubMed=16357133; DOI=10.1158/0008-5472.can-05-3469;
RA Palamarchuk A., Efanov A., Maximov V., Aqeilan R.I., Croce C.M.,
RA Pekarsky Y.;
RT "Akt phosphorylates and regulates Pdcd4 tumor suppressor protein.";
RL Cancer Res. 65:11282-11286(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-152, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [13]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16449643; DOI=10.1128/mcb.26.4.1297-1306.2006;
RA Yang H.-S., Matthews C.P., Clair T., Wang Q., Baker A.R., Li C.-C.,
RA Tan T.-H., Colburn N.H.;
RT "Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein
RT kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell
RT invasion.";
RL Mol. Cell. Biol. 26:1297-1306(2006).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [15]
RP FUNCTION, PHOSPHORYLATION AT SER-67 BY RPS6KB1, PHOSPHODEGRON MOTIF,
RP INTERACTION WITH BTRC AND FBXW11, UBIQUITINATION, IDENTIFICATION BY MASS
RP SPECTROMETRY, AND MUTAGENESIS OF SER-67; SER-71 AND SER-76.
RX PubMed=17053147; DOI=10.1126/science.1130276;
RA Dorrello N.V., Peschiaroli A., Guardavaccaro D., Colburn N.H.,
RA Sherman N.E., Pagano M.;
RT "S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein
RT translation and cell growth.";
RL Science 314:467-471(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-76; SER-78; SER-80 AND
RP SER-94, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-76; SER-78; SER-94 AND SER-457, VARIANT [LARGE SCALE
RP ANALYSIS] VAL-36, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
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 [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71; SER-76; SER-78; SER-313;
RP SER-317 AND SER-457, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-67; SER-68; SER-71; SER-76;
RP SER-78; SER-313 AND SER-317, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP 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 [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [24]
RP STRUCTURE BY NMR OF 320-450.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the MA3 domain of human programmed cell death 4.";
RL Submitted (APR-2007) to the PDB data bank.
RN [25]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 157-320, FUNCTION, DOMAIN,
RP INTERACTION WITH EIF4A, AND SUBUNIT.
RX PubMed=18296639; DOI=10.1073/pnas.0712235105;
RA Suzuki C., Garces R.G., Edmonds K.A., Hiller S., Hyberts S.G.,
RA Marintchev A., Wagner G.;
RT "PDCD4 inhibits translation initiation by binding to eIF4A using both its
RT MA3 domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3274-3279(2008).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 157-469, FUNCTION, INTERACTION
RP WITH EIF4A1 AND EIF4G, SUBUNIT, AND MUTAGENESIS OF GLU-174; GLU-210;
RP GLU-249; LEU-252; ASP-253; PRO-255; HIS-358; ASP-414; ASP-418 AND PRO-420.
RX PubMed=19153607; DOI=10.1038/emboj.2008.278;
RA Loh P.G., Yang H.S., Walsh M.A., Wang Q., Wang X., Cheng Z., Liu D.,
RA Song H.;
RT "Structural basis for translational inhibition by the tumour suppressor
RT Pdcd4.";
RL EMBO J. 28:274-285(2009).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 163-469 IN COMPLEX WITH EIF4A1,
RP FUNCTION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ASP-253; MET-333; GLU-337;
RP LEU-340; PHE-359 AND HIS-361.
RX PubMed=19204291; DOI=10.1073/pnas.0808275106;
RA Chang J.H., Cho Y.H., Sohn S.Y., Choi J.M., Kim A., Kim Y.C., Jang S.K.,
RA Cho Y.;
RT "Crystal structure of the eIF4A-PDCD4 complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:3148-3153(2009).
RN [28]
RP VARIANT [LARGE SCALE ANALYSIS] ARG-120.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Inhibits translation initiation and cap-dependent
CC translation. May excert its function by hindering the interaction
CC between EIF4A1 and EIF4G. Inhibits the helicase activity of EIF4A.
CC Modulates the activation of JUN kinase. Down-regulates the expression
CC of MAP4K1, thus inhibiting events important in driving invasion,
CC namely, MAPK85 activation and consequent JUN-dependent transcription.
CC May play a role in apoptosis. Tumor suppressor. Inhibits tumor
CC promoter-induced neoplastic transformation. Binds RNA (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:16357133, ECO:0000269|PubMed:16449643,
CC ECO:0000269|PubMed:17053147, ECO:0000269|PubMed:18296639,
CC ECO:0000269|PubMed:19153607, ECO:0000269|PubMed:19204291}.
