MELK_HUMAN
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 03-AUG-2022, entry version 199.
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 Q14680; 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";
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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 PDB; 6VXR; X-ray; 2.10 A; A=1-338.
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 PDBsum; 6VXR; -.
DR AlphaFoldDB; Q14680; -.
DR SMR; Q14680; -.
DR BioGRID; 115171; 100.
DR IntAct; Q14680; 27.
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 Antibodypedia; 2095; 472 antibodies from 40 providers.
DR DNASU; 9833; -.
DR Ensembl; ENST00000298048.7; ENSP00000298048.2; ENSG00000165304.8. [Q14680-1]
DR Ensembl; ENST00000536329.5; ENSP00000443550.1; ENSG00000165304.8. [Q14680-5]
DR Ensembl; ENST00000536860.5; ENSP00000439792.1; ENSG00000165304.8. [Q14680-8]
DR Ensembl; ENST00000536987.5; ENSP00000439184.1; ENSG00000165304.8. [Q14680-4]
DR Ensembl; ENST00000541717.4; ENSP00000437804.1; ENSG00000165304.8. [Q14680-7]
DR Ensembl; ENST00000543751.5; ENSP00000441596.1; ENSG00000165304.8. [Q14680-6]
DR Ensembl; ENST00000545008.5; ENSP00000445452.1; ENSG00000165304.8. [Q14680-2]
DR GeneID; 9833; -.
DR KEGG; hsa:9833; -.
DR MANE-Select; ENST00000298048.7; ENSP00000298048.2; NM_014791.4; NP_055606.1.
DR UCSC; uc003zzn.5; human. [Q14680-1]
DR CTD; 9833; -.
DR DisGeNET; 9833; -.
DR GeneCards; MELK; -.
DR HGNC; HGNC:16870; MELK.
DR HPA; ENSG00000165304; Tissue enhanced (bone marrow, lymphoid tissue).
DR MIM; 607025; gene.
DR neXtProt; NX_Q14680; -.
DR OpenTargets; ENSG00000165304; -.
DR PharmGKB; PA134902874; -.
DR VEuPathDB; HostDB:ENSG00000165304; -.
DR eggNOG; KOG0583; Eukaryota.
DR GeneTree; ENSGT00940000154889; -.
DR HOGENOM; CLU_000288_157_8_1; -.
DR InParanoid; Q14680; -.
DR OMA; LRAHYNV; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q14680; -.
DR TreeFam; TF314032; -.
DR PathwayCommons; Q14680; -.
DR SignaLink; Q14680; -.
DR SIGNOR; Q14680; -.
DR BioGRID-ORCS; 9833; 11 hits in 1115 CRISPR screens.
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 secondary oocyte and 145 other tissues.
DR ExpressionAtlas; Q14680; baseline and differential.
DR Genevisible; Q14680; HS.
DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
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:0106310; F:protein serine kinase activity; IEA:RHEA.
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; 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 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 17..25
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 40
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
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:0000269|PubMed:16216881,
FT ECO:0000269|PubMed:16628004, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
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:0000269|PubMed:16216881,
FT ECO:0000269|PubMed:16628004, ECO:0007744|PubMed:18669648"
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:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 505
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16216881,
FT ECO:0000269|PubMed:16628004, ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 518
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:16216881,
FT ECO:0000269|PubMed:16628004, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT MOD_RES 529
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16216881,
FT ECO:0000269|PubMed:16628004, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
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:0007829|PDB:4BKY"
FT HELIX 7..9
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 11..19
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 20..22
FT /evidence="ECO:0007829|PDB:4D2T"
FT STRAND 24..30
FT /evidence="ECO:0007829|PDB:5K00"
FT TURN 31..33
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 36..43
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 44..47
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 48..50
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 51..62
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 72..77
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 79..87
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 94..101
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 106..125
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 135..137
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 138..140
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:4UMP"
FT STRAND 163..166
FT /evidence="ECO:0007829|PDB:4IXP"
FT HELIX 172..174
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 177..181
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 187..204
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 214..223
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 234..243
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 248..250
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 254..258
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 261..264
FT /evidence="ECO:0007829|PDB:5K00"
FT TURN 265..267
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 279..281
FT /evidence="ECO:0007829|PDB:4BKZ"
FT HELIX 284..291
FT /evidence="ECO:0007829|PDB:5K00"
FT STRAND 294..296
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 298..306
FT /evidence="ECO:0007829|PDB:5K00"
FT HELIX 312..326
FT /evidence="ECO:0007829|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
