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Database: UniProt
Entry: Q14680
LinkDB: Q14680
Original site: Q14680 
ID   MELK_HUMAN              Reviewed;         651 AA.
AC   Q14680; A6P3A7; A6P3A8; B1AMQ6; B7Z1E6; B7Z5M5; B7Z6Q7; B7Z6R8; B7Z6Y0;
AC   B7Z7Q1; D3DRP8; F5H0Y0; F5H2R4; F5H689; Q7L3C3;
DT   19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT   19-JUL-2004, sequence version 3.
DT   11-DEC-2019, entry version 187.
DE   RecName: Full=Maternal embryonic leucine zipper kinase;
DE            Short=hMELK;
DE            EC=2.7.11.1;
DE   AltName: Full=Protein kinase Eg3;
DE            Short=pEg3 kinase;
DE   AltName: Full=Protein kinase PK38;
DE            Short=hPK38;
DE   AltName: Full=Tyrosine-protein kinase MELK;
DE            EC=2.7.10.2;
GN   Name=MELK; Synonyms=KIAA0175;
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 [MRNA] (ISOFORMS 5 AND 6).
RA   Katagiri T., Lin M.;
RT   "Identification of MELK whose expression was highly up-regulated in breast
RT   cancers.";
RL   Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC   TISSUE=Bone marrow;
RX   PubMed=8724849; DOI=10.1093/dnares/3.1.17;
RA   Nagase T., Seki N., Ishikawa K., Tanaka A., Nomura N.;
RT   "Prediction of the coding sequences of unidentified human genes. V. The
RT   coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of
RT   cDNA clones from human cell line KG-1.";
RL   DNA Res. 3:17-24(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3; 4; 5; 7 AND 8).
RC   TISSUE=Spleen, and Testis;
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 GENOMIC DNA].
RX   PubMed=15164053; DOI=10.1038/nature02465;
RA   Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA   Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA   Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA   Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA   Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA   Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA   Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA   Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA   Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA   Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA   Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA   Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA   Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA   Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA   Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA   McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA   Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA   Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA   Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA   Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA   West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA   Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA   Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA   Dunham I.;
RT   "DNA sequence and analysis of human chromosome 9.";
RL   Nature 429:369-374(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Colon;
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   INTERACTION WITH ZNF622, AND FUNCTION IN PHOSPHORYLATION OF ZNF622.
RC   TISSUE=Keratinocyte;
RX   PubMed=11802789; DOI=10.1042/0264-6021:3610597;
RA   Seong H.-A., Gil M., Kim K.-T., Kim S.-J., Ha H.;
RT   "Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine
RT   protein serine/threonine kinase 38 (MPK38).";
RL   Biochem. J. 361:597-604(2002).
RN   [8]
RP   FUNCTION IN PHOSPHORYLATION OF CDC25B.
RX   PubMed=12400006; DOI=10.1038/sj.onc.1205870;
RA   Davezac N., Baldin V., Blot J., Ducommun B., Tassan J.P.;
RT   "Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: a
RT   potential role for pEg3 in cell cycle regulation.";
RL   Oncogene 21:7630-7641(2002).
RN   [9]
RP   INTERACTION WITH PPP1R8, AUTOPHOSPHORYLATION, MUTAGENESIS OF ASP-150;
RP   THR-345; THR-387; THR-409; THR-415; THR-428; THR-446; THR-460; THR-466;
RP   THR-478 AND THR-518, PHOSPHORYLATION AT THR-478, AND FUNCTION.
RX   PubMed=14699119; DOI=10.1074/jbc.m311466200;
RA   Vulsteke V., Beullens M., Boudrez A., Keppens S., Van Eynde A., Rider M.H.,
RA   Stalmans W., Bollen M.;
RT   "Inhibition of spliceosome assembly by the cell cycle-regulated protein
RT   kinase MELK and involvement of splicing factor NIPP1.";
RL   J. Biol. Chem. 279:8642-8647(2004).
RN   [10]
RP   PHOSPHORYLATION AT THR-167, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF
RP   THR-167.
RX   PubMed=14976552; DOI=10.1038/sj.emboj.7600110;
RA   Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A., Boudeau J.,
RA   Hawley S.A., Udd L., Maekelae T.P., Hardie D.G., Alessi D.R.;
RT   "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily,
RT   including MARK/PAR-1.";
RL   EMBO J. 23:833-843(2004).
RN   [11]
RP   INVOLVEMENT IN CANCER.
RX   PubMed=16266996; DOI=10.1158/0008-5472.can-04-4531;
RA   Gray D., Jubb A.M., Hogue D., Dowd P., Kljavin N., Yi S., Bai W.,
RA   Frantz G., Zhang Z., Koeppen H., de Sauvage F.J., Davis D.P.;
RT   "Maternal embryonic leucine zipper kinase/murine protein serine-threonine
RT   kinase 38 is a promising therapeutic target for multiple cancers.";
RL   Cancer Res. 65:9751-9761(2005).