CC -!- SUBUNIT: Interacts (via MI domains) with EIF4A2 (By similarity).
CC Interacts (via MI domains) with EIF4A1 (via N-terminal domain).
CC Heterotrimer with EIF4A1; one molecule of PDCD4 binds two molecules of
CC EIF4A1. Interacts with EIF4G1. May form a complex with EIF4A1 and
CC EIF4G1. The interaction between PDCD4 and EIF4A1 interferes with the
CC interaction between EIF4A1 and EIF4G. When phosphorylated, interacts
CC with BTRC and FBXW11. {ECO:0000250, ECO:0000269|PubMed:17053147,
CC ECO:0000269|PubMed:18296639, ECO:0000269|PubMed:19153607,
CC ECO:0000269|PubMed:19204291}.
CC -!- INTERACTION:
CC Q53EL6; P02649: APOE; NbExp=3; IntAct=EBI-935824, EBI-1222467;
CC Q53EL6; P60842: EIF4A1; NbExp=9; IntAct=EBI-935824, EBI-73449;
CC Q53EL6; Q14240: EIF4A2; NbExp=5; IntAct=EBI-935824, EBI-73473;
CC Q53EL6; Q14240-2: EIF4A2; NbExp=3; IntAct=EBI-935824, EBI-10232522;
CC Q53EL6; P38919: EIF4A3; NbExp=6; IntAct=EBI-935824, EBI-299104;
CC Q53EL6; P49810: PSEN2; NbExp=3; IntAct=EBI-935824, EBI-2010251;
CC Q53EL6; Q04206: RELA; NbExp=6; IntAct=EBI-935824, EBI-73886;
CC Q53EL6; P62277: RPS13; NbExp=2; IntAct=EBI-935824, EBI-351850;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q61823}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q61823}. Note=Shuttles between the nucleus and
CC cytoplasm (By similarity). Predominantly nuclear under normal growth
CC conditions, and when phosphorylated at Ser-457 (PubMed:16357133).
CC {ECO:0000269|PubMed:16357133}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q53EL6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q53EL6-2; Sequence=VSP_045622;
CC -!- TISSUE SPECIFICITY: Up-regulated in proliferative cells. Highly
CC expressed in epithelial cells of the mammary gland. Reduced expression
CC in lung cancer and colon carcinoma. {ECO:0000269|PubMed:10632927,
CC ECO:0000269|PubMed:12898601, ECO:0000269|PubMed:16449643}.
CC -!- INDUCTION: IL2/interleukin-2 stimulation inhibits expression, while
CC IL12/interleukin-12 increases expression. {ECO:0000269|PubMed:9759869}.
CC -!- DOMAIN: Binds EIF4A1 via both MI domains. {ECO:0000269|PubMed:18296639,
CC ECO:0000269|PubMed:19204291}.
CC -!- PTM: Polyubiquitinated, leading to its proteasomal degradation. Rapidly
CC degraded in response to mitogens. Phosphorylation of the phosphodegron
CC promotes interaction with BTRC and proteasomal degradation.
CC {ECO:0000269|PubMed:17053147}.
CC -!- PTM: Phosphorylated at Ser-67 by RPS6KB1 in response to mitogens;
CC phosphorylation promotes proteasomal degradation of PDCD4.
CC {ECO:0000269|PubMed:16357133, ECO:0000269|PubMed:17053147}.
CC -!- SIMILARITY: Belongs to the PDCD4 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB42218.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=AAH15036.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PDCD4ID41675ch10q24.html";
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DR EMBL; U83908; AAB42218.1; ALT_SEQ; Genomic_DNA.
DR EMBL; U96628; AAB67706.1; -; mRNA.
DR EMBL; AK315295; BAG37701.1; -; mRNA.
DR EMBL; AK223623; BAD97343.1; -; mRNA.
DR EMBL; AL158163; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL136368; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC015036; AAH15036.1; ALT_SEQ; mRNA.
DR EMBL; BC026104; AAH26104.1; -; mRNA.
DR EMBL; BC031049; AAH31049.1; -; mRNA.
DR CCDS; CCDS44478.1; -. [Q53EL6-2]
DR CCDS; CCDS7567.1; -. [Q53EL6-1]
DR PIR; JC5193; JC5193.
