ID M3K20_HUMAN Reviewed; 800 AA. AC Q9NYL2; B3KPG2; Q53SX1; Q580W8; Q59GY5; Q86YW8; Q9HCC4; Q9HCC5; Q9HDD2; AC Q9NYE9; DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 28-JAN-2026, entry version 206. DE RecName: Full=Mitogen-activated protein kinase kinase kinase 20 {ECO:0000305}; DE EC=2.7.11.25 {ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:14521931, ECO:0000269|PubMed:26999302}; DE AltName: Full=Human cervical cancer suppressor gene 4 protein; DE Short=HCCS-4; DE AltName: Full=Leucine zipper- and sterile alpha motif-containing kinase; DE AltName: Full=MLK-like mitogen-activated protein triple kinase; DE AltName: Full=Mitogen-activated protein kinase kinase kinase MLT; DE AltName: Full=Mixed lineage kinase 7 {ECO:0000303|PubMed:11549352}; DE AltName: Full=Mixed lineage kinase-related kinase {ECO:0000303|PubMed:11042189}; DE Short=MLK-related kinase {ECO:0000303|PubMed:11836244}; DE Short=MRK {ECO:0000303|PubMed:11836244}; DE AltName: Full=Sterile alpha motif- and leucine zipper-containing kinase AZK; GN Name=MAP3K20 {ECO:0000312|HGNC:HGNC:17797}; GN Synonyms=MLK7 {ECO:0000303|PubMed:11549352}, MLTK GN {ECO:0000303|PubMed:11042189}, ZAK {ECO:0000303|PubMed:10924358}; GN ORFNames=HCCS4; 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] {ECO:0000305, ECO:0000312|EMBL:AAF63490.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZAKALPHA), FUNCTION, TISSUE RP SPECIFICITY, HOMODIMERIZATION, AND VARIANT LEU-531. RC TISSUE=Placenta {ECO:0000269|PubMed:10924358}; RX PubMed=10924358; DOI=10.1006/bbrc.2000.3236; RA Liu T.-C., Huang C.-J., Chu Y.-C., Wei C.-C., Chou C.-C., Chou M.-Y., RA Chou C.-K., Yang J.-J.; RT "Cloning and expression of ZAK, a mixed lineage kinase-like protein RT containing a leucine-zipper and a sterile-alpha motif."; RL Biochem. Biophys. Res. Commun. 274:811-816(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ZAKALPHA AND ZAKBETA), FUNCTION, RP PHOSPHORYLATION AT SER-429 (ISOFORM ZAKBETA), AND VARIANT LEU-531. RC TISSUE=Fetal brain; RX PubMed=11042189; DOI=10.1074/jbc.m008595200; RA Gotoh I., Adachi M., Nishida E.; RT "Identification and characterization of a novel MAP kinase kinase kinase, RT MLTK."; RL J. Biol. Chem. 276:4276-4286(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZAKBETA). RC TISSUE=Heart; RX PubMed=11549352; DOI=10.1006/jmcc.2001.1437; RA Bloem L.J., Pickard T.R., Acton S., Donoghue M., Beavis R.C., RA Knierman M.D., Wang X.; RT "Tissue distribution and functional expression of a cDNA encoding a novel RT mixed lineage kinase."; RL J. Mol. Cell. Cardiol. 33:1739-1750(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ZAKALPHA AND ZAKBETA), FUNCTION, RP TISSUE SPECIFICITY, MUTAGENESIS OF LYS-45, AND VARIANT LEU-531. RC TISSUE=T-cell {ECO:0000269|PubMed:11836244}; RX PubMed=11836244; DOI=10.1074/jbc.m111994200; RA Gross E.A., Callow M.G., Waldbaum L., Thomas S., Ruggieri R.; RT "MRK, a mixed lineage kinase-related molecule that plays a role in gamma- RT radiation-induced cell cycle arrest."; RL J. Biol. Chem. 277:13873-13882(2002). RN [5] {ECO:0000305, ECO:0000312|EMBL:BAB12040.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZAKALPHA). RC TISSUE=Lymphoid tissue; RA Abe Y., Ueda N.; RT "Placible mixed-lineage kinase derived from LAK cell."; RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases. RN [6] {ECO:0000305, ECO:0000312|EMBL:BAB12040.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ZAKALPHA), AND VARIANT LEU-531. RA McNee J.J., Frima N., Diamond T.E., Dower S.K., Guesdon F.; RT "Cloning and characterisation of AZK, a mixed lineage kinase containing a RT sterile-alpha motif."; RL Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases. RN [7] {ECO:0000305, ECO:0000312|EMBL:BAB12040.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RA Kim J.W.; RT "Identification of a new tumor suppressor in human cancers."; RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ZAKBETA). 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 [9] {ECO:0000305, ECO:0000312|EMBL:BAB12040.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ZAKALPHA), AND VARIANT RP THR-784. RC TISSUE=Brain {ECO:0000312|EMBL:BAD92211.1}; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [10] {ECO:0000312|EMBL:AAX82002.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [11] {ECO:0000305, ECO:0000312|EMBL:BAB12040.1} 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [12] {ECO:0000305, ECO:0000312|EMBL:AAH01401.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ZAKBETA). RC TISSUE=Colon {ECO:0000312|EMBL:AAH01401.1}; 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 [13] RP FUNCTION, ACTIVITY REGULATION, AND PHOSPHORYLATION. RX PubMed=12220515; DOI=10.1016/s0006-291x(02)02123-x; RA Yang J.-J.; RT "Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun RT N-terminal kinase and playing a role in the cell arrest."; RL Biochem. Biophys. Res. Commun. 297:105-110(2002). RN [14] RP INTERACTION WITH ZNF33A. RX PubMed=12535642; DOI=10.1016/s0006-291x(02)02980-7; RA Yang J.-J.; RT "A novel zinc finger protein, ZZaPK, interacts with ZAK and stimulates the RT ZAK-expressing cells re-entering the cell cycle."; RL Biochem. Biophys. Res. Commun. 301:71-77(2003). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=14521931; DOI=10.1016/j.bbrc.2003.09.075; RA Yu X., Bloem L.J.; RT "Effect of C-terminal truncations on MLK7 catalytic activity and JNK RT activation."; RL Biochem. Biophys. Res. Commun. 310:452-457(2003). RN [16] {ECO:0000305} RP PHOSPHORYLATION, AND ACTIVITY REGULATION. RX PubMed=12761180; DOI=10.1093/jb/mvg022; RA Takahashi M., Gotoh Y., Isagawa T., Nishimura T., Goyama E., Kim H.