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Database: UniProt
Entry: Q92630
LinkDB: Q92630
Original site: Q92630 
ID   DYRK2_HUMAN             Reviewed;         601 AA.
AC   Q92630; B2R9V9; Q9BRB5;
DT   27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT   12-JUN-2007, sequence version 3.
DT   02-JUN-2021, entry version 208.
DE   RecName: Full=Dual specificity tyrosine-phosphorylation-regulated kinase 2;
DE            EC=2.7.12.1 {ECO:0000269|PubMed:22998443};
GN   Name=DYRK2;
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] (ISOFORM 1), FUNCTION, COFACTOR,
RP   PHOSPHORYLATION, AND TISSUE SPECIFICITY.
RC   TISSUE=Fetal brain;
RX   PubMed=9748265; DOI=10.1074/jbc.273.40.25893;
RA   Becker W., Weber Y., Wetzel K., Eirmbter K., Tejedor F.J., Joost H.-G.;
RT   "Sequence characteristics, subcellular localization, and substrate
RT   specificity of DYRK-related kinases, a novel family of dual specificity
RT   protein kinases.";
RL   J. Biol. Chem. 273:25893-25902(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
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   [3]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Muscle, and Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 320-528 (ISOFORMS 1/2).
RC   TISSUE=Placenta;
RA   Becker W., Joost H.-G.;
RL   Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   FUNCTION.
RX   PubMed=11311121; DOI=10.1042/bj3550609;
RA   Woods Y.L., Cohen P., Becker W., Jakes R., Goedert M., Wang X., Proud C.G.;
RT   "The kinase DYRK phosphorylates protein-synthesis initiation factor
RT   eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at
RT   Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming
RT   kinase.";
RL   Biochem. J. 355:609-615(2001).
RN   [7]
RP   INDUCTION IN CANCER.
RX   PubMed=12874018;
RA   Miller C.T., Aggarwal S., Lin T.K., Dagenais S.L., Contreras J.I.,
RA   Orringer M.B., Glover T.W., Beer D.G., Lin L.;
RT   "Amplification and overexpression of the dual-specificity tyrosine-(Y)-
RT   phosphorylation regulated kinase 2 (DYRK2) gene in esophageal and lung
RT   adenocarcinomas.";
RL   Cancer Res. 63:4136-4143(2003).
RN   [8]
RP   FUNCTION.
RX   PubMed=12588975; DOI=10.1128/mcb.23.5.1546-1557.2003;
RA   Wang X., Li W., Parra J.L., Beugnet A., Proud C.G.;
RT   "The C terminus of initiation factor 4E-binding protein 1 contains multiple
RT   regulatory features that influence its function and phosphorylation.";
RL   Mol. Cell. Biol. 23:1546-1557(2003).
RN   [9]
RP   FUNCTION.
RX   PubMed=14593110; DOI=10.1074/jbc.m301769200;
RA   Skurat A.V., Dietrich A.D.;
RT   "Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family
RT   protein kinases.";
RL   J. Biol. Chem. 279:2490-2498(2004).
RN   [10]
RP   INTERACTION WITH CCNL2.
RX   PubMed=14623875; DOI=10.1074/jbc.m310794200;
RA   de Graaf K., Hekerman P., Spelten O., Herrmann A., Packman L.C., Bussow K.,
RA   Muller-Newen G., Becker W.;
RT   "Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich
RT   domain: phosphorylation by DYRK1A and colocalization with splicing
RT   factors.";
RL   J. Biol. Chem. 279:4612-4624(2004).
RN   [11]
RP   FUNCTION.
RX   PubMed=15910284; DOI=10.1042/bj20050733;
RA   Auld G.C., Campbell D.G., Morrice N., Cohen P.;
RT   "Identification of calcium-regulated heat-stable protein of 24 kDa
RT   (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL.";
RL   Biochem. J. 389:775-783(2005).
RN   [12]
RP   FUNCTION AS CRMP4/DPYSL3 KINASE, AND ACTIVITY REGULATION BY PURVALANOL.
RX   PubMed=16611631; DOI=10.1074/jbc.m513344200;
RA   Cole A.R., Causeret F., Yadirgi G., Hastie C.J., McLauchlan H.,
RA   McManus E.J., Hernandez F., Eickholt B.J., Nikolic M., Sutherland C.;
RT   "Distinct priming kinases contribute to differential regulation of
RT   collapsin response mediator proteins by glycogen synthase kinase-3 in
RT   vivo.";
RL   J. Biol. Chem. 281:16591-16598(2006).