DR RefSeq; NP_055271.2; NM_014456.4. [Q53EL6-1]
DR RefSeq; NP_663314.1; NM_145341.3. [Q53EL6-2]
DR PDB; 2GGF; NMR; -; A=327-450.
DR PDB; 2KZT; NMR; -; A=157-318.
DR PDB; 2RG8; X-ray; 1.80 A; A/B=157-320.
DR PDB; 2ZU6; X-ray; 2.80 A; B/E=163-469.
DR PDB; 3EIJ; X-ray; 2.80 A; A/B=157-469.
DR PDBsum; 2GGF; -.
DR PDBsum; 2KZT; -.
DR PDBsum; 2RG8; -.
DR PDBsum; 2ZU6; -.
DR PDBsum; 3EIJ; -.
DR AlphaFoldDB; Q53EL6; -.
DR BMRB; Q53EL6; -.
DR SMR; Q53EL6; -.
DR BioGRID; 118098; 104.
DR CORUM; Q53EL6; -.
DR DIP; DIP-29756N; -.
DR ELM; Q53EL6; -.
DR IntAct; Q53EL6; 35.
DR MINT; Q53EL6; -.
DR STRING; 9606.ENSP00000280154; -.
DR BindingDB; Q53EL6; -.
DR ChEMBL; CHEMBL1781868; -.
DR DrugCentral; Q53EL6; -.
DR CarbonylDB; Q53EL6; -.
DR GlyGen; Q53EL6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q53EL6; -.
DR MetOSite; Q53EL6; -.
DR PhosphoSitePlus; Q53EL6; -.
DR SwissPalm; Q53EL6; -.
DR BioMuta; PDCD4; -.
DR DMDM; 317373317; -.
DR EPD; Q53EL6; -.
DR jPOST; Q53EL6; -.
DR MassIVE; Q53EL6; -.
DR MaxQB; Q53EL6; -.
DR PaxDb; Q53EL6; -.
DR PeptideAtlas; Q53EL6; -.
DR PRIDE; Q53EL6; -.
DR ProteomicsDB; 6218; -.
DR ProteomicsDB; 62437; -. [Q53EL6-1]
DR Antibodypedia; 616; 866 antibodies from 43 providers.
DR DNASU; 27250; -.
DR Ensembl; ENST00000280154.12; ENSP00000280154.7; ENSG00000150593.18. [Q53EL6-1]
DR Ensembl; ENST00000393104.6; ENSP00000376816.2; ENSG00000150593.18. [Q53EL6-2]
DR GeneID; 27250; -.
DR KEGG; hsa:27250; -.
DR MANE-Select; ENST00000280154.12; ENSP00000280154.7; NM_014456.5; NP_055271.2.
DR UCSC; uc001kzg.4; human. [Q53EL6-1]
DR CTD; 27250; -.
DR DisGeNET; 27250; -.
DR GeneCards; PDCD4; -.
DR HGNC; HGNC:8763; PDCD4.
DR HPA; ENSG00000150593; Tissue enhanced (pancreas).
DR MIM; 608610; gene.
DR neXtProt; NX_Q53EL6; -.
DR OpenTargets; ENSG00000150593; -.
DR PharmGKB; PA33113; -.
DR VEuPathDB; HostDB:ENSG00000150593; -.
DR eggNOG; KOG0403; Eukaryota.
DR GeneTree; ENSGT00390000015948; -.
DR HOGENOM; CLU_025354_1_0_1; -.
DR InParanoid; Q53EL6; -.
DR OMA; HHELIYE; -.
DR OrthoDB; 434771at2759; -.
DR PhylomeDB; Q53EL6; -.
DR TreeFam; TF323207; -.
DR PathwayCommons; Q53EL6; -.
DR Reactome; R-HSA-8950505; Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation.
DR SignaLink; Q53EL6; -.
DR SIGNOR; Q53EL6; -.
DR BioGRID-ORCS; 27250; 10 hits in 1081 CRISPR screens.
DR ChiTaRS; PDCD4; human.
DR EvolutionaryTrace; Q53EL6; -.
DR GeneWiki; PDCD4; -.
DR GenomeRNAi; 27250; -.
DR Pharos; Q53EL6; Tchem.
DR PRO; PR:Q53EL6; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q53EL6; protein.
DR Bgee; ENSG00000150593; Expressed in body of pancreas and 205 other tissues.
DR ExpressionAtlas; Q53EL6; baseline and differential.