-S., RA Mukai H., Ono Y.; RT "Regulation of a mitogen-activated protein kinase kinase kinase, MLTK by RT PKN."; RL J. Biochem. 133:181-187(2003). RN [17] {ECO:0000305} RP FUNCTION. RX PubMed=15172994; DOI=10.1158/0008-5472.can-04-0201; RA Cho Y.-Y., Bode A.M., Mizuno H., Choi B.Y., Choi H.S., Dong Z.; RT "A novel role for mixed-lineage kinase-like mitogen-activated protein RT triple kinase alpha in neoplastic cell transformation and tumor RT development."; RL Cancer Res. 64:3855-3864(2004). RN [18] {ECO:0000305} RP FUNCTION IN DNA DAMAGE CHECKPOINTS, FUNCTION IN PHOSPHORYLATION OF CHEK2, RP ACTIVITY REGULATION, PHOSPHORYLATION AT THR-161 AND SER-165, AND RP MUTAGENESIS OF THR-161; THR-162 AND SER-165. RX PubMed=15342622; DOI=10.1074/jbc.m409961200; RA Tosti E., Waldbaum L., Warshaw G., Gross E.A., Ruggieri R.; RT "The stress kinase MRK contributes to regulation of DNA damage checkpoints RT through a p38gamma-independent pathway."; RL J. Biol. Chem. 279:47652-47660(2004). RN [19] RP FUNCTION. RX PubMed=15350844; DOI=10.1016/j.yjmcc.2004.06.004; RA Christe M., Jin N., Wang X., Gould K.E., Iversen P.W., Yu X., Lorenz J.N., RA Kadambi V., Zuckerman S.H., Bloem L.J.; RT "Transgenic mice with cardiac-specific over-expression of MLK7 have RT increased mortality when exposed to chronic beta-adrenergic stimulation."; RL J. Mol. Cell. Cardiol. 37:705-715(2004). RN [20] RP FUNCTION IN PHOSPHORYLATION OF HISTONE H3 (ISOFORM 1), AND SUBCELLULAR RP LOCATION. RX PubMed=15684425; DOI=10.1074/jbc.m410521200; RA Choi H.S., Choi B.Y., Cho Y.-Y., Zhu F., Bode A.M., Dong Z.; RT "Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase- RT like mitogen-activated protein triple kinase alpha."; RL J. Biol. Chem. 280:13545-13553(2005). RN [21] RP FUNCTION. RX PubMed=15737997; DOI=10.1074/jbc.m413059200; RA Wang X., Mader M.M., Toth J.E., Yu X., Jin N., Campbell R.M., RA Smallwood J.K., Christe M.E., Chatterjee A., Goodson T. Jr., Vlahos C.J., RA Matter W.F., Bloem L.J.; RT "Complete inhibition of anisomycin and UV radiation but not cytokine RT induced JNK and p38 activation by an aryl-substituted RT dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small RT interfering RNA."; RL J. Biol. Chem. 280:19298-19305(2005). RN [22] RP FUNCTION. RX PubMed=18331592; DOI=10.1111/j.1462-5822.2008.01139.x; RA Jandhyala D.M., Ahluwalia A., Obrig T., Thorpe C.M.; RT "ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced RT proinflammatory cytokine expression."; RL Cell. Microbiol. 10:1468-1477(2008). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-275; SER-302; THR-628; RP SER-727 AND SER-733, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-339; RP SER-434 AND SER-454 (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-599; THR-628; SER-633; RP SER-727 AND SER-733, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-454 RP (ISOFORM 2), AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP 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 [25] 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 [26] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-275; THR-628; SER-633 AND SER-727, PHOSPHORYLATION [LARGE RP SCALE ANALYSIS] AT SER-339; SER-434 AND SER-454 (ISOFORM 2), CLEAVAGE OF RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [27] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-633, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [28] RP FUNCTION. RX PubMed=20559024; DOI=10.4161/cbt.10.3.12367; RA Sauter K.A., Magun E.A., Iordanov M.S., Magun B.E.; RT "ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce RT SAPK activation and apoptosis in HaCaT cells."; RL Cancer Biol. Ther. 10:258-266(2010). RN [29] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE 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 [30] 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 [31] RP FUNCTION, AND IDENTIFICATION IN A COMPLEX WITH AKAP13; PKN1; MAPK14 AND RP MAP2K3. RX PubMed=21224381; DOI=10.1074/jbc.m110.185645; RA Cariolato L., Cavin S., Diviani D.; RT "A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling RT complex involved in alpha1-adrenergic receptor-induced p38 activation."; RL J. Biol. Chem. 286:7925-7937(2011). RN [32] RP IDENTIFICATION BY 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 [33] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [34] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-567; SER-593; THR-628; RP SER-633; SER-637; SER-648; SER-649; SER-685; SER-727 AND SER-733, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [35] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND IDENTIFICATION BY RP 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 [36] RP FUNCTION (ISOFORMS ZAKALPHA AND ZAKBETA), AND SUBUNIT. RX PubMed=27859413; DOI=10.1002/cbf.3234; RA Fu C.Y., Kuo W.W., Ho T.J., Wen S.Y., Lin L.C., Tseng Y.S., Hung H.C., RA Viswanadha V.P., Yang J.J., Huang C.Y.; RT "ZAKbeta antagonizes and ameliorates the cardiac hypertrophic and apoptotic RT effects induced by ZAKalpha."; RL Cell Biochem. Funct. 