RN   [13]
RP   FUNCTION, AND INTERACTION WITH NFATC1.
RX   PubMed=16511445; DOI=10.1038/nature04631;
RA   Gwack Y., Sharma S., Nardone J., Tanasa B., Iuga A., Srikanth S.,
RA   Okamura H., Bolton D., Feske S., Hogan P.G., Rao A.;
RT   "A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as
RT   regulators of NFAT.";
RL   Nature 441:646-650(2006).
RN   [14]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=17349958; DOI=10.1016/j.molcel.2007.02.007;
RA   Taira N., Nihira K., Yamaguchi T., Miki Y., Yoshida K.;
RT   "DYRK2 is targeted to the nucleus and controls p53 via Ser46
RT   phosphorylation in the apoptotic response to DNA damage.";
RL   Mol. Cell 25:725-738(2007).
RN   [15]
RP   FUNCTION IN APOPTOSIS AS P53/TP53 KINASE, SUBCELLULAR LOCATION,
RP   PHOSPHORYLATION BY ATM, AND GENE FAMILY.
RX   PubMed=18599021; DOI=10.1016/j.bcp.2008.05.021;
RA   Yoshida K.;
RT   "Role for DYRK family kinases on regulation of apoptosis.";
RL   Biochem. Pharmacol. 76:1389-1394(2008).
RN   [16]
RP   FUNCTION, AND PHOSPHORYLATION AT THR-381 AND SER-449.
RX   PubMed=18455992; DOI=10.1016/j.cell.2008.02.047;
RA   Varjosalo M., Bjorklund M., Cheng F., Syvanen H., Kivioja T., Kilpinen S.,
RA   Sun Z., Kallioniemi O., Stunnenberg H.G., He W.W., Ojala P., Taipale J.;
RT   "Application of active and kinase-deficient kinome collection for
RT   identification of kinases regulating hedgehog signaling.";
RL   Cell 133:537-548(2008).
RN   [17]
RP   SUBCELLULAR LOCATION.
RX   PubMed=18539531; DOI=10.1016/j.molmed.2008.05.003;
RA   Yoshida K.;
RT   "Nuclear trafficking of pro-apoptotic kinases in response to DNA damage.";
RL   Trends Mol. Med. 14:305-313(2008).
RN   [18]
RP   ACTIVITY REGULATION BY HARMINE.
RX   PubMed=19796173; DOI=10.1111/j.1742-4658.2009.07346.x;
RA   Goeckler N., Jofre G., Papadopoulos C., Soppa U., Tejedor F.J., Becker W.;
RT   "Harmine specifically inhibits protein kinase DYRK1A and interferes with
RT   neurite formation.";
RL   FEBS J. 276:6324-6337(2009).
RN   [19]
RP   FUNCTION IN E3 LIGASE REGULATION, FUNCTION AS KATNA1 KINASE, AND
RP   INTERACTION WITH EDVP COMPLEX.
RX   PubMed=19287380; DOI=10.1038/ncb1848;
RA   Maddika S., Chen J.;
RT   "Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3
RT   ligase.";
RL   Nat. Cell Biol. 11:409-419(2009).
RN   [20]
RP   ACTIVITY REGULATION BY ACRIDINE ANALOGS.
RX   PubMed=20836251; DOI=10.1016/j.bmcl.2010.04.150;
RA   Cuny G.D., Robin M., Ulyanova N.P., Patnaik D., Pique V., Casano G.,
RA   Liu J.-F., Lin X., Xian J., Glicksman M.A., Stein R.L., Higgins J.M.G.;
RT   "Structure-activity relationship study of acridine analogs as haspin and
RT   DYRK2 kinase inhibitors.";
RL   Bioorg. Med. Chem. Lett. 20:3491-3494(2010).
RN   [21]
RP   SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-106 AND SER-442 BY ATM,
RP   UBIQUITINATION BY MDM2, INTERACTION WITH MDM2, MUTAGENESIS OF THR-106;
RP   SER-442 AND 189-LYS--ARG-191, NUCLEAR LOCALIZATION SIGNAL, AND INDUCTION BY
RP   DNA DAMAGE.
