DYRK2_MOUSE
ID DYRK2_MOUSE Reviewed; 599 AA.
AC Q5U4C9;
DT 12-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Dual specificity tyrosine-phosphorylation-regulated kinase 2;
DE EC=2.7.12.1 {ECO:0000250|UniProtKB:Q92630};
GN Name=Dyrk2 {ECO:0000312|MGI:MGI:1330301};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1] {ECO:0000312|EMBL:AAH85145.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:AAH85145.1};
RC TISSUE=Brain {ECO:0000312|EMBL:AAH85145.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP SUBCELLULAR LOCATION.
RX PubMed=20167603; DOI=10.1074/jbc.m110.102574;
RA Guo X., Williams J.G., Schug T.T., Li X.;
RT "DYRK1A and DYRK3 promote cell survival through phosphorylation and
RT activation of SIRT1.";
RL J. Biol. Chem. 285:13223-13232(2010).
RN [3]
RP FUNCTION.
RX PubMed=22359282; DOI=10.1002/cm.21021;
RA Slepak T.I., Salay L.D., Lemmon V.P., Bixby J.L.;
RT "Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal
RT organization, and neuronal morphology.";
RL Cytoskeleton 69:514-527(2012).
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. Phosphorylates
CC CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1,
CC JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can
CC phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can
CC phosphorylate CARHSP1 (in vitro) (By similarity). Plays a role in
CC cytoskeleton organization and neurite outgrowth via its phosphorylation
CC of DCX. {ECO:0000250, ECO:0000269|PubMed:22359282}.
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:0000250|UniProtKB:Q92630};
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:0000250|UniProtKB:Q92630};
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:0000250|UniProtKB:Q92630};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q92630};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q92630};
CC -!- ACTIVITY REGULATION: Activated by autophosphorylation on the second
CC tyrosine residue in the Tyr-X-Tyr motif in the activation loop.
CC {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20167603}. Nucleus
CC {ECO:0000250|UniProtKB:Q92630}. Note=Translocates into the nucleus
CC following DNA damage. {ECO:0000250|UniProtKB:Q92630}.
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-104 and Ser-440 by ATM in response to genotoxic stress.
CC -!- PTM: Under normal conditions, polyubiquitinated in the nucleus by MDM2,
CC leading to its proteasomal degradation. Phosphorylation on Thr-104 and
CC Ser-440 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.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MNB/DYRK subfamily. {ECO:0000305}.
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DR EMBL; BC085145; AAH85145.1; -; mRNA.
DR CCDS; CCDS24201.1; -.
DR RefSeq; NP_001014412.1; NM_001014390.2.
DR AlphaFoldDB; Q5U4C9; -.
DR SMR; Q5U4C9; -.
DR BioGRID; 213275; 5.
DR STRING; 10090.ENSMUSP00000004281; -.
DR iPTMnet; Q5U4C9; -.
DR PhosphoSitePlus; Q5U4C9; -.
DR MaxQB; Q5U4C9; -.
DR PaxDb; Q5U4C9; -.
DR PeptideAtlas; Q5U4C9; -.
DR PRIDE; Q5U4C9; -.
DR ProteomicsDB; 277619; -.
DR Antibodypedia; 16684; 341 antibodies from 37 providers.
DR DNASU; 69181; -.
DR Ensembl; ENSMUST00000004281; ENSMUSP00000004281; ENSMUSG00000028630.
DR GeneID; 69181; -.
DR KEGG; mmu:69181; -.
DR UCSC; uc007hea.1; mouse.
DR CTD; 8445; -.
DR MGI; MGI:1330301; Dyrk2.
DR VEuPathDB; HostDB:ENSMUSG00000028630; -.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000158113; -.
DR HOGENOM; CLU_000288_5_13_1; -.
DR InParanoid; Q5U4C9; -.
DR OMA; YPRYCSI; -.
DR OrthoDB; 870358at2759; -.
DR PhylomeDB; Q5U4C9; -.
DR TreeFam; TF314624; -.
DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR BioGRID-ORCS; 69181; 4 hits in 76 CRISPR screens.
DR ChiTaRS; Dyrk2; mouse.
DR PRO; PR:Q5U4C9; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q5U4C9; protein.
DR Bgee; ENSMUSG00000028630; Expressed in otolith organ and 210 other tissues.
DR Genevisible; Q5U4C9; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:MGI.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0030145; F:manganese ion binding; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; ISO:MGI.
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:0018108; P:peptidyl-tyrosine phosphorylation; ISO:MGI.
DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0007224; P:smoothened signaling pathway; ISO:MGI.
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 2: Evidence at transcript level;
KW Apoptosis; ATP-binding; Cytoplasm; Kinase; Magnesium; Manganese;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..599
FT /note="Dual specificity tyrosine-phosphorylation-regulated
FT kinase 2"
FT /id="PRO_0000291265"
FT DOMAIN 220..533
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 187..189
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT ACT_SITE 346
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 226..234
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 249
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 299..302
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 30
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
FT MOD_RES 104
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
FT MOD_RES 379
FT /note="Phosphothreonine; by MAP3K10"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
FT MOD_RES 380
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
FT MOD_RES 440
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
FT MOD_RES 447
FT /note="Phosphoserine; by MAP3K10"
FT /evidence="ECO:0000250|UniProtKB:Q92630"
SQ SEQUENCE 599 AA; 66556 MW; 2378D39A5E1E8056 CRC64;
MLTRKPSAAA PAAYPTGRGG DTAVRQLQAS PGIGAGAPRS GVGTGPPSPI ALPPLRASNA
TTTAHTIGGS KHTMNDHLHL NSHGQIQVQQ LFEDNSNKRT VLTTQPNGLT TVGKTGLPGV
PERQLESIHR RQGSSTSLKS MEGMGKVKAS PMTPEQAMKQ YMQKLTAFEH HEIFSYPEIY
FLGPNAKKRQ GMTGGPNNGG YDDDQGSYVQ VPHDHVAYRY EVLKVIGKGS FGQVVKAYDH
KVHQHVALKM VRNEKRFHRQ AAEEIRILEH LRKQDKDNTM NVIHMLENFT FRNHICMTFE
LLSMNLYELI KKNKFQGFSL PLVRKFAHSI LQCLDALHKN RIIHCDLKPE NILLKQQGRS
SIKVIDFGSS CYEHQRVYTY IQSRFYRAPE VILGARYGMP IDMWSLGCIL AELLTGYPLL
PGEDEGDQLA CMIELLGMPS QKLLDASKRA KNFVSSKGYP RYCTVTTLSD GSVVLNGGRS
RRGKLRGPPE SREWGNALKG CDDPLFLDFL KQCLEWDPAV RMTPGQALRH PWLRRRLPKP
PTGEKTAVKR VTESTGAITS ISKLPPPSSS ASKLRTNLAQ MTDANGNIQQ RTVLPKLVS