RN   [12]
RP   FUNCTION IN PHOSPHORYLATION OF CDC25B.
RX   PubMed=15908796; DOI=10.4161/cc.4.6.1716;
RA   Mirey G., Chartrain I., Froment C., Quaranta M., Bouche J.P., Monsarrat B.,
RA   Tassan J.P., Ducommun B.;
RT   "CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle
RT   poles at mitosis.";
RL   Cell Cycle 4:806-811(2005).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-505, 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   [14]
RP   PHOSPHORYLATION AT THR-167; SER-343; SER-356; TYR-367; THR-398; THR-409;
RP   SER-431; THR-494; SER-505 AND SER-529.
RX   PubMed=16628004; DOI=10.4161/cc.5.8.2683;
RA   Badouel C., Korner R., Frank-Vaillant M., Couturier A., Nigg E.A.,
RA   Tassan J.P.;
RT   "M-phase MELK activity is regulated by MPF and MAPK.";
RL   Cell Cycle 5:883-889(2006).
RN   [15]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AUTOPHOSPHORYLATION,
RP   CALCIUM-BINDING, PHOSPHORYLATION AT THR-56; TYR-163; THR-167; SER-171;
RP   SER-253; SER-336; SER-343; SER-356; SER-391; THR-398; SER-407; SER-431;
RP   THR-494; SER-505; SER-529 AND THR-539, AND MUTAGENESIS OF CYS-29; CYS-70;
RP   CYS-89; ASP-150; CYS-154; TYR-163; CYS-168; CYS-169; SER-171; CYS-204;
RP   283-ASP--ASP-285; CYS-286 AND CYS-339.
RX   PubMed=16216881; DOI=10.1074/jbc.m507274200;
RA   Beullens M., Vancauwenbergh S., Morrice N., Derua R., Ceulemans H.,
RA   Waelkens E., Bollen M.;
RT   "Substrate specificity and activity regulation of protein kinase MELK.";
RL   J. Biol. Chem. 280:40003-40011(2005).
RN   [16]
RP   SUBCELLULAR LOCATION.
RX   PubMed=16159311; DOI=10.1042/bc20050041;
RA   Chartrain I., Couturier A., Tassan J.P.;
RT   "Cell-cycle-dependent cortical localization of pEg3 protein kinase in
RT   Xenopus and human cells.";
RL   Biol. Cell 98:253-263(2006).
RN   [17]
RP   FUNCTION IN PHOSPHORYLATION OF BCL2L14, AND MUTAGENESIS OF ASP-150.
RX   PubMed=17280616; DOI=10.1186/bcr1650;
RA   Lin M.L., Park J.H., Nishidate T., Nakamura Y., Katagiri T.;
RT   "Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary
RT   carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of
RT   the Bcl-2 family.";
RL   Breast Cancer Res. 9:R17-R17(2007).
RN   [18]
RP   INVOLVEMENT IN CANCER.
RX   PubMed=17960622; DOI=10.1002/ijc.23189;
RA   Marie S.K., Okamoto O.K., Uno M., Hasegawa A.P., Oba-Shinjo S.M., Cohen T.,
RA   Camargo A.A., Kosoy A., Carlotti C.G. Jr., Toledo S., Moreira-Filho C.A.,
RA   Zago M.A., Simpson A.J., Caballero O.L.;
RT   "Maternal embryonic leucine zipper kinase transcript abundance correlates
RT   with malignancy grade in human astrocytomas.";
RL   Int. J. Cancer 122:807-815(2008).
RN   [19]
RP   INVOLVEMENT IN CANCER.
RX   PubMed=17722061; DOI=10.1002/jnr.21471;
RA   Nakano I., Masterman-Smith M., Saigusa K., Paucar A.A., Horvath S.,
RA   Shoemaker L., Watanabe M., Negro A., Bajpai R., Howes A., Lelievre V.,
RA   Waschek J.A., Lazareff J.A., Freije W.A., Liau L.M., Gilbertson R.J.,
RA   Cloughesy T.F., Geschwind D.H., Nelson S.F., Mischel P.S., Terskikh A.V.,
RA   Kornblum H.I.;
RT   "Maternal embryonic leucine zipper kinase is a key regulator of the
RT   proliferation of malignant brain tumors, including brain tumor stem
RT   cells.";
RL   J. Neurosci. Res. 86:48-60(2008).
RN   [20]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356; SER-498; SER-505;
RP   THR-518 AND SER-529, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   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   [21]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-431 AND SER-505, AND
RP   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   [22]
RP   INVOLVEMENT IN CANCER.
RX   PubMed=19671159; DOI=10.1186/bcr2350;
RA   Pickard M.R., Green A.R., Ellis I.O., Caldas C., Hedge V.L.,
RA   Mourtada-Maarabouni M., Williams G.T.;
RT   "Dysregulated expression of Fau and MELK is associated with poor prognosis
RT   in breast cancer.";
RL   Breast Cancer Res. 11:R60-R60(2009).