RX   PubMed=19965871; DOI=10.1074/jbc.m109.042341;
RA   Taira N., Yamamoto H., Yamaguchi T., Miki Y., Yoshida K.;
RT   "ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the
RT   apoptotic response to DNA damage.";
RL   J. Biol. Chem. 285:4909-4919(2010).
RN   [22]
RP   FUNCTION.
RX   PubMed=22307329; DOI=10.1172/jci60818;
RA   Taira N., Mimoto R., Kurata M., Yamaguchi T., Kitagawa M., Miki Y.,
RA   Yoshida K.;
RT   "DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle
RT   progression in human cancer cells.";
RL   J. Clin. Invest. 122:859-872(2012).
RN   [23]
RP   FUNCTION, AND UBIQUITINATION BY SIAH2.
RX   PubMed=22878263; DOI=10.1093/jmcb/mjs047;
RA   Perez M., Garcia-Limones C., Zapico I., Marina A., Schmitz M.L., Munoz E.,
RA   Calzado M.A.;
RT   "Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic
RT   signaling pathways.";
RL   J. Mol. Cell Biol. 4:316-330(2012).
RN   [24]
RP   FUNCTION, AND MUTAGENESIS OF LYS-251.
RX   PubMed=23362280; DOI=10.1074/jbc.m112.416792;
RA   Jung H.Y., Wang X., Jun S., Park J.I.;
RT   "Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT
RT   degradation.";
RL   J. Biol. Chem. 288:7252-7262(2013).
RN   [25]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-30, AND IDENTIFICATION BY
RP   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   [26]
RP   X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) OF 146-552 IN COMPLEX WITH
RP   INDIRUBIN.
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of dual-specificity tyrosine phosphorylation regulated
RT   kinase 2 (DYRK2) in complex with an indirubin ligand.";
RL   Submitted (JAN-2010) to the PDB data bank.
RN   [27]
RP   X-RAY CRYSTALLOGRAPHY (2.55 ANGSTROMS) OF 146-540 IN COMPLEX WITH
RP   LEUCETTAMINE DERIVATIVE, PHOSPHORYLATION AT TYR-382, AUTOPHOSPHORYLATION,
RP   ACTIVITY REGULATION, AND CATALYTIC ACTIVITY.
RX   PubMed=22998443; DOI=10.1021/jm301034u;
RA   Tahtouh T., Elkins J.M., Filippakopoulos P., Soundararajan M., Burgy G.,
RA   Durieu E., Cochet C., Schmid R.S., Lo D.C., Delhommel F., Oberholzer A.E.,
RA   Pearl L.H., Carreaux F., Bazureau J.P., Knapp S., Meijer L.;
RT   "Selectivity, cocrystal structures, and neuroprotective properties of
RT   leucettines, a family of protein kinase inhibitors derived from the marine
RT   sponge alkaloid leucettamine B.";
RL   J. Med. Chem. 55:9312-9330(2012).
RN   [28]
RP   X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 146-552.
RX   PubMed=23665168; DOI=10.1016/j.str.2013.03.012;
RA   Soundararajan M., Roos A.K., Savitsky P., Filippakopoulos P.,
RA   Kettenbach A.N., Olsen J.V., Gerber S.A., Eswaran J., Knapp S.,
RA   Elkins J.M.;
RT   "Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase
RT   activation and substrate recognition.";
RL   Structure 21:986-996(2013).
RN   [29]
RP   VARIANTS [LARGE SCALE ANALYSIS] GLY-98; LEU-198; ASN-245; SER-295; GLN-451
RP   AND TYR-455.
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 the regulation of
CC       the mitotic cell cycle, cell proliferation, apoptosis, organization of
CC       the cytoskeleton and neurite outgrowth. Functions in part via its role
CC       in ubiquitin-dependent proteasomal protein degradation. Functions
CC       downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby
CC       contributes to the induction of apoptosis in response to DNA damage.
CC       Phosphorylates NFATC1, and thereby inhibits its accumulation in the
CC       nucleus and its transcription factor activity. Phosphorylates EIF2B5 at
CC       'Ser-544', enabling its subsequent phosphorylation and inhibition by
CC       GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and
CC       CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May
CC       play a general role in the priming of GSK3 substrates. Inactivates GYS1
CC       by phosphorylation at 'Ser-641', and potentially also a second
CC       phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP
CC       E3 ligase complex formation and is required for the phosphorylation and
CC       subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457',
CC       promoting TERT ubiquitination by the EDVP complex. Phosphorylates
CC       SIAH2, and thereby increases its ubiquitin ligase activity. Promotes
CC       the proteasomal degradation of MYC and JUN, and thereby regulates
CC       progress through the mitotic cell cycle and cell proliferation.