DR Genevisible; Q53EL6; HS.
DR GO; GO:0005737; C:cytoplasm; IMP:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IMP:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:BHF-UCL.
DR GO; GO:0060940; P:epithelial to mesenchymal transition involved in cardiac fibroblast development; ISS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:BHF-UCL.
DR GO; GO:0043508; P:negative regulation of JUN kinase activity; ISS:UniProtKB.
DR GO; GO:1904761; P:negative regulation of myofibroblast differentiation; IMP:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:1905064; P:negative regulation of vascular associated smooth muscle cell differentiation; IDA:BHF-UCL.
DR GO; GO:1904706; P:negative regulation of vascular associated smooth muscle cell proliferation; IMP:BHF-UCL.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IMP:BHF-UCL.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS:BHF-UCL.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:BHF-UCL.
DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; IMP:BHF-UCL.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003891; Initiation_fac_eIF4g_MI.
DR InterPro; IPR039778; PDCD4.
DR PANTHER; PTHR12626; PTHR12626; 1.
DR Pfam; PF02847; MA3; 2.
DR SMART; SM00544; MA3; 2.
DR SUPFAM; SSF48371; SSF48371; 2.
DR PROSITE; PS51366; MI; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; Cytoplasm;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; RNA-binding;
KW Tumor suppressor; Ubl conjugation.
FT CHAIN 1..469
FT /note="Programmed cell death protein 4"
FT /id="PRO_0000256519"
FT DOMAIN 163..284
FT /note="MI 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698"
FT DOMAIN 326..449
FT /note="MI 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00698"
FT REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 58..128
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 58..64
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 70..76
FT /note="Phosphodegron"
FT MOTIF 241..250
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 11..27
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 73..89
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JID1"
FT MOD_RES 67
FT /note="Phosphoserine; by PKB and RPS6KB1"
FT /evidence="ECO:0000269|PubMed:16357133,
FT ECO:0000269|PubMed:17053147, ECO:0007744|PubMed:24275569"
FT MOD_RES 68
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 71
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 76
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 78
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 80
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 94
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 152
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15592455"
FT MOD_RES 313
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 317
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 457
FT /note="Phosphoserine; by PKB"
FT /evidence="ECO:0000269|PubMed:16357133,
FT ECO:0007744|PubMed:15144186, ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..15
FT /note="MDVENEQILNVNPAD -> MTKY (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045622"
FT VARIANT 36
FT /note="I -> V (in dbSNP:rs7081726)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9759869,
FT ECO:0000269|Ref.1, ECO:0000269|Ref.4,
FT ECO:0007744|PubMed:20068231"
FT /id="VAR_028901"
FT VARIANT 48
FT /note="S -> Y (in dbSNP:rs11548765)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_028902"
FT VARIANT 120
FT /note="G -> R (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036375"
FT MUTAGEN 67
FT /note="S->A: Loss of phosphorylation site. Reduces
FT interaction with BTRC. Abolishes phosphorylation by PKB;
FT when associated with A-457."
FT /evidence="ECO:0000269|PubMed:16357133,
FT ECO:0000269|PubMed:17053147"
FT MUTAGEN 71
FT /note="S->A: Strongly reduced interaction with BTRC.
FT Strongly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:17053147"
FT MUTAGEN 76
FT /note="S->A: Strongly reduced interaction with BTRC.
FT Strongly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:17053147"
FT MUTAGEN 174
FT /note="E->A: Reduced inhibition of EIF4A1 helicase
FT activity."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 210
FT /note="E->A: Reduced inhibition of EIF4A1 helicase
FT activity. Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 249
FT /note="E->A: Reduced interaction with EIF4A1."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 252
FT /note="L->A: Strongly reduced interaction with EIF4A1.
FT Reduced inhibition of EIF4A1 helicase activity. Strongly
FT reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 253
FT /note="D->A: Strongly reduced interaction with EIF4A1.
FT Strongly reduced inhibition of translation. Reduced
FT inhibition of EIF4A1 helicase activity."
FT /evidence="ECO:0000269|PubMed:19153607,
FT ECO:0000269|PubMed:19204291"
FT MUTAGEN 255
FT /note="P->A: Reduced inhibition of EIF4A1 helicase
FT activity. Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 333
FT /note="M->A: No effect on inhibition of EIF4A1 and on
FT inhibition of translation; when associated with A-340."