34:606-612(2016). RN [37] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH RP EIF2AK4, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LYS-45. RX PubMed=32610081; DOI=10.1016/j.cell.2020.06.006; RA Wu C.C., Peterson A., Zinshteyn B., Regot S., Green R.; RT "Ribosome collisions trigger general stress responses to regulate cell RT fate."; RL Cell 182:404-416(2020). RN [38] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AUTOPHOSPHORYLATION, RP PHOSPHORYLATION AT SER-2; SER-3; SER-7; SER-302; THR-586; SER-587; SER-649; RP SER-660; THR-664; SER-718; SER-720 AND THR-742, AND MUTAGENESIS OF SER-657 RP AND 752-THR--SER-761. RX PubMed=32289254; DOI=10.1016/j.molcel.2020.03.021; RA Vind A.C., Snieckute G., Blasius M., Tiedje C., Krogh N., RA Bekker-Jensen D.B., Andersen K.L., Nordgaard C., Tollenaere M.A.X., RA Lund A.H., Olsen J.V., Nielsen H., Bekker-Jensen S.; RT "ZAKalpha recognizes stalled ribosomes through partially redundant sensor RT domains."; RL Mol. Cell 78:700-713(2020). RN [39] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-45. RX PubMed=35857590; DOI=10.1126/science.abl6324; RA Robinson K.S., Toh G.A., Rozario P., Chua R., Bauernfried S., Sun Z., RA Firdaus M.J., Bayat S., Nadkarni R., Poh Z.S., Tham K.C., Harapas C.R., RA Lim C.K., Chu W., Tay C.W.S., Tan K.Y., Zhao T., Bonnard C., Sobota R., RA Connolly J.E., Common J., Masters S.L., Chen K.W., Ho L., Wu B., RA Hornung V., Zhong F.L.; RT "ZAKalpha-driven ribotoxic stress response activates the human NLRP1 RT inflammasome."; RL Science 377:328-335(2022). RN [40] {ECO:0007744|PDB:5HES} RP X-RAY CRYSTALLOGRAPHY (2.14 ANGSTROMS) OF 5-309 IN COMPLEX WITH RP VEMURAFENIB, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND RP PHOSPHORYLATION AT THR-161 AND SER-165. RX PubMed=26999302; DOI=10.1021/acschembio.6b00043; RA Mathea S., Abdul Azeez K.R., Salah E., Tallant C., Wolfreys F., RA Konietzny R., Fischer R., Lou H.J., Brennan P.E., Schnapp G., Pautsch A., RA Kessler B.M., Turk B.E., Knapp S.; RT "Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib."; RL ACS Chem. Biol. 11:1595-1602(2016). RN [41] {ECO:0007744|PDB:5X5O} RP X-RAY CRYSTALLOGRAPHY (1.87 ANGSTROMS) OF 5-309 IN COMPLEX WITH COMPOUND RP 3H, AND ACTIVITY REGULATION. RX PubMed=28586211; DOI=10.1021/acs.jmedchem.7b00572; RA Chang Y., Lu X., Shibu M.A., Dai Y.B., Luo J., Zhang Y., Li Y., Zhao P., RA Zhang Z., Xu Y., Tu Z.C., Zhang Q.W., Yun C.H., Huang C.Y., Ding K.; RT "Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5- RT yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile- RT alpha Motif Kinase (ZAK) Inhibitors."; RL J. Med. Chem. 60:5927-5932(2017). RN [42] {ECO:0007744|PDB:6JUT, ECO:0007744|PDB:6JUU} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 5-309 IN COMPLEX WITH RP 1,2,3-TRIAZOLE BENZENESULFONAMIDES INHOBITORS, AND ACTIVITY REGULATION. RX PubMed=31244114; DOI=10.1021/acs.jmedchem.9b00664; RA Yang J., Shibu M.A., Kong L., Luo J., BadrealamKhan F., Huang Y., Tu Z.C., RA Yun C.H., Huang C.Y., Ding K., Lu X.; RT "Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole RT Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-alpha Motif RT Kinase (ZAK) Inhibitors."; RL J. Med. Chem. 63:2114-2130(2020). RN [43] RP VARIANTS [LARGE SCALE ANALYSIS] MET-267; THR-281; VAL-281; LEU-531; RP TRP-580; THR-740; HIS-773 AND THR-784. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [44] RP INVOLVEMENT IN SFMMP, SUBUNIT, VARIANT SFMMP CYS-368, AND CHARACTERIZATION RP OF VARIANT SFMMP CYS-368. RX PubMed=26755636; DOI=10.1101/gr.199430.115; RA Spielmann M., Kakar N., Tayebi N., Leettola C., Nuernberg G., Sowada N., RA Lupianez D.G., Harabula I., Floettmann R., Horn D., Chan W.L., Wittler L., RA Yilmaz R., Altmueller J., Thiele H., van Bokhoven H., Schwartz C.E., RA Nuernberg P., Bowie J.U., Ahmad J., Kubisch C., Mundlos S., Borck G.; RT "Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK RT as a cause of limb defects in humans and mice."; RL Genome Res. 26:183-191(2016). RN [45] RP INVOLVEMENT IN CNM6, VARIANTS CNM6 95-ASN--PHE-800 DEL AND 172-TRP--PHE-800 RP DEL, AND CHARACTERIZATION OF VARIANTS CNM6 95-ASN--PHE-800 DEL AND RP 172-TRP--PHE-800 DEL. RX PubMed=27816943; DOI=10.1093/brain/aww257; RA Vasli N., Harris E., Karamchandani J., Bareke E., Majewski J., Romero N.B., RA Stojkovic T., Barresi R., Tasfaout H., Charlton R., Malfatti E., Bohm J., RA Marini-Bettolo C., Choquet K., Dicaire M.J., Shao Y.H., Topf A., RA O'Ferrall E., Eymard B., Straub V., Blanco G., Lochmueller H., Brais B., RA Laporte J., Tetreault M.; RT "Recessive mutations in the kinase ZAK cause a congenital myopathy with RT fibre type disproportion."; RL Brain 140:37-48(2017). RN [46] RP VARIANT CNM6 TRP-250. RX PubMed=30237576; DOI=10.1038/s41436-018-0138-x; RA Maddirevula S., Alzahrani F., Al-Owain M., Al Muhaizea M.A., Kayyali H.R., RA AlHashem A., Rahbeeni Z., Al-Otaibi M., Alzaidan H.I., Balobaid A., RA El Khashab H.Y., Bubshait D.K., Faden M., Yamani S.A., Dabbagh O., RA Al-Mureikhi M., Jasser A.A., Alsaif H.S., Alluhaydan I., Seidahmed M.Z., RA Alabbasi B.H., Almogarri I., Kurdi W., Akleh H., Qari A., Al Tala S.M., RA Alhomaidi S., Kentab A.Y., Salih M.A., Chedrawi A., Alameer S., Tabarki B., RA Shamseldin H.E., Patel N., Ibrahim N., Abdulwahab F., Samira M., Goljan E., RA Abouelhoda M., Meyer B.F., Hashem M., Shaheen R., AlShahwan S., RA Alfadhel M., Ben-Omran T., Al-Qattan M.M., Monies D., Alkuraya F.S.; RT "Autozygome and high throughput confirmation of disease genes candidacy."; RL Genet. Med. 21:736-742(2019). RN [47] RP VARIANT SFMMP SER-505, AND CHARACTERIZATION OF VARIANT SFMMP SER-505. RX PubMed=32266845; DOI=10.1177/0300060519879293; RA Funk C.R., Huey E.S., May M.M., Peng Y., Michonova E., Best R.G., RA Schwartz C.E., Blenda A.V.; RT "Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient RT with split-hand/foot malformation from a non-consanguineous pedigree."; RL J. Int. Med. Res. 48:300060519879293-300060519879293(2020). CC -!