RN   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356; SER-498; SER-505 AND
RP   SER-529, AND IDENTIFICATION BY MASS 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   [24]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356, 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   [25]
RP   INVOLVEMENT IN CANCER.
RX   PubMed=20861186; DOI=10.1158/0008-5472.can-10-1295;
RA   Hebbard L.W., Maurer J., Miller A., Lesperance J., Hassell J., Oshima R.G.,
RA   Terskikh A.V.;
RT   "Maternal embryonic leucine zipper kinase is upregulated and required in
RT   mammary tumor-initiating cells in vivo.";
RL   Cancer Res. 70:8863-8873(2010).
RN   [26]
RP   SUBCELLULAR LOCATION.
RX   PubMed=21145462; DOI=10.1016/j.cell.2010.11.028;
RA   Moravcevic K., Mendrola J.M., Schmitz K.R., Wang Y.H., Slochower D.,
RA   Janmey P.A., Lemmon M.A.;
RT   "Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by
RT   binding acidic phospholipids.";
RL   Cell 143:966-977(2010).
RN   [27]
RP   DEVELOPMENTAL STAGE, AND PHOSPHORYLATION.
RX   PubMed=20420823; DOI=10.1016/j.yexcr.2010.04.019;
RA   Badouel C., Chartrain I., Blot J., Tassan J.P.;
RT   "Maternal embryonic leucine zipper kinase is stabilized in mitosis by
RT   phosphorylation and is partially degraded upon mitotic exit.";
RL   Exp. Cell Res. 316:2166-2173(2010).
RN   [28]
RP   INDUCTION.
RX   PubMed=21806965; DOI=10.1016/j.bbrc.2011.07.060;
RA   Choi S., Ku J.L.;
RT   "Resistance of colorectal cancer cells to radiation and 5-FU is associated
RT   with MELK expression.";
RL   Biochem. Biophys. Res. Commun. 412:207-213(2011).
RN   [29]
RP   INDUCTION.
RX   PubMed=21558073; DOI=10.1093/neuonc/nor023;
RA   Nakano I., Joshi K., Visnyei K., Hu B., Watanabe M., Lam D., Wexler E.,
RA   Saigusa K., Nakamura Y., Laks D.R., Mischel P.S., Viapiano M.,
RA   Kornblum H.I.;
RT   "Siomycin A targets brain tumor stem cells partially through a MELK-
RT   mediated pathway.";
RL   Neuro-oncol. 13:622-634(2011).
RN   [30]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356; SER-498; SER-505 AND
RP   SER-529, AND 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   [31]
RP   VARIANTS [LARGE SCALE ANALYSIS] MET-56; ARG-219; LYS-333; ILE-348 AND
RP   MET-460.
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).
CC   -!- FUNCTION: Serine/threonine-protein kinase involved in various processes
CC       such as cell cycle regulation, self-renewal of stem cells, apoptosis
CC       and splicing regulation. Has a broad substrate specificity;
CC       phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an
CC       activator of apoptosis by phosphorylating and activating MAP3K5/ASK1.
CC       Acts as a regulator of cell cycle, notably by mediating phosphorylation
CC       of CDC25B, promoting localization of CDC25B to the centrosome and the
CC       spindle poles during mitosis. Plays a key role in cell proliferation
CC       and carcinogenesis. Required for proliferation of embryonic and
CC       postnatal multipotent neural progenitors. Phosphorylates and inhibits
CC       BCL2L14, possibly leading to affect mammary carcinogenesis by mediating
CC       inhibition of the pro-apoptotic function of BCL2L14. Also involved in
CC       the inhibition of spliceosome assembly during mitosis by
CC       phosphorylating ZNF622, thereby contributing to its redirection to the
CC       nucleus. May also play a role in primitive hematopoiesis.
CC       {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:12400006,
CC       ECO:0000269|PubMed:14699119, ECO:0000269|PubMed:15908796,
CC       ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC         [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10027,
CC         ECO:0000269|PubMed:16216881};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC         [protein]; 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=2.7.11.1;
CC         Evidence={ECO:0000269|PubMed:16216881};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC         threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC         Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16216881};
CC   -!- ACTIVITY REGULATION: Activated by autophosphorylation of the T-loop at
CC       Thr-167 and Ser-171: in contrast to other members of the SNF1
CC       subfamily, phosphorylation at Thr-167 is not mediated by STK11/LKB1 but
CC       via autophosphorylation instead. Inhibited by calcium-binding. Kinase
CC       activity is also regulated by reducing agents: dithiothreitol (DTT) or
CC       reduced glutathione are required for kinase activity in vitro; such
CC       dependence is however not due to the presence of disulfide bonds.
CC       {ECO:0000269|PubMed:16216881}.