FT /evidence="ECO:0000269|PubMed:19204291"
FT MUTAGEN 337
FT /note="E->A: No effect on inhibition of EIF4A1 and on
FT inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19204291"
FT MUTAGEN 340
FT /note="L->A: No effect on inhibition of EIF4A1 and on
FT inhibition of translation; when associated with A-333."
FT /evidence="ECO:0000269|PubMed:19204291"
FT MUTAGEN 358
FT /note="H->A: Strongly reduced interaction with EIF4A1."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 359
FT /note="F->A: Strongly reduced inhibition of EIF4A1.
FT Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19204291"
FT MUTAGEN 361
FT /note="H->A: Strongly reduced inhibition of EIF4A1.
FT Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19204291"
FT MUTAGEN 414
FT /note="D->A: Strongly reduced interaction with EIF4A1.
FT Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 418
FT /note="D->A: Reduced interaction with EIF4A1. Strongly
FT reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 420
FT /note="P->A: Strongly reduced interaction with EIF4A1.
FT Strongly reduced inhibition of translation."
FT /evidence="ECO:0000269|PubMed:19153607"
FT MUTAGEN 457
FT /note="S->A: Loss of phosphorylation site, and loss of
FT nuclear accumulation. Abolishes phosphorylation by PKB;
FT when associated with A-67."
FT /evidence="ECO:0000269|PubMed:16357133"
FT CONFLICT 79
FT /note="D -> E (in Ref. 1; AAB42218)"
FT /evidence="ECO:0000305"
FT CONFLICT 102
FT /note="R -> G (in Ref. 2; AAB67706)"
FT /evidence="ECO:0000305"
FT CONFLICT 130
FT /note="V -> G (in Ref. 2; AAB67706)"
FT /evidence="ECO:0000305"
FT CONFLICT 220
FT /note="S -> T (in Ref. 1; AAB42218)"
FT /evidence="ECO:0000305"
FT CONFLICT 222
FT /note="L -> F (in Ref. 2; AAB67706)"
FT /evidence="ECO:0000305"
FT CONFLICT 309
FT /note="K -> R (in Ref. 3; BAG37701)"
FT /evidence="ECO:0000305"
FT CONFLICT 314
FT /note="V -> A (in Ref. 3; BAG37701)"
FT /evidence="ECO:0000305"
FT CONFLICT 440
FT /note="S -> W (in Ref. 2; AAB67706)"
FT /evidence="ECO:0000305"
FT HELIX 161..178
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 181..191
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 195..198
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 199..209
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 213..226
FT /evidence="ECO:0007829|PDB:2RG8"
FT TURN 227..229
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 233..253
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 257..270
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 278..281
FT /evidence="ECO:0007829|PDB:2RG8"
FT TURN 282..284
FT /evidence="ECO:0007829|PDB:2RG8"
FT HELIX 289..303
FT /evidence="ECO:0007829|PDB:2RG8"
FT STRAND 308..313
FT /evidence="ECO:0007829|PDB:2KZT"
FT HELIX 324..341
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 344..354
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 357..359
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 360..372
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 378..393
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 398..418
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 422..435
FT /evidence="ECO:0007829|PDB:2ZU6"
FT HELIX 441..445
FT /evidence="ECO:0007829|PDB:2ZU6"
SQ SEQUENCE 469 AA; 51735 MW; 2CAE1D2055491177 CRC64;
MDVENEQILN VNPADPDNLS DSLFSGDEEN AGTEEIKNEI NGNWISASSI NEARINAKAK
RRLRKNSSRD SGRGDSVSDS GSDALRSGLT VPTSPKGRLL DRRSRSGKGR GLPKKGGAGG
KGVWGTPGQV YDVEEVDVKD PNYDDDQENC VYETVVLPLD ERAFEKTLTP IIQEYFEHGD
TNEVAEMLRD LNLGEMKSGV PVLAVSLALE GKASHREMTS KLLSDLCGTV MSTTDVEKSF
DKLLKDLPEL ALDTPRAPQL VGQFIARAVG DGILCNTYID SYKGTVDCVQ ARAALDKATV
LLSMSKGGKR KDSVWGSGGG QQSVNHLVKE IDMLLKEYLL SGDISEAEHC LKELEVPHFH
HELVYEAIIM VLESTGESTF KMILDLLKSL WKSSTITVDQ MKRGYERIYN EIPDINLDVP
HSYSVLERFV EECFQAGIIS KQLRDLCPSR GRKRFVSEGD GGRLKPESY