- FUNCTION: Stress-activated component of a protein kinase signal CC transduction cascade that promotes programmed cell death in response to CC various stress, such as ribosomal stress, osmotic shock and ionizing CC radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, CC PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, CC PubMed:20559024, PubMed:26999302, PubMed:32289254, PubMed:32610081, CC PubMed:35857590). Acts by catalyzing phosphorylation of MAP kinase CC kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 CC and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or CC MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, CC PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32289254, CC PubMed:32610081, PubMed:35857590). Activates JNK through CC phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 CC gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 CC (PubMed:11836244, PubMed:12220515). Involved in stress associated with CC adrenergic stimulation: contributes to cardiac decompensation during CC periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, CC PubMed:27859413). May be involved in regulation of S and G2 cell cycle CC checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622). CC {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:11042189, CC ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:12220515, CC ECO:0000269|PubMed:14521931, ECO:0000269|PubMed:15172994, CC ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:15350844, CC ECO:0000269|PubMed:15737997, ECO:0000269|PubMed:18331592, CC ECO:0000269|PubMed:20559024, ECO:0000269|PubMed:21224381, CC ECO:0000269|PubMed:26999302, ECO:0000269|PubMed:27859413, CC ECO:0000269|PubMed:32289254, ECO:0000269|PubMed:32610081, CC ECO:0000269|PubMed:35857590}. CC -!- FUNCTION: [Isoform ZAKalpha]: Key component of the stress-activated CC protein kinase signaling cascade in response to ribotoxic stress or UV- CC B irradiation (PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts CC as the proximal sensor of ribosome collisions during the ribotoxic CC stress response (RSR): directly binds to the ribosome by inserting its CC flexible C-terminus into the ribosomal intersubunit space, thereby CC acting as a sentinel for colliding ribosomes (PubMed:32289254, CC PubMed:32610081). Upon ribosome collisions, activates either the CC stress-activated protein kinase signal transduction cascade or the CC integrated stress response (ISR), leading to programmed cell death or CC cell survival, respectively (PubMed:32610081). Dangerous levels of CC ribosome collisions trigger the autophosphorylation and activation of CC MAP3K20, which dissociates from colliding ribosomes and phosphorylates CC MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 CC pathways that promote programmed cell death (PubMed:32289254, CC PubMed:32610081). Less dangerous levels of ribosome collisions trigger CC the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 CC independently of its protein-kinase activity, promoting EIF2AK4/GCN2- CC mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also CC part of the stress-activated protein kinase signaling cascade CC triggering the NLRP1 inflammasome in response to UV-B irradiation: CC ribosome collisions activate MAP3K20, which directly phosphorylates CC NLRP1, leading to activation of the NLRP1 inflammasome and subsequent CC pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP CC kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a CC histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) CC (PubMed:15684425). {ECO:0000269|PubMed:15684425, CC ECO:0000269|PubMed:32289254, ECO:0000269|PubMed:32610081, CC ECO:0000269|PubMed:35857590}. CC -!- FUNCTION: [Isoform ZAKbeta]: Isoform that lacks the C-terminal region CC that mediates ribosome-binding: does not act as a sensor of ribosome CC collisions in response to ribotoxic stress (PubMed:32289254, CC PubMed:32610081, PubMed:35857590). May act as an antagonist of isoform CC ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the CC expression of isoform ZAKalpha (PubMed:27859413). CC {ECO:0000269|PubMed:27859413, ECO:0000269|PubMed:32289254, CC ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25; CC Evidence={ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:14521931, CC ECO:0000269|PubMed:26999302, ECO:0000269|PubMed:32289254, CC ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990; CC Evidence={ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:14521931, CC ECO:0000269|PubMed:26999302, ECO:0000269|PubMed:32289254, CC ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.25; CC Evidence={ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:14521931, CC ECO:0000269|PubMed:26999302, ECO:0000269|PubMed:32289254, CC ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609; CC Evidence={ECO:0000269|PubMed:11836244, ECO:0000269|PubMed:14521931, CC ECO:0000269|PubMed:26999302, ECO:0000269|PubMed:32289254, CC ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:11836244}; CC -!- ACTIVITY REGULATION: Activated in response to stress, such as ribosomal CC stress, osmotic shock and ionizing radiation (PubMed:11042189, CC PubMed:12761180, PubMed:15342622, PubMed:32289254, PubMed:32610081). CC Activated by phosphorylation by PKN1, followed by autophosphorylation CC on Thr-161 and Ser-165 (PubMed:11042189, PubMed:12220515, CC PubMed:12761180, PubMed:15342622, PubMed:26999302). Inhibited by CC nilotinib, sorafenib, dabrafenib, rebastinib and vemurafenib CC (PubMed:26999302). Selectively inhibited by N-(3)-((1H-Pyrazolo[3,4- CC b]pyridin-5-yl)ethynyl)benzenesulfonamide compound 3h CC (PubMed:28586211). Selectively inhibited by 1,2,3-triazole CC benzenesulfonamides (PubMed:31244114). {ECO:0000269|PubMed:11042189, CC ECO:0000269|PubMed:12220515, ECO:0000269|PubMed:12761180, CC ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:26999302, CC ECO:0000269|PubMed:28586211, ECO:0000269|PubMed:31244114, CC ECO:0000269|PubMed:32289254, ECO:0000269|PubMed:32610081}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=60 uM for ATP {ECO:0000269|PubMed:14521931}; CC -!