CC   -!- SUBUNIT: Monomer. Interacts with ZNF622 and PPP1R8.
CC       {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:14699119}.
CC   -!- INTERACTION:
CC       Q9BZR8:BCL2L14; NbExp=4; IntAct=EBI-1046702, EBI-1385773;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16159311,
CC       ECO:0000269|PubMed:21145462}; Peripheral membrane protein
CC       {ECO:0000269|PubMed:16159311, ECO:0000269|PubMed:21145462}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=8;
CC       Name=1;
CC         IsoId=Q14680-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q14680-2; Sequence=VSP_044715;
CC       Name=3;
CC         IsoId=Q14680-3; Sequence=VSP_045208;
CC       Name=4;
CC         IsoId=Q14680-4; Sequence=VSP_045209;
CC       Name=5;
CC         IsoId=Q14680-5; Sequence=VSP_045430;
CC       Name=6;
CC         IsoId=Q14680-6; Sequence=VSP_045431;
CC       Name=7;
CC         IsoId=Q14680-7; Sequence=VSP_046760;
CC       Name=8;
CC         IsoId=Q14680-8; Sequence=VSP_046759;
CC   -!- TISSUE SPECIFICITY: Expressed in placenta, kidney, thymus, testis,
CC       ovary and intestine. {ECO:0000269|PubMed:8724849}.
CC   -!- DEVELOPMENTAL STAGE: Increases during G2/M phase compared to
CC       interphase. Protein level decreases when cells exit mitosis, probably
CC       due to degradation. {ECO:0000269|PubMed:20420823}.
CC   -!- INDUCTION: Up-regulated in many cancers cells. Up-regulated upon
CC       treatment with radiation or 5-fluorouracil (5-FU) in colorectal cancer
CC       cells, suggesting that it might be associated with increased resistance
CC       of colorectal cells against radiation and 5-FU. Down-regulated upon
CC       siomycin A, a thiazole antibiotic, treatment, leading to inhibit tumor
CC       growth in vivo. {ECO:0000269|PubMed:21558073,
CC       ECO:0000269|PubMed:21806965}.
CC   -!- DOMAIN: The KA1 domain mediates binding to phospholipids and targeting
CC       to membranes. {ECO:0000250}.
CC   -!- PTM: Autophosphorylated: autophosphorylation of the T-loop at Thr-167
CC       and Ser-171 is required for activation. Thr-478 phosphorylation during
CC       mitosis promotes interaction with PPP1R8 (Probable).
CC       {ECO:0000305|PubMed:14699119, ECO:0000305|PubMed:14976552,
CC       ECO:0000305|PubMed:16216881, ECO:0000305|PubMed:16628004,
CC       ECO:0000305|PubMed:20420823}.
CC   -!- DISEASE: Note=Defects in MELK are associated with some cancers, such as
CC       brain or breast cancers. Expression is dramatically increased in
CC       aggressive undifferentiated tumors, correlating with poor patient
CC       outcome in breast and brain cancers, suggesting a role in tumor-
CC       initiating cells and proliferation via its function in cell
CC       proliferation regulation.
CC   -!- MISCELLANEOUS: Potential therapeutic target for treatment of somatic
CC       tumors, such as brain and breast cancers, down-regulation of MELK
CC       inhibiting tumorigenesis (PubMed:17960622, PubMed:20861186).
CC       {ECO:0000305|PubMed:17960622, ECO:0000305|PubMed:20861186}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC       protein kinase family. SNF1 subfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA11492.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/MELKID43360ch9p13.html";
DR   EMBL; AB183427; BAF73615.1; -; mRNA.
DR   EMBL; AB183428; BAF73616.1; -; mRNA.
DR   EMBL; D79997; BAA11492.2; ALT_INIT; mRNA.
DR   EMBL; AK293284; BAH11482.1; -; mRNA.
DR   EMBL; AK293447; BAH11508.1; -; mRNA.
DR   EMBL; AK299164; BAH12961.1; -; mRNA.
DR   EMBL; AK300761; BAH13343.1; -; mRNA.
DR   EMBL; AK300821; BAH13354.1; -; mRNA.
DR   EMBL; AK301131; BAH13416.1; -; mRNA.
DR   EMBL; AK302374; BAH13687.1; -; mRNA.
DR   EMBL; AL354932; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL442063; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471071; EAW58303.1; -; Genomic_DNA.
DR   EMBL; CH471071; EAW58304.1; -; Genomic_DNA.
DR   EMBL; BC014039; AAH14039.1; -; mRNA.
