DYRK2_HUMAN
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 03-AUG-2022, entry version 212.
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 PDB; 7AKF; X-ray; 2.60 A; A=146-552.
DR PDB; 7AKH; X-ray; 2.85 A; A=146-552.
DR PDB; 7DG4; X-ray; 2.58 A; A=215-538.
DR PDB; 7DH3; X-ray; 2.33 A; A=213-538.
DR PDB; 7DH9; X-ray; 2.19 A; A=215-538.
DR PDB; 7DHC; X-ray; 2.59 A; A=215-538.
DR PDB; 7DHH; X-ray; 2.49 A; A=215-538.
DR PDB; 7DHK; X-ray; 2.34 A; A=215-538.
DR PDB; 7DHN; X-ray; 2.38 A; A=215-538.
DR PDB; 7DHO; X-ray; 3.29 A; A=215-538.
DR PDB; 7DHV; X-ray; 2.68 A; A=212-538.
DR PDB; 7DJO; X-ray; 2.50 A; A=215-538.
DR PDB; 7DL6; X-ray; 2.65 A; A=215-538.
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 PDBsum; 7AKF; -.
DR PDBsum; 7AKH; -.
DR PDBsum; 7DG4; -.
DR PDBsum; 7DH3; -.
DR PDBsum; 7DH9; -.
DR PDBsum; 7DHC; -.
DR PDBsum; 7DHH; -.
DR PDBsum; 7DHK; -.
DR PDBsum; 7DHN; -.
DR PDBsum; 7DHO; -.
DR PDBsum; 7DHV; -.
DR PDBsum; 7DJO; -.
DR PDBsum; 7DL6; -.
DR AlphaFoldDB; Q92630; -.
DR SMR; Q92630; -.
DR BioGRID; 114023; 73.
DR CORUM; Q92630; -.
DR IntAct; Q92630; 236.
DR STRING; 9606.ENSP00000342105; -.
DR BindingDB; Q92630; -.
DR ChEMBL; CHEMBL4376; -.
DR DrugCentral; Q92630; -.
DR GuidetoPHARMACOLOGY; 2011; -.
DR GlyGen; Q92630; 1 site, 1 O-linked glycan (1 site).
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; 341 antibodies from 37 providers.
DR DNASU; 8445; -.
DR Ensembl; ENST00000344096.4; ENSP00000342105.4; ENSG00000127334.11. [Q92630-1]
DR Ensembl; ENST00000393555.3; ENSP00000377186.3; ENSG00000127334.11. [Q92630-2]
DR GeneID; 8445; -.
DR KEGG; hsa:8445; -.
DR MANE-Select; ENST00000344096.4; ENSP00000342105.4; NM_006482.3; NP_006473.2.
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; -.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000158113; -.
DR HOGENOM; CLU_000288_5_13_1; -.
DR InParanoid; Q92630; -.
DR OMA; YPRYCSI; -.
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; 14 hits in 1111 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 jejunal mucosa and 203 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:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
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; 3.30.10.30; -; 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 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 228..236
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 251
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 301..304
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
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 278..280
FT /evidence="ECO:0007829|PDB:7AKH"
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 369..371
FT /evidence="ECO:0007829|PDB:7DHO"
FT HELIX 375..377
FT /evidence="ECO:0007829|PDB:7DHK"
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
