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 27-MAR-2024, entry version 160. 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="https://atlasgeneticsoncology.org/gene/41675/PDCD4"; 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; 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; 166. DR CORUM; Q53EL6; -. DR DIP; DIP-29756N; -. DR ELM; Q53EL6; -. DR IntAct; Q53EL6; 36. 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; 9606-ENSP00000280154; -. DR PeptideAtlas; Q53EL6; -. DR ProteomicsDB; 6218; -. DR ProteomicsDB; 62437; -. [Q53EL6-1] DR Pumba; Q53EL6; -. DR Antibodypedia; 616; 949 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 AGR; HGNC:8763; -. 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; GMEQGFI; -. DR OrthoDB; 1217702at2759; -. 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; 11 hits in 1162 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 207 other cell types or tissues. DR ExpressionAtlas; Q53EL6; baseline and differential. 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:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. 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: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 non-canonical NF-kappaB signal transduction; IMP:BHF-UCL. DR GO; GO:1905461; P:positive regulation of vascular associated smooth muscle cell apoptotic process; IMP:BHF-UCL. DR GO; GO:0043279; P:response to alkaloid; IEA:Ensembl. DR GO; GO:0009725; P:response to hormone; IEA:Ensembl. DR Gene3D; 1.25.40.180; -; 2. DR IDEAL; IID00729; -. DR InterPro; IPR016024; ARM-type_fold. DR InterPro; IPR003891; Initiation_fac_eIF4g_MI. DR InterPro; IPR039778; PDCD4. DR PANTHER; PTHR12626; PROGRAMMED CELL DEATH 4; 1. DR PANTHER; PTHR12626:SF3; PROGRAMMED CELL DEATH PROTEIN 4; 1. DR Pfam; PF02847; MA3; 2. DR SMART; SM00544; MA3; 2. DR SUPFAM; SSF48371; ARM repeat; 2. DR PROSITE; PS51366; MI; 2. DR Genevisible; Q53EL6; HS. 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 //