DR   CCDS; CCDS59123.1; -. [Q14680-7]
DR   CCDS; CCDS59124.1; -. [Q14680-8]
DR   CCDS; CCDS59125.1; -. [Q14680-2]
DR   CCDS; CCDS59126.1; -. [Q14680-6]
DR   CCDS; CCDS59127.1; -. [Q14680-5]
DR   CCDS; CCDS59128.1; -. [Q14680-4]
DR   CCDS; CCDS6606.1; -. [Q14680-1]
DR   RefSeq; NP_001243614.1; NM_001256685.1. [Q14680-7]
DR   RefSeq; NP_001243616.1; NM_001256687.1. [Q14680-8]
DR   RefSeq; NP_001243617.1; NM_001256688.1. [Q14680-2]
DR   RefSeq; NP_001243618.1; NM_001256689.1. [Q14680-6]
DR   RefSeq; NP_001243619.1; NM_001256690.1. [Q14680-5]
DR   RefSeq; NP_001243621.1; NM_001256692.1. [Q14680-4]
DR   RefSeq; NP_001243622.1; NM_001256693.1. [Q14680-3]
DR   RefSeq; NP_055606.1; NM_014791.3. [Q14680-1]
DR   RefSeq; XP_011516378.1; XM_011518076.2. [Q14680-1]
DR   RefSeq; XP_011516379.1; XM_011518077.1. [Q14680-1]
DR   RefSeq; XP_011516380.1; XM_011518078.2. [Q14680-1]
DR   RefSeq; XP_011516381.1; XM_011518079.1. [Q14680-1]
DR   RefSeq; XP_011516383.1; XM_011518081.2. [Q14680-6]
DR   RefSeq; XP_011516384.1; XM_011518082.2. [Q14680-6]
DR   RefSeq; XP_011516385.1; XM_011518083.2. [Q14680-6]
DR   RefSeq; XP_011516386.1; XM_011518084.2. [Q14680-6]
DR   PDB; 4BKY; X-ray; 1.83 A; A=2-340.
DR   PDB; 4BKZ; X-ray; 2.20 A; A=2-340.
DR   PDB; 4BL1; X-ray; 2.60 A; A=2-340.
DR   PDB; 4D2P; X-ray; 2.55 A; A/B/C/D=1-336.
DR   PDB; 4D2T; X-ray; 2.70 A; A/B/C/D=1-336.
DR   PDB; 4D2V; X-ray; 2.45 A; A/B/C/D=1-336.
DR   PDB; 4D2W; X-ray; 1.92 A; A/B/C/D=1-336.
DR   PDB; 4IXP; X-ray; 2.75 A; A=1-340.
DR   PDB; 4UMP; X-ray; 2.30 A; A/B/C/D=1-336.
DR   PDB; 4UMQ; X-ray; 2.60 A; A=1-336.
DR   PDB; 4UMR; X-ray; 3.00 A; A=1-336.
DR   PDB; 4UMT; X-ray; 1.98 A; A=1-336.
DR   PDB; 4UMU; X-ray; 2.02 A; A=1-336.
DR   PDB; 5IH8; X-ray; 1.85 A; A=3-330.
DR   PDB; 5IH9; X-ray; 1.79 A; A=3-330.
DR   PDB; 5IHA; X-ray; 1.96 A; A=3-330.
DR   PDB; 5IHC; X-ray; 2.14 A; A=3-330.
DR   PDB; 5K00; X-ray; 1.77 A; A=3-330.
DR   PDB; 5M5A; X-ray; 1.90 A; A=2-340.
DR   PDB; 5MAF; X-ray; 2.80 A; A=2-340.
DR   PDB; 5MAG; X-ray; 2.35 A; A=2-340.
DR   PDB; 5MAH; X-ray; 2.00 A; A=2-340.
DR   PDB; 5MAI; X-ray; 2.15 A; A=2-340.
DR   PDB; 5TVT; X-ray; 2.28 A; A=2-333.
DR   PDB; 5TWL; X-ray; 2.42 A; A=2-340.
DR   PDB; 5TWU; X-ray; 2.60 A; A/B=1-340.
DR   PDB; 5TWY; X-ray; 2.91 A; A/B=2-340.
DR   PDB; 5TWZ; X-ray; 2.63 A; A=2-340.
DR   PDB; 5TX3; X-ray; 2.90 A; A/B=1-340.
DR   PDB; 6GVX; X-ray; 2.24 A; A/B=1-340.
DR   PDBsum; 4BKY; -.
DR   PDBsum; 4BKZ; -.
DR   PDBsum; 4BL1; -.
DR   PDBsum; 4D2P; -.
DR   PDBsum; 4D2T; -.
DR   PDBsum; 4D2V; -.
DR   PDBsum; 4D2W; -.
DR   PDBsum; 4IXP; -.
DR   PDBsum; 4UMP; -.
DR   PDBsum; 4UMQ; -.
DR   PDBsum; 4UMR; -.
DR   PDBsum; 4UMT; -.
DR   PDBsum; 4UMU; -.
DR   PDBsum; 5IH8; -.
DR   PDBsum; 5IH9; -.
DR   PDBsum; 5IHA; -.
DR   PDBsum; 5IHC; -.