CC       Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a
CC       role in smoothened and sonic hedgehog signaling. Plays a role in
CC       cytoskeleton organization and neurite outgrowth via its phosphorylation
CC       of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX,
CC       EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53,
CC       TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and
CC       histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).
CC       {ECO:0000269|PubMed:11311121, ECO:0000269|PubMed:12588975,
CC       ECO:0000269|PubMed:14593110, ECO:0000269|PubMed:15910284,
CC       ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:16611631,
CC       ECO:0000269|PubMed:17349958, ECO:0000269|PubMed:18455992,
CC       ECO:0000269|PubMed:18599021, ECO:0000269|PubMed:19287380,
CC       ECO:0000269|PubMed:22307329, ECO:0000269|PubMed:22878263,
CC       ECO:0000269|PubMed:23362280, ECO:0000269|PubMed:9748265}.
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=2.7.12.1;
CC         Evidence={ECO:0000269|PubMed:22998443};
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=2.7.12.1; Evidence={ECO:0000269|PubMed:22998443};
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=2.7.12.1;
CC         Evidence={ECO:0000269|PubMed:22998443};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:9748265};
CC   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:9748265};
CC   -!- ACTIVITY REGULATION: Activated by autophosphorylation on the second
CC       tyrosine residue in the Tyr-X-Tyr motif in the activation loop.
CC       Inhibited by acridine analogs, purvalanol, and barely by harmine.
CC       Inhibited by leucettine and leucettine derivatives.
CC       {ECO:0000269|PubMed:16611631, ECO:0000269|PubMed:19796173,
CC       ECO:0000269|PubMed:20836251, ECO:0000269|PubMed:22998443}.
CC   -!- SUBUNIT: Component of an E3 ligase complex containing DYRK2, EDD/UBR5,
CC       DDB1 and DCAF1 (EDVP complex). Interacts directly with EDD/UBR5, DDB1
CC       and DCAF1. Interacts with SIAH2 and MDM2. Interacts with MAP3K10 and
CC       NFATC1. May also interact with CCNL2. {ECO:0000269|PubMed:14623875,
CC       ECO:0000269|PubMed:16511445, ECO:0000269|PubMed:19287380,
CC       ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:22998443,
CC       ECO:0000269|Ref.26}.
CC   -!- INTERACTION:
CC       Q92630; Q9NR20: DYRK4; NbExp=3; IntAct=EBI-749432, EBI-3914009;
CC       Q92630; Q13422: IKZF1; NbExp=3; IntAct=EBI-749432, EBI-745305;
CC       Q92630; Q9BQD3: KXD1; NbExp=3; IntAct=EBI-749432, EBI-739657;
CC       Q92630; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-749432, EBI-741037;
CC       Q92630; P23497: SP100; NbExp=3; IntAct=EBI-749432, EBI-751145;
CC       Q92630; O43379: WDR62; NbExp=3; IntAct=EBI-749432, EBI-714790;
CC       Q92630; Q96C00: ZBTB9; NbExp=3; IntAct=EBI-749432, EBI-395708;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates into the
CC       nucleus following DNA damage.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q92630-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q92630-2; Sequence=VSP_026115;
CC   -!- TISSUE SPECIFICITY: Testis, after the onset of spermatogenesis.
CC       {ECO:0000269|PubMed:9748265}.
CC   -!- INDUCTION: Accumulates in nucleus upon DNA damage. Induced in both
CC       esophageal and lung adenocarcinomas. {ECO:0000269|PubMed:12874018,
CC       ECO:0000269|PubMed:19965871}.
CC   -!- PTM: Autophosphorylates cotranslationally on the second tyrosine
CC       residue in the Tyr-X-Tyr motif in the activation loop, but once mature,
CC       does not have any protein tyrosine kinase activity. Phosphorylated at
CC       Thr-106 and Ser-442 by ATM in response to genotoxic stress.
CC       {ECO:0000269|PubMed:19965871}.
