DYRK4_HUMAN
ID DYRK4_HUMAN Reviewed; 520 AA.
AC Q9NR20; A8K8F7; Q8NEF2; Q92631;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 2.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Dual specificity tyrosine-phosphorylation-regulated kinase 4;
DE EC=2.7.12.1;
GN Name=DYRK4;
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 2), AND VARIANTS ILE-95 AND SER-189.
RC TISSUE=Brain, and Kidney;
RX PubMed=11062477; DOI=10.1038/81664;
RA White K.E., Evans W.E., O'Riordan J.L.H., Speer M.C., Econs M.J.,
RA Lorenz-Depiereux B., Grabowski M., Meitinger T., Strom T.M.;
RT "Autosomal dominant hypophosphataemic rickets is associated with mutations
RT in FGF23.";
RL Nat. Genet. 26:345-348(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 1-430 (ISOFORM 3).
RC TISSUE=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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 280-520 (ISOFORM 2).
RC TISSUE=Lung;
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 [5]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-133.
RX PubMed=17292540; DOI=10.1016/j.mce.2006.12.041;
RA Sacher F., Moeller C., Bone W., Gottwald U., Fritsch M.;
RT "The expression of the testis-specific Dyrk4 kinase is highly restricted to
RT step 8 spermatids but is not required for male fertility in mice.";
RL Mol. Cell. Endocrinol. 267:80-88(2007).
RN [6]
RP ALTERNATIVE SPLICING (ISOFORMS 4 AND 5), SUBCELLULAR LOCATION (ISOFORM 4),
RP MUTAGENESIS OF TYR-264, AND PHOSPHORYLATION AT TYR-264.
RX PubMed=21127067; DOI=10.1074/jbc.m110.157909;
RA Papadopoulos C., Arato K., Lilienthal E., Zerweck J., Schutkowski M.,
RA Chatain N., Muller-Newen G., Becker W., de la Luna S.;
RT "Splice variants of the dual specificity tyrosine phosphorylation-regulated
RT kinase 4 (DYRK4) differ in their subcellular localization and catalytic
RT activity.";
RL J. Biol. Chem. 286:5494-5505(2011).
RN [7]
RP VARIANT [LARGE SCALE ANALYSIS] SER-70.
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: Possible non-essential role in spermiogenesis. {ECO:0000250}.
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 -!- 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;
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 -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- INTERACTION:
CC Q9NR20; Q92630: DYRK2; NbExp=3; IntAct=EBI-3914009, EBI-749432;
CC Q9NR20; P07900: HSP90AA1; NbExp=2; IntAct=EBI-3914009, EBI-296047;
CC Q9NR20; P08238: HSP90AB1; NbExp=2; IntAct=EBI-3914009, EBI-352572;
CC Q9NR20; O15344: MID1; NbExp=3; IntAct=EBI-3914009, EBI-2340316;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000269|PubMed:17292540}.
CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm
CC {ECO:0000269|PubMed:21127067}. Nucleus {ECO:0000269|PubMed:21127067}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q9NR20-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NR20-2; Sequence=VSP_013745;
CC Name=3;
CC IsoId=Q9NR20-3; Sequence=VSP_057132;
CC Name=4; Synonyms=DYRK4-L;
CC IsoId=Q9NR20-4; Sequence=VSP_057133;
CC Name=5;
CC IsoId=Q9NR20-5; Sequence=VSP_057134;
CC -!- PTM: Autophosphorylation on Tyr-264 in the activation loop is required
CC for kinase activity. {ECO:0000269|PubMed:21127067}.
CC -!- MISCELLANEOUS: [Isoform 1]: May be due to a competing acceptor splice
CC site.
CC -!- MISCELLANEOUS: [Isoform 5]: Due to an alternative splicing donor site
CC in exon 19. Markedly reduced enzymatic activity.
CC {ECO:0000269|PubMed:21127067}.
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=AAF91393.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AK308260; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF263541; AAF91393.1; ALT_INIT; mRNA.
DR EMBL; AK292322; BAF85011.1; -; mRNA.
DR EMBL; AK308260; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC031244; AAH31244.1; -; mRNA.
DR EMBL; Y09305; CAA70488.1; -; mRNA.
DR CCDS; CCDS8530.1; -. [Q9NR20-1]
DR RefSeq; NP_003836.1; NM_003845.2. [Q9NR20-1]
DR AlphaFoldDB; Q9NR20; -.
DR SMR; Q9NR20; -.
DR BioGRID; 114326; 22.
DR IntAct; Q9NR20; 30.
DR STRING; 9606.ENSP00000441755; -.
DR BindingDB; Q9NR20; -.
DR ChEMBL; CHEMBL1075115; -.
DR GuidetoPHARMACOLOGY; 2013; -.
DR iPTMnet; Q9NR20; -.
DR PhosphoSitePlus; Q9NR20; -.
DR BioMuta; DYRK4; -.
DR DMDM; 68566308; -.
DR EPD; Q9NR20; -.
DR jPOST; Q9NR20; -.
DR MassIVE; Q9NR20; -.
DR MaxQB; Q9NR20; -.
DR PaxDb; Q9NR20; -.
DR PeptideAtlas; Q9NR20; -.
DR PRIDE; Q9NR20; -.
DR ProteomicsDB; 82254; -. [Q9NR20-1]
DR ProteomicsDB; 82255; -. [Q9NR20-2]
DR Antibodypedia; 22291; 294 antibodies from 28 providers.
DR DNASU; 8798; -.
DR Ensembl; ENST00000010132.6; ENSP00000010132.5; ENSG00000010219.14. [Q9NR20-1]
DR Ensembl; ENST00000540757.6; ENSP00000441755.1; ENSG00000010219.14. [Q9NR20-1]
DR GeneID; 8798; -.