DR   PDBsum; 5K00; -.
DR   PDBsum; 5M5A; -.
DR   PDBsum; 5MAF; -.
DR   PDBsum; 5MAG; -.
DR   PDBsum; 5MAH; -.
DR   PDBsum; 5MAI; -.
DR   PDBsum; 5TVT; -.
DR   PDBsum; 5TWL; -.
DR   PDBsum; 5TWU; -.
DR   PDBsum; 5TWY; -.
DR   PDBsum; 5TWZ; -.
DR   PDBsum; 5TX3; -.
DR   PDBsum; 6GVX; -.
DR   SMR; Q14680; -.
DR   BioGrid; 115171; 61.
DR   IntAct; Q14680; 17.
DR   MINT; Q14680; -.
DR   STRING; 9606.ENSP00000298048; -.
DR   BindingDB; Q14680; -.
DR   ChEMBL; CHEMBL4578; -.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugCentral; Q14680; -.
DR   GuidetoPHARMACOLOGY; 2102; -.
DR   iPTMnet; Q14680; -.
DR   PhosphoSitePlus; Q14680; -.
DR   BioMuta; MELK; -.
DR   DMDM; 50400857; -.
DR   CPTAC; CPTAC-1169; -.
DR   EPD; Q14680; -.
DR   jPOST; Q14680; -.
DR   MassIVE; Q14680; -.
DR   MaxQB; Q14680; -.
DR   PaxDb; Q14680; -.
DR   PeptideAtlas; Q14680; -.
DR   PRIDE; Q14680; -.
DR   ProteomicsDB; 1664; -.
DR   ProteomicsDB; 1665; -.
DR   ProteomicsDB; 25479; -.
DR   ProteomicsDB; 26046; -.
DR   ProteomicsDB; 27114; -.
DR   ProteomicsDB; 60115; -. [Q14680-1]
DR   ProteomicsDB; 6817; -.
DR   ProteomicsDB; 6894; -.
DR   DNASU; 9833; -.
DR   Ensembl; ENST00000298048; ENSP00000298048; ENSG00000165304. [Q14680-1]
DR   Ensembl; ENST00000536329; ENSP00000443550; ENSG00000165304. [Q14680-5]
DR   Ensembl; ENST00000536860; ENSP00000439792; ENSG00000165304. [Q14680-8]
DR   Ensembl; ENST00000536987; ENSP00000439184; ENSG00000165304. [Q14680-4]
DR   Ensembl; ENST00000541717; ENSP00000437804; ENSG00000165304. [Q14680-7]
DR   Ensembl; ENST00000543751; ENSP00000441596; ENSG00000165304. [Q14680-6]
DR   Ensembl; ENST00000545008; ENSP00000445452; ENSG00000165304. [Q14680-2]
DR   GeneID; 9833; -.
DR   KEGG; hsa:9833; -.
DR   UCSC; uc003zzn.5; human. [Q14680-1]
DR   CTD; 9833; -.
DR   DisGeNET; 9833; -.
DR   EuPathDB; HostDB:ENSG00000165304.7; -.
DR   GeneCards; MELK; -.
DR   HGNC; HGNC:16870; MELK.
DR   HPA; HPA017214; -.
DR   MIM; 607025; gene.
DR   neXtProt; NX_Q14680; -.
DR   OpenTargets; ENSG00000165304; -.
DR   PharmGKB; PA134902874; -.
DR   eggNOG; KOG0583; Eukaryota.
DR   eggNOG; COG0515; LUCA.
DR   GeneTree; ENSGT00940000154889; -.
DR   HOGENOM; HOG000233023; -.
DR   InParanoid; Q14680; -.
DR   KO; K08799; -.
DR   OMA; KTLLHQH; -.
DR   OrthoDB; 1127668at2759; -.
DR   PhylomeDB; Q14680; -.
DR   TreeFam; TF314032; -.
DR   SignaLink; Q14680; -.
DR   SIGNOR; Q14680; -.
DR   ChiTaRS; MELK; human.
DR   GeneWiki; MELK; -.
DR   GenomeRNAi; 9833; -.
DR   Pharos; Q14680; Tchem.
DR   PRO; PR:Q14680; -.
DR   Proteomes; UP000005640; Chromosome 9.
DR   RNAct; Q14680; protein.
DR   Bgee; ENSG00000165304; Expressed in 142 organ(s), highest expression level in secondary oocyte.
DR   ExpressionAtlas; Q14680; baseline and differential.
DR   Genevisible; Q14680; HS.
DR   GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR   GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR   GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR   GO; GO:0008283; P:cell population proliferation; IDA:UniProtKB.
DR   GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:UniProtKB.
DR   GO; GO:0030097; P:hemopoiesis; ISS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; IEA:Ensembl.
DR   GO; GO:0061351; P:neural precursor cell proliferation; ISS:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR   CDD; cd14078; STKc_MELK; 1.