CC   -!- PTM: Under normal conditions, polyubiquitinated in the nucleus by MDM2,
CC       leading to its proteasomal degradation. Phosphorylation on Thr-106 and
CC       Ser-442 by ATM in response to genotoxic stress disrupts MDM2 binding
CC       and prevents MDM2-mediated ubiquitination and subsequent proteasomal
CC       degradation. Polyubiquitinated by SIAH2, leading to its proteasomal
CC       degradation. Polyubiquitinated by SIAH2 occurs under normal conditions,
CC       and is enhanced in response to hypoxia. {ECO:0000269|PubMed:19965871,
CC       ECO:0000269|PubMed:22878263}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. MNB/DYRK subfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA73885.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; Y13493; CAA73885.1; ALT_INIT; mRNA.
DR   EMBL; AK313937; BAG36656.1; -; mRNA.
DR   EMBL; CH471054; EAW97176.1; -; Genomic_DNA.
DR   EMBL; BC005809; AAH05809.1; -; mRNA.
DR   EMBL; BC006375; AAH06375.1; -; mRNA.
DR   EMBL; Y09216; CAA70418.1; -; mRNA.
DR   CCDS; CCDS8978.1; -. [Q92630-1]
DR   CCDS; CCDS8979.1; -. [Q92630-2]
DR   RefSeq; NP_003574.1; NM_003583.3. [Q92630-2]
DR   RefSeq; NP_006473.2; NM_006482.2. [Q92630-1]
DR   RefSeq; XP_016875521.1; XM_017020032.1. [Q92630-2]
DR   PDB; 3K2L; X-ray; 2.36 A; A=146-552.
DR   PDB; 3KVW; X-ray; 2.28 A; A=146-552.
DR   PDB; 4AZF; X-ray; 2.55 A; A=146-540.
DR   PDB; 5LXC; X-ray; 2.15 A; A/B=146-552.
DR   PDB; 5LXD; X-ray; 2.58 A; A/B=146-552.
DR   PDB; 5ZTN; X-ray; 2.50 A; A/B=146-552.
DR   PDB; 6HDP; X-ray; 2.30 A; A=146-552.
DR   PDB; 6HDR; X-ray; 2.20 A; A=146-552.
DR   PDB; 6K0J; X-ray; 2.35 A; A=212-536.
DR   PDBsum; 3K2L; -.
DR   PDBsum; 3KVW; -.
DR   PDBsum; 4AZF; -.
DR   PDBsum; 5LXC; -.
DR   PDBsum; 5LXD; -.
DR   PDBsum; 5ZTN; -.
DR   PDBsum; 6HDP; -.
DR   PDBsum; 6HDR; -.
DR   PDBsum; 6K0J; -.
DR   SMR; Q92630; -.
DR   BioGRID; 114023; 67.
DR   CORUM; Q92630; -.
DR   IntAct; Q92630; 13.
DR   STRING; 9606.ENSP00000342105; -.
DR   BindingDB; Q92630; -.
DR   ChEMBL; CHEMBL4376; -.
DR   DrugCentral; Q92630; -.
DR   GuidetoPHARMACOLOGY; 2011; -.
DR   iPTMnet; Q92630; -.
DR   PhosphoSitePlus; Q92630; -.
DR   BioMuta; DYRK2; -.
DR   DMDM; 148887370; -.
DR   EPD; Q92630; -.
DR   jPOST; Q92630; -.
DR   MassIVE; Q92630; -.
DR   MaxQB; Q92630; -.
DR   PaxDb; Q92630; -.
DR   PeptideAtlas; Q92630; -.
DR   PRIDE; Q92630; -.
DR   ProteomicsDB; 75387; -. [Q92630-1]
DR   ProteomicsDB; 75388; -. [Q92630-2]
DR   Antibodypedia; 16684; 329 antibodies.
DR   DNASU; 8445; -.
DR   Ensembl; ENST00000344096; ENSP00000342105; ENSG00000127334. [Q92630-1]
DR   Ensembl; ENST00000393555; ENSP00000377186; ENSG00000127334. [Q92630-2]
DR   GeneID; 8445; -.
DR   KEGG; hsa:8445; -.
DR   UCSC; uc001str.5; human. [Q92630-1]
DR   CTD; 8445; -.
DR   DisGeNET; 8445; -.
DR   GeneCards; DYRK2; -.