- SUBUNIT: Homodimer (PubMed:10924358, PubMed:26755636). Interacts with CC ZNF33A (PubMed:12535642). Component of a signaling complex containing CC at least AKAP13, PKN1, MAPK14, MAP3K20 and MAP2K3 (PubMed:21224381). CC Within this complex, AKAP13 interacts directly with PKN1, which in turn CC recruits MAPK14, MAP2K3 and MAP3K20 (PubMed:21224381). Interacts with CC EIF2AK4/GCN2; promoting EIF2AK4/GCN2 kinase activity (PubMed:32610081). CC {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:12535642, CC ECO:0000269|PubMed:21224381, ECO:0000269|PubMed:26755636, CC ECO:0000269|PubMed:32610081}. CC -!- SUBUNIT: [Isoform ZAKalpha]: Interacts with isoform ZAKbeta. CC {ECO:0000269|PubMed:27859413}. CC -!- SUBUNIT: [Isoform ZAKbeta]: Interacts with isoform ZAKalpha. CC {ECO:0000269|PubMed:27859413}. CC -!- INTERACTION: CC Q9NYL2; O75582: RPS6KA5; NbExp=4; IntAct=EBI-602273, EBI-73869; CC Q9NYL2; P31947: SFN; NbExp=4; IntAct=EBI-602273, EBI-476295; CC Q9NYL2; P61981: YWHAG; NbExp=6; IntAct=EBI-602273, EBI-359832; CC Q9NYL2; P63104: YWHAZ; NbExp=8; IntAct=EBI-602273, EBI-347088; CC Q9NYL2; Q8N184: ZNF567; NbExp=3; IntAct=EBI-602273, EBI-749400; CC Q9NYL2-1; Q16512: PKN1; NbExp=2; IntAct=EBI-687346, EBI-602382; CC Q9NYL2-2; Q6P2D0: ZFP1; NbExp=4; IntAct=EBI-10255081, EBI-2555749; CC Q9NYL2-2; Q6ZN57: ZFP2; NbExp=7; IntAct=EBI-10255081, EBI-7236323; CC Q9NYL2-2; P13682: ZNF35; NbExp=3; IntAct=EBI-10255081, EBI-11041653; CC Q9NYL2-2; Q8N184: ZNF567; NbExp=7; IntAct=EBI-10255081, EBI-749400; CC Q9NYL2-2; Q6AZW8: ZNF660; NbExp=3; IntAct=EBI-10255081, EBI-12376497; CC Q9NYL2-2; Q9NQZ8: ZNF71; NbExp=4; IntAct=EBI-10255081, EBI-7138235; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15684425}. Nucleus CC {ECO:0000269|PubMed:15684425}. Note=Translocates to the nucleus upon CC ultraviolet B irradiation. {ECO:0000269|PubMed:15684425}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=ZAKalpha {ECO:0000303|PubMed:32289254, CC ECO:0000303|PubMed:32610081}; Synonyms=Alpha; CC IsoId=Q9NYL2-1; Sequence=Displayed; CC Name=ZAKbeta {ECO:0000303|PubMed:32289254}; Synonyms=Beta, MLK7 CC {ECO:0000303|PubMed:11549352}; CC IsoId=Q9NYL2-2; Sequence=VSP_051743, VSP_051744; CC Name=3; Synonyms=HCCS-4; CC IsoId=Q9NYL2-3; Sequence=VSP_051741, VSP_051742; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Isoform ZAKbeta is the CC predominant form in all tissues examined, except for liver, in which CC isoform ZAKalpha is more highly expressed. CC {ECO:0000269|PubMed:10924358, ECO:0000269|PubMed:11836244}. CC -!- DOMAIN: [Isoform ZAKalpha]: Recognizes stalled ribosomes via two CC separate and partially redundant sensor domains: the C-terminal domain CC (CTD) that binds the 18S ribosomal RNA (18S rRNA) and the sensing CC domain (S). {ECO:0000269|PubMed:32289254}. CC -!- PTM: Activated by phosphorylation by PKN1, followed by CC autophosphorylation on Thr-161 and Ser-165 (PubMed:12220515, CC PubMed:12761180, PubMed:15342622, PubMed:26999302). Autophosphorylation CC in response to ribotoxic stress promotes dissociation from colliding CC ribosomes and activation (PubMed:32289254, PubMed:32610081). CC {ECO:0000269|PubMed:12220515, ECO:0000269|PubMed:12761180, CC ECO:0000269|PubMed:15342622, ECO:0000269|PubMed:26999302, CC ECO:0000269|PubMed:32289254, ECO:0000269|PubMed:32610081}. CC -!- DISEASE: Split-foot malformation with mesoaxial polydactyly (SFMMP) CC [MIM:616890]: An autosomal recessive disorder characterized by a split- CC foot defect, mesoaxial polydactyly, nail abnormalities of the hands, CC and sensorineural hearing loss. {ECO:0000269|PubMed:26755636, CC ECO:0000269|PubMed:32266845}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Myopathy, centronuclear, 6, with fiber-type disproportion CC (CNM6) [MIM:617760]: A form of centronuclear myopathy, a congenital CC muscle disorder characterized by progressive muscular weakness and CC wasting involving mainly limb girdle, trunk, and neck muscles. It may CC also affect distal muscles. Weakness may be present during childhood or CC adolescence or may not become evident until the third decade of life. CC Ptosis is a frequent clinical feature. The most prominent CC histopathologic features include high frequency of centrally located CC nuclei in muscle fibers not secondary to regeneration, radial CC arrangement of sarcoplasmic strands around the central nuclei, and CC predominance and hypotrophy of type 1 fibers. CNM6 is an autosomal CC recessive, slowly progressive form with onset in infancy or early CC childhood. {ECO:0000269|PubMed:27816943, ECO:0000269|PubMed:30237576}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr CC protein kinase family. MAP kinase kinase kinase subfamily. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAD92211.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; 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; AF238255; AAF63490.1; -; mRNA. DR EMBL; AB049733; BAB16444.1; -; mRNA. DR EMBL; AB049734; BAB16445.1; -; mRNA. DR EMBL; AF325454; AAK11615.1; -; mRNA. DR EMBL; AF480461; AAL85891.1; -; mRNA. DR EMBL; AF480462; AAL85892.1; -; mRNA. DR EMBL; AB030034; BAB12040.1; -; mRNA. DR EMBL; AF251441; AAF65822.1; -; mRNA. DR EMBL; AF465843; AAO33376.1; -; mRNA. DR EMBL; AK056310; BAG51674.1; -; mRNA. DR EMBL; AB208974; BAD92211.1; ALT_INIT; mRNA. DR EMBL; AC092573; AAX82002.1; -; Genomic_DNA. DR EMBL; AC013461; AAX93067.1; -; Genomic_DNA. DR EMBL; AC019046; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471058; EAX11164.1; -; Genomic_DNA. DR EMBL; BC001401; AAH01401.1; -; mRNA. DR CCDS; CCDS2251.1; -. [Q9NYL2-2] DR CCDS; CCDS42777.1; -. [Q9NYL2-1] DR RefSeq; NP_057737.2; NM_016653.3. [Q9NYL2-1] DR