CLK4_HUMAN
ID CLK4_HUMAN Reviewed; 481 AA.
AC Q9HAZ1;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Dual specificity protein kinase CLK4;
DE EC=2.7.12.1;
DE AltName: Full=CDC-like kinase 4;
GN Name=CLK4;
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], FUNCTION, TISSUE SPECIFICITY,
RP AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LYS-189.
RC TISSUE=Kidney;
RX PubMed=11170754; DOI=10.1006/geno.2000.6447;
RA Schultz J., Jones T., Bork P., Sheer D., Blencke S., Steyrer S.,
RA Wellbrock U., Bevec D., Ullrich A., Wallasch C.;
RT "Molecular characterization of a cDNA encoding functional human CLK4 kinase
RT and localization to chromosome 5q35.";
RL Genomics 71:368-370(2001).
RN [2]
RP ERRATUM OF PUBMED:11170754.
RA Schultz J., Jones T., Bork P., Sheer D., Blencke S., Steyrer S.,
RA Wellbrock U., Bevec D., Ullrich A., Wallasch C.;
RL Genomics 74:251-251(2001).
RN [3]
RP INTERACTION WITH UBL5.
RX PubMed=12824502; DOI=10.1110/ps.0382803;
RA McNally T., Huang Q., Janis R.S., Liu Z., Olejniczak E.T., Reilly R.M.;
RT "Structural analysis of UBL5, a novel ubiquitin-like modifier.";
RL Protein Sci. 12:1562-1566(2003).
RN [4]
RP INTERACTION WITH UBL5.
RX PubMed=12705895; DOI=10.1016/s0006-291x(03)00549-7;
RA Kantham L., Kerr-Bayles L., Godde N., Quick M., Webb R., Sunderland T.,
RA Bond J., Walder K., Augert G., Collier G.;
RT "Beacon interacts with cdc2/cdc28-like kinases.";
RL Biochem. Biophys. Res. Commun. 304:125-129(2003).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-136 AND SER-138, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP FUNCTION, ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RX PubMed=19168442; DOI=10.1161/circresaha.108.183905;
RA Eisenreich A., Bogdanov V.Y., Zakrzewicz A., Pries A., Antoniak S.,
RA Poller W., Schultheiss H.P., Rauch U.;
RT "Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of
RT tissue factor in human endothelial cells.";
RL Circ. Res. 104:589-599(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=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 [11]
RP VARIANTS [LARGE SCALE ANALYSIS] PHE-352 AND VAL-363.
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: Dual specificity kinase acting on both serine/threonine and
CC tyrosine-containing substrates. Phosphorylates serine- and arginine-
CC rich (SR) proteins of the spliceosomal complex and may be a constituent
CC of a network of regulatory mechanisms that enable SR proteins to
CC control RNA splicing. Phosphorylates SRSF1 and SRSF3. Required for the
CC regulation of alternative splicing of MAPT/TAU. Regulates the
CC alternative splicing of tissue factor (F3) pre-mRNA in endothelial
CC cells. {ECO:0000269|PubMed:11170754, ECO:0000269|PubMed:19168442}.
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 -!- ACTIVITY REGULATION: TG003 inhibits its kinase activity and affects the
CC regulation of alternative splicing mediated by phosphorylation of SR
CC proteins. {ECO:0000250}.
CC -!- SUBUNIT: Interacts with UBL5. {ECO:0000269|PubMed:12705895,
CC ECO:0000269|PubMed:12824502}.
CC -!- INTERACTION:
CC Q9HAZ1; P52294: KPNA1; NbExp=3; IntAct=EBI-633400, EBI-358383;
CC Q9HAZ1; P60371: KRTAP10-6; NbExp=3; IntAct=EBI-633400, EBI-12012928;
CC Q9HAZ1; P60409: KRTAP10-7; NbExp=6; IntAct=EBI-633400, EBI-10172290;
CC Q9HAZ1; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-633400, EBI-10171774;
CC Q9HAZ1; P60411: KRTAP10-9; NbExp=3; IntAct=EBI-633400, EBI-10172052;
CC Q9HAZ1; A7MD48: SRRM4; NbExp=3; IntAct=EBI-633400, EBI-3867173;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed in liver, kidney, heart, muscle, brain
CC and endothelial cells. {ECO:0000269|PubMed:11170754,
CC ECO:0000269|PubMed:19168442}.
CC -!- PTM: Autophosphorylates on all three types of residues.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. Lammer subfamily. {ECO:0000305}.
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DR EMBL; AF294429; AAG10074.1; -; mRNA.
DR CCDS; CCDS4437.1; -.
DR RefSeq; NP_065717.1; NM_020666.2.
DR PDB; 6FYV; X-ray; 2.46 A; A=146-480.
DR PDBsum; 6FYV; -.
DR AlphaFoldDB; Q9HAZ1; -.
DR SMR; Q9HAZ1; -.
DR BioGRID; 121501; 28.
DR IntAct; Q9HAZ1; 28.
DR STRING; 9606.ENSP00000316948; -.
DR BindingDB; Q9HAZ1; -.
DR ChEMBL; CHEMBL4203; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9HAZ1; -.
DR GuidetoPHARMACOLOGY; 1993; -.
DR iPTMnet; Q9HAZ1; -.
DR PhosphoSitePlus; Q9HAZ1; -.
DR BioMuta; CLK4; -.