DR   HGNC; HGNC:3093; DYRK2.
DR   HPA; ENSG00000127334; Low tissue specificity.
DR   MIM; 603496; gene.
DR   neXtProt; NX_Q92630; -.
DR   OpenTargets; ENSG00000127334; -.
DR   PharmGKB; PA27550; -.
DR   VEuPathDB; HostDB:ENSG00000127334.10; -.
DR   eggNOG; KOG0667; Eukaryota.
DR   GeneTree; ENSGT00940000158113; -.
DR   HOGENOM; CLU_000288_5_13_1; -.
DR   InParanoid; Q92630; -.
DR   OMA; HHEVFSY; -.
DR   OrthoDB; 870358at2759; -.
DR   PhylomeDB; Q92630; -.
DR   TreeFam; TF314624; -.
DR   BRENDA; 2.7.12.1; 2681.
DR   PathwayCommons; Q92630; -.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   SignaLink; Q92630; -.
DR   SIGNOR; Q92630; -.
DR   BioGRID-ORCS; 8445; 9 hits in 1025 CRISPR screens.
DR   ChiTaRS; DYRK2; human.
DR   EvolutionaryTrace; Q92630; -.
DR   GeneWiki; DYRK2; -.
DR   GenomeRNAi; 8445; -.
DR   Pharos; Q92630; Tchem.
DR   PRO; PR:Q92630; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; Q92630; protein.
DR   Bgee; ENSG00000127334; Expressed in neocortex and 249 other tissues.
DR   ExpressionAtlas; Q92630; baseline and differential.
DR   Genevisible; Q92630; HS.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005856; C:cytoskeleton; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:1990904; C:ribonucleoprotein complex; IEA:Ensembl.
DR   GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR   GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR   GO; GO:0030145; F:manganese ion binding; 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:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:UniProtKB-EC.
DR   GO; GO:0106311; F:protein threonine kinase activity; IEA:RHEA.
DR   GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
DR   GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA:RHEA.
DR   GO; GO:0006974; P:cellular response to DNA damage stimulus; IEP:UniProtKB.
DR   GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IDA:UniProtKB.
DR   GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; IMP:UniProtKB.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR   GO; GO:0018107; P:peptidyl-threonine phosphorylation; IBA:GO_Central.
DR   GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
DR   GO; GO:0007224; P:smoothened signaling pathway; IMP:UniProtKB.
DR   Gene3D; 1.10.8.980; -; 1.
DR   InterPro; IPR042521; DYRK.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; SSF56112; 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; Cytoplasm;
KW   Kinase; Magnesium; Manganese; Nucleotide-binding; Nucleus; Phosphoprotein;
KW   Reference proteome; Serine/threonine-protein kinase; Transferase;
KW   Tyrosine-protein kinase; Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..601
FT                   /note="Dual specificity tyrosine-phosphorylation-regulated
FT                   kinase 2"
FT                   /id="PRO_0000085936"
FT   DOMAIN          222..535
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   NP_BIND         228..236
FT                   /note="ATP"
FT                   /evidence="ECO:0000305"
FT   NP_BIND         301..304
FT                   /note="ATP"
FT                   /evidence="ECO:0000305"
FT   REGION          1..24
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           189..191
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000305|PubMed:19965871"
FT   ACT_SITE        348
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         251
FT                   /note="ATP"
FT                   /evidence="ECO:0000305"
FT   MOD_RES         30
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         106
FT                   /note="Phosphothreonine; by ATM"
FT                   /evidence="ECO:0000269|PubMed:19965871"
FT   MOD_RES         381
FT                   /note="Phosphothreonine; by MAP3K10"
FT                   /evidence="ECO:0000269|PubMed:18455992"
FT   MOD_RES         382
FT                   /note="Phosphotyrosine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:22998443"
FT   MOD_RES         442
FT                   /note="Phosphoserine; by ATM"
FT                   /evidence="ECO:0000269|PubMed:19965871"
FT   MOD_RES         449
FT                   /note="Phosphoserine; by MAP3K10"
FT                   /evidence="ECO:0000269|PubMed:18455992"
FT   VAR_SEQ         1..73
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_026115"
FT   VARIANT         98
FT                   /note="S -> G (in dbSNP:rs35139851)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040458"
FT   VARIANT         198
FT                   /note="P -> L (in a glioblastoma multiforme sample; somatic
FT                   mutation; dbSNP:rs1384093596)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040459"
FT   VARIANT         245
FT                   /note="H -> N (in dbSNP:rs34166200)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040460"
FT   VARIANT         295
FT                   /note="N -> S (in dbSNP:rs56293072)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040461"
FT   VARIANT         451
FT                   /note="R -> Q (in dbSNP:rs35688869)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040462"
FT   VARIANT         455
FT                   /note="F -> Y (in dbSNP:rs55774594)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040463"
FT   MUTAGEN         106
FT                   /note="T->A: Impaired ATM-mediated phosphorylation, reduced
FT                   affinity with MDM2 and altered MDM2-triggered
FT                   ubiquitination."