DR KEGG; hsa:8798; -.
DR UCSC; uc001qmx.5; human. [Q9NR20-1]
DR CTD; 8798; -.
DR DisGeNET; 8798; -.
DR GeneCards; DYRK4; -.
DR HGNC; HGNC:3095; DYRK4.
DR HPA; ENSG00000010219; Tissue enhanced (testis).
DR MIM; 609181; gene.
DR neXtProt; NX_Q9NR20; -.
DR OpenTargets; ENSG00000010219; -.
DR PharmGKB; PA27552; -.
DR VEuPathDB; HostDB:ENSG00000010219; -.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000159401; -.
DR HOGENOM; CLU_000288_5_9_1; -.
DR InParanoid; Q9NR20; -.
DR OrthoDB; 870358at2759; -.
DR PhylomeDB; Q9NR20; -.
DR TreeFam; TF314624; -.
DR BRENDA; 2.7.12.1; 2681.
DR PathwayCommons; Q9NR20; -.
DR SignaLink; Q9NR20; -.
DR SIGNOR; Q9NR20; -.
DR BioGRID-ORCS; 8798; 11 hits in 1112 CRISPR screens.
DR ChiTaRS; DYRK4; human.
DR GenomeRNAi; 8798; -.
DR Pharos; Q9NR20; Tchem.
DR PRO; PR:Q9NR20; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9NR20; protein.
DR Bgee; ENSG00000010219; Expressed in left testis and 167 other tissues.
DR ExpressionAtlas; Q9NR20; baseline and differential.
DR Genevisible; Q9NR20; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005856; C:cytoskeleton; IBA:GO_Central.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IBA:GO_Central.
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 Alternative splicing; ATP-binding; Cytoplasm; Kinase; Magnesium;
KW Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Tyrosine-protein kinase.
FT CHAIN 1..520
FT /note="Dual specificity tyrosine-phosphorylation-regulated
FT kinase 4"
FT /id="PRO_0000085940"
FT DOMAIN 104..400
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..32
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 404..467
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 406..421
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 422..461
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 230
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 110..118
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 133
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 183..186
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 264
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:21127067"
FT VAR_SEQ 1
FT /note="M -> MQLLPPPIRTGTKTQMDAKKPRKCDLTPFLVLKARKKQKFTSAKVGS
FT KLSVQIQKPPSNIKNSRMTQVFHKNTSVTSLPFVDTKGKKNTVSFPHISKKVLLKSSLL
FT YQENQAHNQM (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_057132"
FT VAR_SEQ 1
FT /note="M -> MQLLPPPIRTGTKTQMDAKKPRKCDLTPFLVLKARKKQKFTSAKGPT
FT LSEIYMVGSKLSVQIQKPPSNIKNSRMTQVFHKNTSVTSLPFVDTKGKKNTVSFPHISK
FT KVLLKSSLLYQENQAHNQM (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:21127067"
FT /id="VSP_057133"
FT VAR_SEQ 380..382
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:21127067"
FT /id="VSP_057134"
FT VAR_SEQ 441
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11062477,
FT ECO:0000303|PubMed:9748265"
FT /id="VSP_013745"
FT VARIANT 61
FT /note="A -> T (in dbSNP:rs12306130)"
FT /id="VAR_033900"
FT VARIANT 70
FT /note="A -> S"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040465"
FT VARIANT 95
FT /note="V -> I (in dbSNP:rs746486416)"
FT /evidence="ECO:0000269|PubMed:11062477"
FT /id="VAR_010721"
FT VARIANT 189
FT /note="N -> S (in dbSNP:rs3741927)"
FT /evidence="ECO:0000269|PubMed:11062477"
FT /id="VAR_010722"
FT VARIANT 454
FT /note="D -> V (in dbSNP:rs1801016)"
FT /id="VAR_014948"
FT MUTAGEN 133
FT /note="K->R: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:17292540"
FT MUTAGEN 264
FT /note="Y->F: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:21127067"
FT CONFLICT 165
FT /note="N -> I (in Ref. 2; BAF85011)"
FT /evidence="ECO:0000305"
FT MOTIF Q9NR20-4:19..37
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:21127067"
SQ SEQUENCE 520 AA; 59608 MW; 33FECD8249DDB223 CRC64;
MPASELKASE IPFHPSIKTQ DPKAEEKSPK KQKVTLTAAE ALKLFKNQLS PYEQSEILGY
AELWFLGLEA KKLDTAPEKF SKTSFDDEHG FYLKVLHDHI AYRYEVLETI GKGSFGQVAK
CLDHKNNELV ALKIIRNKKR FHQQALMELK ILEALRKKDK DNTYNVVHMK DFFYFRNHFC
ITFELLGINL YELMKNNNFQ GFSLSIVRRF TLSVLKCLQM LSVEKIIHCD LKPENIVLYQ
KGQASVKVID FGSSCYEHQK VYTYIQSRFY RSPEVILGHP YDVAIDMWSL GCITAELYTG
YPLFPGENEV EQLACIMEVL GLPPAGFIQT ASRRQTFFDS KGFPKNITNN RGKKRYPDSK
DLTMVLKTYD TSFLDFLRRC LVWEPSLRMT PDQALKHAWI HQSRNLKPQP RPQTLRKSNS
FFPSETRKDK VQGCHHSSRK ADEITKETTE KTKDSPTKHV QHSGDQQDCL QHGADTVQLP
QLVDAPKKSE AAVGAEVSMT SPGQSKNFSL KNTNVLPPIV