DR   InterPro; IPR028375; KA1/Ssp2_C.
DR   InterPro; IPR001772; KA1_dom.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR034673; MELK.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF02149; KA1; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF103243; SSF103243; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS50032; KA1; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Apoptosis; ATP-binding; Calcium;
KW   Cell cycle; Cell membrane; Kinase; Lipid-binding; Membrane;
KW   Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase.
FT   CHAIN           1..651
FT                   /note="Maternal embryonic leucine zipper kinase"
FT                   /id="PRO_0000086323"
FT   DOMAIN          11..263
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          602..651
FT                   /note="KA1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00565"
FT   NP_BIND         17..25
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          282..321
FT                   /note="UBA-like"
FT   REGION          326..651
FT                   /note="Autoinhibitory region"
FT   ACT_SITE        132
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         40
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         56
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         163
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         167
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:14976552,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:16628004"
FT   MOD_RES         171
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         253
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         336
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         343
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881,
FT                   ECO:0000269|PubMed:16628004"
FT   MOD_RES         356
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:19690332,
FT                   ECO:0000244|PubMed:23186163, ECO:0000269|PubMed:16216881,
FT                   ECO:0000269|PubMed:16628004"
FT   MOD_RES         367
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000269|PubMed:16628004"
FT   MOD_RES         391
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         398
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881,
FT                   ECO:0000269|PubMed:16628004"
FT   MOD_RES         407
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MOD_RES         409
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:16628004"
FT   MOD_RES         431
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000244|PubMed:18669648,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:16628004"
FT   MOD_RES         478
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MOD_RES         494
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881,
FT                   ECO:0000269|PubMed:16628004"
FT   MOD_RES         498
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:23186163"
FT   MOD_RES         505
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000244|PubMed:17081983,
FT                   ECO:0000244|PubMed:18669648, ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:23186163,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:16628004"
FT   MOD_RES         518
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000244|PubMed:18691976"
FT   MOD_RES         529
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:23186163,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:16628004"
FT   MOD_RES         529
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:23186163,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:16628004"
FT   MOD_RES         539
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   VAR_SEQ         1..194
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_045208"
FT   VAR_SEQ         1..135
FT                   /note="MKDYDELLKYYELHETIGTGGFAKVKLACHILTGEMVAIKIMDKNTLGSDLP
FT                   RIKTEIEALKNLRHQHICQLYHVLETANKIFMVLEYCPGGELFDYIISQDRLSEEETRV
FT                   VFRQIVSAVAYVHSQGYAHRDLKP -> MVLE (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_045209"
FT   VAR_SEQ         1..87
FT                   /note="MKDYDELLKYYELHETIGTGGFAKVKLACHILTGEMVAIKIMDKNTLGSDLP
FT                   RIKTEIEALKNLRHQHICQLYHVLETANKIFMVLE -> MMNFSNIMNYMKLLGQ (in
FT                   isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.1"
FT                   /id="VSP_045430"
FT   VAR_SEQ         1..48
FT                   /note="MKDYDELLKYYELHETIGTGGFAKVKLACHILTGEMVAIKIMDKNTLG ->
FT                   MMNFSNIMNYMKLLGQ (in isoform 6)"
FT                   /evidence="ECO:0000303|Ref.1"
FT                   /id="VSP_045431"
FT   VAR_SEQ         88..158
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_044715"
FT   VAR_SEQ         88..135
FT                   /note="Missing (in isoform 8)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_046759"
FT   VAR_SEQ         352..392
FT                   /note="Missing (in isoform 7)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_046760"
FT   VARIANT         56
FT                   /note="T -> M (in dbSNP:rs35233455)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040794"
FT   VARIANT         219
FT                   /note="K -> R (in dbSNP:rs35142210)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040795"
FT   VARIANT         333
FT                   /note="R -> K (in dbSNP:rs34655121)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040796"
FT   VARIANT         348
FT                   /note="T -> I (in dbSNP:rs55845414)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040797"
FT   VARIANT         460
FT                   /note="T -> M (in an ovarian mucinous carcinoma sample;
FT                   somatic mutation; dbSNP:rs144052967)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040798"
FT   MUTAGEN         29
FT                   /note="C->V: Abolishes dependence to reducing agents; when
FT                   associated with V-70; A-89; A-154; A-168; A-169; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         70
FT                   /note="C->V: Abolishes dependence to reducing agents; when
FT                   associated with V-29; A-89; A-154; A-168; A-169; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         89
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-154; A-168; A-169; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         150
FT                   /note="D->A: Abolishes enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:14699119,
FT                   ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616"
FT   MUTAGEN         154
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-168; A-169; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         163
FT                   /note="Y->F: Abolishes autophosphorylation on tyrosine but
FT                   still active on exogenous substrates."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         167
FT                   /note="T->A: Abolishes activation of serine/threonine-
FT                   protein kinase activity and has only weak activity."