DR DMDM; 34922132; -.
DR EPD; Q9HAZ1; -.
DR jPOST; Q9HAZ1; -.
DR MassIVE; Q9HAZ1; -.
DR MaxQB; Q9HAZ1; -.
DR PaxDb; Q9HAZ1; -.
DR PeptideAtlas; Q9HAZ1; -.
DR PRIDE; Q9HAZ1; -.
DR ProteomicsDB; 81459; -.
DR Antibodypedia; 29447; 116 antibodies from 25 providers.
DR DNASU; 57396; -.
DR Ensembl; ENST00000316308.9; ENSP00000316948.4; ENSG00000113240.14.
DR GeneID; 57396; -.
DR KEGG; hsa:57396; -.
DR MANE-Select; ENST00000316308.9; ENSP00000316948.4; NM_020666.3; NP_065717.1.
DR UCSC; uc003mjf.2; human.
DR CTD; 57396; -.
DR GeneCards; CLK4; -.
DR HGNC; HGNC:13659; CLK4.
DR HPA; ENSG00000113240; Low tissue specificity.
DR MIM; 607969; gene.
DR neXtProt; NX_Q9HAZ1; -.
DR OpenTargets; ENSG00000113240; -.
DR PharmGKB; PA26598; -.
DR VEuPathDB; HostDB:ENSG00000113240; -.
DR eggNOG; KOG0671; Eukaryota.
DR GeneTree; ENSGT00940000160245; -.
DR HOGENOM; CLU_000288_5_16_1; -.
DR InParanoid; Q9HAZ1; -.
DR OMA; SSNFRCV; -.
DR OrthoDB; 915778at2759; -.
DR PhylomeDB; Q9HAZ1; -.
DR TreeFam; TF101041; -.
DR PathwayCommons; Q9HAZ1; -.
DR SignaLink; Q9HAZ1; -.
DR SIGNOR; Q9HAZ1; -.
DR BioGRID-ORCS; 57396; 10 hits in 1112 CRISPR screens.
DR ChiTaRS; CLK4; human.
DR GenomeRNAi; 57396; -.
DR Pharos; Q9HAZ1; Tchem.
DR PRO; PR:Q9HAZ1; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q9HAZ1; protein.
DR Bgee; ENSG00000113240; Expressed in cerebellar hemisphere and 197 other tissues.
DR ExpressionAtlas; Q9HAZ1; baseline and differential.
DR Genevisible; Q9HAZ1; HS.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP 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; 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; IBA:GO_Central.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IBA:GO_Central.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0043484; P:regulation of RNA splicing; IMP:UniProtKB.
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; ATP-binding; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1..481
FT /note="Dual specificity protein kinase CLK4"
FT /id="PRO_0000085873"
FT DOMAIN 159..475
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 102..143
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..23
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 103..134
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 286
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 165..173
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 189
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 136
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 138
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163"
FT VARIANT 352
FT /note="L -> F (in dbSNP:rs35272416)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040414"
FT VARIANT 363
FT /note="I -> V (in dbSNP:rs55746655)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040415"
FT MUTAGEN 189
FT /note="K->R: Loss of function."
FT /evidence="ECO:0000269|PubMed:11170754"
FT TURN 156..158
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 159..167
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 169..178
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 179..181
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 185..191
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 195..214
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 234..239
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 246..252
FT /evidence="ECO:0007829|PDB:6FYV"
FT TURN 253..255
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 260..278
FT /evidence="ECO:0007829|PDB:6FYV"
FT TURN 279..281
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 289..291
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 292..295
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 299..303
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 310..315
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 319..321
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 341..343
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 346..349
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 357..372
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 382..393
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 398..403
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 407..409
FT /evidence="ECO:0007829|PDB:6FYV"
FT STRAND 410..415
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 422..430
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 434..437
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 443..455
FT /evidence="ECO:0007829|PDB:6FYV"
FT TURN 460..462
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 466..470
FT /evidence="ECO:0007829|PDB:6FYV"
FT HELIX 473..478
FT /evidence="ECO:0007829|PDB:6FYV"
SQ SEQUENCE 481 AA; 57492 MW; F402C36835CDA306 CRC64;
MRHSKRTHCP DWDSRESWGH ESYRGSHKRK RRSHSSTQEN RHCKPHHQFK ESDCHYLEAR
SLNERDYRDR RYVDEYRNDY CEGYVPRHYH RDIESGYRIH CSKSSVRSRR SSPKRKRNRH
CSSHQSRSKS HRRKRSRSIE DDEEGHLICQ SGDVLRARYE IVDTLGEGAF GKVVECIDHG
MDGMHVAVKI VKNVGRYREA ARSEIQVLEH LNSTDPNSVF RCVQMLEWFD HHGHVCIVFE
LLGLSTYDFI KENSFLPFQI DHIRQMAYQI CQSINFLHHN KLTHTDLKPE NILFVKSDYV
VKYNSKMKRD ERTLKNTDIK VVDFGSATYD DEHHSTLVST RHYRAPEVIL ALGWSQPCDV
WSIGCILIEY YLGFTVFQTH DSKEHLAMME RILGPIPQHM IQKTRKRKYF HHNQLDWDEH
SSAGRYVRRR CKPLKEFMLC HDEEHEKLFD LVRRMLEYDP TQRITLDEAL QHPFFDLLKK
K