RefSeq; NP_598407.1; NM_133646.3. [Q9NYL2-2] DR RefSeq; XP_005246697.1; XM_005246640.3. [Q9NYL2-1] DR RefSeq; XP_016859812.1; XM_017004323.2. [Q9NYL2-2] DR RefSeq; XP_016859813.1; XM_017004324.2. [Q9NYL2-2] DR RefSeq; XP_047300702.1; XM_047444746.1. [Q9NYL2-1] DR RefSeq; XP_047300703.1; XM_047444747.1. [Q9NYL2-1] DR RefSeq; XP_047300704.1; XM_047444748.1. [Q9NYL2-2] DR RefSeq; XP_054198527.1; XM_054342552.1. [Q9NYL2-1] DR RefSeq; XP_054198528.1; XM_054342553.1. [Q9NYL2-1] DR RefSeq; XP_054198529.1; XM_054342554.1. [Q9NYL2-1] DR RefSeq; XP_054198530.1; XM_054342555.1. [Q9NYL2-2] DR RefSeq; XP_054198531.1; XM_054342556.1. [Q9NYL2-2] DR RefSeq; XP_054198532.1; XM_054342557.1. [Q9NYL2-2] DR PDB; 5HES; X-ray; 2.14 A; A/B=5-309. DR PDB; 5X5O; X-ray; 1.87 A; A=5-309. DR PDB; 6JUT; X-ray; 2.10 A; A=5-309. DR PDB; 6JUU; X-ray; 1.90 A; A=5-309. DR PDB; 7YAW; X-ray; 2.10 A; A/B/C/D=5-309. DR PDB; 7YAZ; X-ray; 2.54 A; A=5-309. DR PDBsum; 5HES; -. DR PDBsum; 5X5O; -. DR PDBsum; 6JUT; -. DR PDBsum; 6JUU; -. DR PDBsum; 7YAW; -. DR PDBsum; 7YAZ; -. DR AlphaFoldDB; Q9NYL2; -. DR SMR; Q9NYL2; -. DR BioGRID; 119725; 107. DR CORUM; Q9NYL2; -. DR FunCoup; Q9NYL2; 1616. DR IntAct; Q9NYL2; 82. DR MINT; Q9NYL2; -. DR STRING; 9606.ENSP00000364361; -. DR BindingDB; Q9NYL2; -. DR ChEMBL; CHEMBL3886; -. DR DrugBank; DB01254; Dasatinib. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; Q9NYL2; -. DR GuidetoPHARMACOLOGY; 2289; -. DR GlyGen; Q9NYL2; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9NYL2; -. DR MetOSite; Q9NYL2; -. DR PhosphoSitePlus; Q9NYL2; -. DR BioMuta; MAP3K20; -. DR DMDM; 313104215; -. DR jPOST; Q9NYL2; -. DR MassIVE; Q9NYL2; -. DR PaxDb; 9606-ENSP00000364361; -. DR PeptideAtlas; Q9NYL2; -. DR ProteomicsDB; 83246; -. [Q9NYL2-1] DR ProteomicsDB; 83248; -. [Q9NYL2-3] DR Pumba; Q9NYL2; -. DR Antibodypedia; 2065; 317 antibodies from 33 providers. DR DNASU; 51776; -. DR Ensembl; ENST00000338983.7; ENSP00000340257.3; ENSG00000091436.18. [Q9NYL2-2] DR Ensembl; ENST00000375213.8; ENSP00000364361.3; ENSG00000091436.18. [Q9NYL2-1] DR Ensembl; ENST00000409176.6; ENSP00000387259.2; ENSG00000091436.18. [Q9NYL2-1] DR Ensembl; ENST00000539448.5; ENSP00000439414.1; ENSG00000091436.18. [Q9NYL2-2] DR GeneID; 51776; -. DR KEGG; hsa:51776; -. DR MANE-Select; ENST00000375213.8; ENSP00000364361.3; NM_016653.3; NP_057737.2. DR UCSC; uc002uhz.4; human. [Q9NYL2-1] DR AGR; HGNC:17797; -. DR CTD; 51776; -. DR DisGeNET; 51776; -. DR GeneCards; MAP3K20; -. DR HGNC; HGNC:17797; MAP3K20. DR HPA; ENSG00000091436; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; MAP3K20; -. DR MIM; 609479; gene. DR MIM; 616890; phenotype. DR MIM; 617760; phenotype. DR OpenTargets; ENSG00000091436; -. DR Orphanet; 2020; Congenital fiber-type disproportion myopathy. DR Orphanet; 488232; Split-foot malformation-mesoaxial polydactyly syndrome. DR VEuPathDB; HostDB:ENSG00000091436; -. DR eggNOG; KOG0192; Eukaryota. DR GeneTree; ENSGT00940000161352; -. DR HOGENOM; CLU_019131_1_0_1; -. DR InParanoid; Q9NYL2; -. DR OMA; TEMSCQI; -. DR OrthoDB; 339325at2759; -. DR PAN-GO; Q9NYL2; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q9NYL2; -. DR PathwayCommons; Q9NYL2; -. DR SignaLink; Q9NYL2; -. DR SIGNOR; Q9NYL2; -. DR Agora; ENSG00000091436; -. DR BioGRID-ORCS; 51776; 13 hits in 1141 CRISPR screens. DR ChiTaRS; MAP3K20; human. DR GeneWiki; ZAK; -. DR GenomeRNAi; 51776; -. DR Pharos; Q9NYL2; Tchem. DR PRO; PR:Q9NYL2; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q9NYL2; protein. DR Bgee; ENSG00000091436; Expressed in heart right ventricle and 192 other cell types or tissues. DR ExpressionAtlas; Q9NYL2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProt. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IDA:UniProt. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IDA:UniProt. DR GO; GO:0030295; F:protein kinase activator activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProt. DR GO; GO:0043022; F:ribosome binding; IDA:UniProtKB. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0070181; F:small ribosomal subunit rRNA binding; IDA:UniProtKB. DR GO; GO:0170011; F:stalled ribosome sensor activity; IDA:UniProt. DR GO; GO:0008219; P:cell death; NAS:UniProtKB. DR GO; GO:0030154; P:cell differentiation; NAS:UniProtKB. DR GO; GO:0071480; P:cellular response to gamma radiation; IDA:UniProtKB. DR GO; GO:0071493; P:cellular response to UV-B; IDA:UniProt. DR GO; GO:0007059; P:chromosome segregation; IBA:GO_Central. DR GO; GO:0007010; P:cytoskeleton organization; IEA:Ensembl. DR GO; GO:0000077; P:DNA damage checkpoint signaling; IMP:UniProtKB. DR GO; GO:0042733; P:embryonic digit morphogenesis; IMP:UniProtKB. DR GO; GO:0140469; P:GCN2-mediated signaling; IDA:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IMP:GO_Central. DR GO; GO:0007254; P:JNK cascade; IDA:UniProtKB. DR GO; GO:0060173; P:limb development; IMP:UniProtKB. DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB. DR GO; GO:0070303; P:negative regulation of stress-activated protein kinase signaling cascade; IDA:UniProt. DR GO; GO:1902010; P:negative regulation of translation in response to endoplasmic reticulum stress; IDA:UniProt. DR GO; GO:0038066; P:p38MAPK cascade; IDA:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:1904291; P:positive regulation of mitotic DNA damage checkpoint; IDA:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0070269; P:pyroptotic inflammatory response; IDA:UniProtKB. DR GO; GO:0030071; P:regulation of mitotic metaphase/anaphase transition; IBA:GO_Central. DR GO; GO:0051403; P:stress-activated MAPK cascade; IDA:UniProtKB. DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IDA:UniProt. DR CDD; cd09529; SAM_MLTK; 1. DR CDD; cd14060; STKc_MLTK; 1. DR FunFam; 1.10.150.50:FF:000065; mitogen-activated protein kinase kinase kinase 20 isoform X1; 1. DR FunFam; 3.30.200.20:FF:000220; mitogen-activated protein kinase kinase kinase 20 isoform X1; 1. DR FunFam; 1.10.510.10:FF:000243; mitogen-activated protein kinase kinase kinase 20 isoform X2; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.150.50; Transcription Factor, Ets-1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR001660; SAM. DR InterPro; IPR013761; SAM/pointed_sf. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR051681; Ser/Thr_Kinases-Pseudokinases. DR PANTHER; PTHR44329:SF288; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 20; 1. DR PANTHER; PTHR44329; SERINE/THREONINE-PROTEIN KINASE TNNI3K-RELATED; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR Pfam; PF07647; SAM_2; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00220; S_TKc; 1. DR SMART; SM00454; SAM; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF47769; SAM/Pointed domain; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50105; SAM_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cell cycle; KW Cytoplasm; Disease variant; Kinase; Magnesium; Metal-binding; KW Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; KW Reference proteome; RNA-binding; rRNA-binding; KW Serine/threonine-protein kinase; Transferase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:22223895" FT CHAIN 2..800 FT /note="Mitogen-activated protein kinase kinase kinase 20" FT /id="PRO_0000086338" FT DOMAIN 16..277 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 339..410 FT /note="SAM" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184" FT REGION 287..308 FT /note="Leucine-zipper" FT REGION 652..800 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 670..713 FT /note="Sensing domain (S)" FT /evidence="ECO:0000269|PubMed:32289254" FT REGION 774..800 FT /note="C-terminal domain (CTD)" FT /evidence="ECO:0000269|PubMed:32289254" FT COMPBIAS 652..666 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 667..678 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 686..706 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 717..726 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 728..738 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 750..763 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 785..800 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 133 FT /note="Proton acceptor" FT /evidence="ECO:0000250|UniProtKB:P80192, FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10027" FT BINDING 22..30 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:P80192, FT ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 45 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:11836244" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:22223895" FT MOD_RES 2 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 3 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 7 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 161 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15342622, FT ECO:0000269|PubMed:26999302" FT MOD_RES 165 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15342622, FT ECO:0000269|PubMed:26999302" FT MOD_RES 275 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195" FT MOD_RES 302 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254, FT ECO:0007744|PubMed:18691976" FT MOD_RES 567 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 586 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 587 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 593 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 599 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 628 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:23186163" FT MOD_RES 633 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT MOD_RES 637 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 648 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 649 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254, FT ECO:0007744|PubMed:23186163" FT MOD_RES 660 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 664 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 685 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 718 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 720 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT MOD_RES 727 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 733 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163" FT MOD_RES 742 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:32289254" FT VAR_SEQ 285..312 FT /note="CEIEATLERLKKLERDLSFKEQELKERE -> WVAPTAGHSVWLSKTITRLN FT EEVNQRSE (in isoform 3)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_051741" FT VAR_SEQ 313..800 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_051742" FT VAR_SEQ 332..455 FT /note="PSFEIGAWTEDDVYCWVQQLVRKGDSSAEMSVYASLFKENNITGKRLLLLEE FT EDLKDMGIVSKGHIIHFKSAIEKLTHDYINLFHFPPLIKDSGGEPEENEEKIVNLELVF FT GFHLKPGTGPQDC -> LPLAARMSEESYFESKTEESNSAEMSCQITATSNGEGHGMNP FT SLQAMMLMGFGDIFSMNKAGAVMHSGMQINMQAKQNSSKTTSKRRGKKVNMALGFSDFD FT LSEGDDDDDDDGEEEDNDMDNSE (in isoform ZAKbeta)" FT /evidence="ECO:0000303|PubMed:11042189, FT ECO:0000303|PubMed:11549352, ECO:0000303|PubMed:11836244, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334" FT /id="VSP_051743" FT VAR_SEQ 456..800 FT /note="Missing (in isoform ZAKbeta)" FT /evidence="ECO:0000303|PubMed:11042189, FT ECO:0000303|PubMed:11549352, ECO:0000303|PubMed:11836244, FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334" FT /id="VSP_051744" FT VARIANT 95..800 FT /note="Missing (in CNM6; decrease of protein abundance)" FT /evidence="ECO:0000269|PubMed:27816943" FT /id="VAR_080563" FT VARIANT 172..800 FT /note="Missing (in CNM6; decrease of protein abundance)" FT /evidence="ECO:0000269|PubMed:27816943" FT /id="VAR_080564" FT VARIANT 250 FT /note="R -> W (in CNM6; uncertain significance; FT dbSNP:rs763481300)" FT /evidence="ECO:0000269|PubMed:30237576" FT /id="VAR_082158" FT VARIANT 267 FT /note="T -> M (in dbSNP:rs6758025)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040806" FT VARIANT 281 FT /note="A -> T (in an ovarian endometrioid sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040807" FT VARIANT 281 FT /note="A -> V (in dbSNP:rs34683477)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040808" FT VARIANT 368 FT /note="F -> C (in SFMMP; produces protein aggregation; FT dbSNP:rs863225437)" FT /evidence="ECO:0000269|PubMed:26755636" FT /id="VAR_076448" FT VARIANT 505 FT /note="A -> S (in SFMMP; mild destabilization of the FT protein)" FT /evidence="ECO:0000269|PubMed:32266845" FT /id="VAR_087102" FT VARIANT 531 FT /note="S -> L (in dbSNP:rs3769148)" FT /evidence="ECO:0000269|PubMed:10924358, FT ECO:0000269|PubMed:11042189, ECO:0000269|PubMed:11836244, FT ECO:0000269|PubMed:17344846, ECO:0000269|Ref.6" FT /id="VAR_022827" FT VARIANT 580 FT /note="R -> W (in dbSNP:rs7593622)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040809" FT VARIANT 740 FT /note="P -> T (in dbSNP:rs56202258)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040810" FT VARIANT 773 FT /note="Y -> H (in dbSNP:rs35608243)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040811" FT VARIANT 784 FT /note="K -> T (in dbSNP:rs55830025)" FT /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.9" FT /id="VAR_040812" FT MUTAGEN 45 FT /note="K->M: Loss of kinase activity. Does not affect FT ability to activate EIF2AK4/GCN2 in response to mild FT ribosome collision." FT /evidence="ECO:0000269|PubMed:11836244, FT ECO:0000269|PubMed:32610081, ECO:0000269|PubMed:35857590" FT MUTAGEN 161 FT /note="T->A: Loss of autophosphorylation activity." FT /evidence="ECO:0000269|PubMed:15342622" FT MUTAGEN 162 FT /note="T->A: Slight loss of autophosphorylation activity." FT /evidence="ECO:0000269|PubMed:15342622" FT MUTAGEN 165 FT /note="S->A: Loss of autophosphorylation activity." FT /evidence="ECO:0000269|PubMed:15342622" FT MUTAGEN 657 FT /note="S->A: Abolished association with BTRC without FT affecting protein stability." FT /evidence="ECO:0000269|PubMed:32289254" FT MUTAGEN 752..761 FT /note="TDSRASEEDS->DDDRADEEDD,EDERAEEEDE: Mimics FT phosphorylation; impaired ribosome-binding." FT /evidence="ECO:0000269|PubMed:32289254" FT CONFLICT 346 FT /note="C -> W (in Ref. 1; AAF63490)" FT /evidence="ECO:0000305" FT HELIX 13..15 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 16..20 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 24..26 FT /evidence="ECO:0007829|PDB:6JUT" FT STRAND 30..35 FT /evidence="ECO:0007829|PDB:5X5O" FT TURN 36..39 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 40..48 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 52..57 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 68..74 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 77..83 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 90..94 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 97..101 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 104..123 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 136..138 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 139..141 FT /evidence="ECO:0007829|PDB:5X5O" FT STRAND 147..149 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 154..157 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 159..162 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 163..166 FT /evidence="ECO:0007829|PDB:6JUT" FT TURN 167..169 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 170..172 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 175..178 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 186..201 FT /evidence="ECO:0007829|PDB:5X5O" FT TURN 205..208 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 211..220 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 233..242 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 247..249 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 253..264 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 269..277 FT /evidence="ECO:0007829|PDB:5X5O" FT HELIX 280..298 FT /evidence="ECO:0007829|PDB:5X5O" FT MOD_RES Q9NYL2-2:339 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195" FT MOD_RES Q9NYL2-2:429 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:11042189" FT MOD_RES Q9NYL2-2:434 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195" FT MOD_RES Q9NYL2-2:454 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19369195" SQ SEQUENCE 800 AA; 91155 MW; B2814509EC54B07A CRC64; MSSLGASFVQ IKFDDLQFFE NCGGGSFGSV YRAKWISQDK EVAVKKLLKI EKEAEILSVL SHRNIIQFYG VILEPPNYGI VTEYASLGSL YDYINSNRSE EMDMDHIMTW ATDVAKGMHY LHMEAPVKVI HRDLKSRNVV IAADGVLKIC DFGASRFHNH TTHMSLVGTF PWMAPEVIQS LPVSETCDTY SYGVVLWEML TREVPFKGLE GLQVAWLVVE KNERLTIPSS CPRSFAELLH QCWEADAKKR PSFKQIISIL ESMSNDTSLP DKCNSFLHNK AEWRCEIEAT LERLKKLERD LSFKEQELKE RERRLKMWEQ KLTEQSNTPL LPSFEIGAWT EDDVYCWVQQ LVRKGDSSAE MSVYASLFKE NNITGKRLLL LEEEDLKDMG IVSKGHIIHF KSAIEKLTHD YINLFHFPPL IKDSGGEPEE NEEKIVNLEL VFGFHLKPGT GPQDCKWKMY MEMDGDEIAI TYIKDVTFNT NLPDAEILKM TKPPFVMEKW IVGIAKSQTV ECTVTYESDV RTPKSTKHVH SIQWSRTKPQ DEVKAVQLAI QTLFTNSDGN PGSRSDSSAD CQWLDTLRMR QIASNTSLQR SQSNPILGSP FFSHFDGQDS YAAAVRRPQV PIKYQQITPV NQSRSSSPTQ YGLTKNFSSL HLNSRDSGFS SGNTDTSSER GRYSDRSRNK YGRGSISLNS SPRGRYSGKS QHSTPSRGRY PGKFYRVSQS ALNPHQSPDF KRSPRDLHQP NTIPGMPLHP ETDSRASEED SKVSEGGWTK VEYRKKPHRP SPAKTNKERA RGDHRGWRNF //