FT                   /evidence="ECO:0000269|PubMed:14976552"
FT   MUTAGEN         167
FT                   /note="T->D,E: Phosphomimetic mutant that has similar
FT                   kinase activity as wild-type."
FT                   /evidence="ECO:0000269|PubMed:14976552"
FT   MUTAGEN         168
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-154; A-169; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         169
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-154; A-168; A-204; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         171
FT                   /note="S->A: Abolishes activation of serine/threonine-
FT                   protein kinase activity and has only weak activity."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         171
FT                   /note="S->D: Inactive."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         204
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-154; A-168; A-169; A-
FT                   286 and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         283..285
FT                   /note="DDD->KKK: Inactive."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         286
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-154; A-168; A-169; A-
FT                   204; and A-339."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         339
FT                   /note="C->A: Abolishes dependence to reducing agents; when
FT                   associated with V-29; V-70; A-89; A-154; A-168; A-169; A-
FT                   204 and A-286."
FT                   /evidence="ECO:0000269|PubMed:16216881"
FT   MUTAGEN         345
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         387
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         409
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         415
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         428
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         446
FT                   /note="T->A: Inhibits interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         460
FT                   /note="T->A: Inhibits interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         466
FT                   /note="T->A: Inhibits interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         478
FT                   /note="T->A: Strongly inhibits interaction with PPP1R8.
FT                   Enhances enzymatic activity."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   MUTAGEN         518
FT                   /note="T->A: No effect on interaction with PPP1R8."
FT                   /evidence="ECO:0000269|PubMed:14699119"
FT   CONFLICT        69
FT                   /note="I -> M (in Ref. 3; BAH12961)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        398
FT                   /note="T -> A (in Ref. 3; BAH12961)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        428
FT                   /note="T -> A (in Ref. 3; BAH11482)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        474
FT                   /note="C -> R (in Ref. 3; BAH13343)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        483
FT                   /note="P -> L (in Ref. 3; BAH13354)"
FT                   /evidence="ECO:0000305"
FT   TURN            4..6
FT                   /evidence="ECO:0000244|PDB:4BKY"
FT   HELIX           7..9
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          11..19
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          20..22
FT                   /evidence="ECO:0000244|PDB:4D2T"
FT   STRAND          24..30
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   TURN            31..33
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          36..43
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           44..47
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           48..50
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           51..62
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          72..77
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          79..87
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           94..101
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           106..125
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           135..137
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          138..140
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          146..148
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          157..159
FT                   /evidence="ECO:0000244|PDB:4UMP"
FT   STRAND          163..166
FT                   /evidence="ECO:0000244|PDB:4IXP"
FT   HELIX           172..174
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           177..181
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           187..204
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           214..223
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           234..243
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           248..250
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           254..258
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           261..264
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   TURN            265..267
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          279..281
FT                   /evidence="ECO:0000244|PDB:4BKZ"
FT   HELIX           284..291
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   STRAND          294..296
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           298..306
FT                   /evidence="ECO:0000244|PDB:5K00"
FT   HELIX           312..326
FT                   /evidence="ECO:0000244|PDB:5K00"
SQ   SEQUENCE   651 AA;  74642 MW;  57F05CDC6122E570 CRC64;
     MKDYDELLKY YELHETIGTG GFAKVKLACH ILTGEMVAIK IMDKNTLGSD LPRIKTEIEA
     LKNLRHQHIC QLYHVLETAN KIFMVLEYCP GGELFDYIIS QDRLSEEETR VVFRQIVSAV
     AYVHSQGYAH RDLKPENLLF DEYHKLKLID FGLCAKPKGN KDYHLQTCCG SLAYAAPELI
     QGKSYLGSEA DVWSMGILLY VLMCGFLPFD DDNVMALYKK IMRGKYDVPK WLSPSSILLL
     QQMLQVDPKK RISMKNLLNH PWIMQDYNYP VEWQSKNPFI HLDDDCVTEL SVHHRNNRQT
     MEDLISLWQY DHLTATYLLL LAKKARGKPV RLRLSSFSCG QASATPFTDI KSNNWSLEDV
     TASDKNYVAG LIDYDWCEDD LSTGAATPRT SQFTKYWTES NGVESKSLTP ALCRTPANKL
     KNKENVYTPK SAVKNEEYFM FPEPKTPVNK NQHKREILTT PNRYTTPSKA RNQCLKETPI
     KIPVNSTGTD KLMTGVISPE RRCRSVELDL NQAHMEETPK RKGAKVFGSL ERGLDKVITV
     LTRSKRKGSA RDGPRRLKLH YNVTTTRLVN PDQLLNEIMS ILPKKHVDFV QKGYTLKCQT
     QSDFGKVTMQ FELEVCQLQK PDVVGIRRQR LKGDAWVYKR LVEDILSSCK V
//
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