FT                   /evidence="ECO:0000269|PubMed:19965871"
FT   MUTAGEN         189..191
FT                   /note="KKR->NNN: Impaired nuclear translocation."
FT                   /evidence="ECO:0000269|PubMed:19965871"
FT   MUTAGEN         251
FT                   /note="K->R: Abolishes protein serine/threonine kinase
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:23362280"
FT   MUTAGEN         442
FT                   /note="S->A: Impaired ATM-mediated phosphorylation, reduced
FT                   affinity with MDM2 and altered MDM2-triggered
FT                   ubiquitination."
FT                   /evidence="ECO:0000269|PubMed:19965871"
FT   CONFLICT        37
FT                   /note="A -> P (in Ref. 1; CAA73885)"
FT                   /evidence="ECO:0000305"
FT   STRAND          150..152
FT                   /evidence="ECO:0007829|PDB:6HDR"
FT   HELIX           156..163
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           164..166
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           169..174
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           175..177
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          179..181
FT                   /evidence="ECO:0007829|PDB:3K2L"
FT   HELIX           198..202
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          206..208
FT                   /evidence="ECO:0007829|PDB:3K2L"
FT   TURN            219..221
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          222..231
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          234..241
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   TURN            242..245
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          246..253
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           257..274
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          287..292
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          297..301
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           308..314
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   TURN            315..317
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           322..341
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           351..353
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          354..358
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          364..366
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           375..377
FT                   /evidence="ECO:0007829|PDB:6K0J"
FT   HELIX           386..388
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           391..395
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           402..417
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           427..438
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           443..447
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           452..455
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          458..460
FT                   /evidence="ECO:0007829|PDB:6HDP"
FT   STRAND          465..469
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          471..473
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   STRAND          475..478
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           496..499
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   TURN            500..502
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           506..515
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   TURN            520..522
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           526..529
FT                   /evidence="ECO:0007829|PDB:5LXC"
FT   HELIX           533..535
FT                   /evidence="ECO:0007829|PDB:5LXC"
SQ   SEQUENCE   601 AA;  66652 MW;  A7BEE25CDF944436 CRC64;
     MLTRKPSAAA PAAYPTGRGG DSAVRQLQAS PGLGAGATRS GVGTGPPSPI ALPPLRASNA
     AAAAHTIGGS KHTMNDHLHV GSHAHGQIQV QQLFEDNSNK RTVLTTQPNG LTTVGKTGLP
     VVPERQLDSI HRRQGSSTSL KSMEGMGKVK ATPMTPEQAM KQYMQKLTAF EHHEIFSYPE
     IYFLGLNAKK RQGMTGGPNN GGYDDDQGSY VQVPHDHVAY RYEVLKVIGK GSFGQVVKAY
     DHKVHQHVAL KMVRNEKRFH RQAAEEIRIL EHLRKQDKDN TMNVIHMLEN FTFRNHICMT
     FELLSMNLYE LIKKNKFQGF SLPLVRKFAH SILQCLDALH KNRIIHCDLK PENILLKQQG
     RSGIKVIDFG SSCYEHQRVY TYIQSRFYRA PEVILGARYG MPIDMWSLGC ILAELLTGYP
     LLPGEDEGDQ LACMIELLGM PSQKLLDASK RAKNFVSSKG YPRYCTVTTL SDGSVVLNGG
     RSRRGKLRGP PESREWGNAL KGCDDPLFLD FLKQCLEWDP AVRMTPGQAL RHPWLRRRLP
     KPPTGEKTSV KRITESTGAI TSISKLPPPS SSASKLRTNL AQMTDANGNI QQRTVLPKLV
     S
//
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