CLK2_MOUSE
ID CLK2_MOUSE Reviewed; 499 AA.
AC O35491; E9Q721;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Dual specificity protein kinase CLK2;
DE EC=2.7.12.1;
DE AltName: Full=CDC-like kinase 2;
GN Name=Clk2;
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]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AUTOPHOSPHORYLATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=9307018; DOI=10.1042/bj3260693;
RA Nayler O., Stamm S., Ullrich A.;
RT "Characterization and comparison of four serine- and arginine-rich (SR)
RT protein kinases.";
RL Biochem. J. 326:693-700(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP PHOSPHORYLATION AT SER-141, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF SER-141.
RX PubMed=9852100; DOI=10.1074/jbc.273.51.34341;
RA Nayler O., Schnorrer F., Stamm S., Ullrich A.;
RT "The cellular localization of the murine serine/arginine-rich protein
RT kinase CLK2 is regulated by serine 141 autophosphorylation.";
RL J. Biol. Chem. 273:34341-34348(1998).
RN [4]
RP ACTIVITY REGULATION.
RX PubMed=15010457; DOI=10.1074/jbc.m314298200;
RA Muraki M., Ohkawara B., Hosoya T., Onogi H., Koizumi J., Koizumi T.,
RA Sumi K., Yomoda J., Murray M.V., Kimura H., Furuichi K., Shibuya H.,
RA Krainer A.R., Suzuki M., Hagiwara M.;
RT "Manipulation of alternative splicing by a newly developed inhibitor of
RT Clks.";
RL J. Biol. Chem. 279:24246-24254(2004).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, PHOSPHORYLATION AT SER-98; TYR-99 AND THR-343, INDUCTION, AND
RP INTERACTION WITH AKT1.
RX PubMed=20074525; DOI=10.1016/j.cmet.2009.11.006;
RA Rodgers J.T., Haas W., Gygi S.P., Puigserver P.;
RT "Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic
RT gluconeogenesis.";
RL Cell Metab. 11:23-34(2010).
RN [7]
RP FUNCTION.
RX PubMed=21329884; DOI=10.1016/j.molcel.2011.02.007;
RA Rodgers J.T., Vogel R.O., Puigserver P.;
RT "Clk2 and B56-beta mediate insulin-regulated assembly of the PP2A
RT phosphatase holoenzyme complex on Akt.";
RL Mol. Cell 41:471-479(2011).
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. May be a constituent of
CC a network of regulatory mechanisms that enable SR proteins to control
CC RNA splicing and can cause redistribution of SR proteins from speckles
CC to a diffuse nucleoplasmic distribution. Acts as a suppressor of
CC hepatic gluconeogenesis and glucose output by repressing PPARGC1A
CC transcriptional activity on gluconeogenic genes via its
CC phosphorylation. Phosphorylates PPP2R5B thereby stimulating the
CC assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to
CC dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3.
CC Regulates the alternative splicing of tissue factor (F3) pre-mRNA in
CC endothelial cells. Phosphorylates PAGE4 at several serine and threonine
CC residues and this phosphorylation attenuates the ability of PAGE4 to
CC potentiate the transcriptional activator activity of JUN (By
CC similarity). {ECO:0000250|UniProtKB:P49760,
CC ECO:0000269|PubMed:20074525, ECO:0000269|PubMed:21329884,
CC ECO:0000269|PubMed:9307018}.
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: 5,6-dichloro-1-b-D-ribofuranosylbenzimidazole
CC (DRB) inhibits autophosphorylation. TG003 inhibits its kinase activity
CC and affects the regulation of alternative splicing mediated by
CC phosphorylation of SR proteins. {ECO:0000269|PubMed:15010457,
CC ECO:0000269|PubMed:9852100}.
CC -!- SUBUNIT: Interacts with RBMX and UBL5 (By similarity). Interacts with
CC AKT1. {ECO:0000250, ECO:0000269|PubMed:20074525}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9307018,
CC ECO:0000269|PubMed:9852100}. Nucleus speckle
CC {ECO:0000269|PubMed:9852100}. Note=Inhibition of phosphorylation at
CC Ser-141 results in accumulation in the nuclear speckle.
CC {ECO:0000269|PubMed:9852100}.
CC -!- INDUCTION: By insulin (at protein level).
CC {ECO:0000269|PubMed:20074525}.
CC -!- PTM: Autophosphorylates on all three types of residues. Phosphorylation
CC on Ser-34 and Thr-127 by AKT1 is induced by ionizing radiation or
CC insulin. Phosphorylation plays a critical role in cell proliferation
CC following low dose radiation and prevents cell death following high
CC dose radiation. Phosphorylation at Thr-343 by PKB/AKT2 induces its
CC kinase activity which is required for its stability. The
CC phosphorylation status at Ser-141 influences its subnuclear
CC localization; inhibition of phosphorylation at Ser-141 results in
CC accumulation in the nuclear speckle. {ECO:0000269|PubMed:20074525,
CC ECO:0000269|PubMed:9852100}.
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; AF033564; AAB87508.1; -; mRNA.
DR EMBL; AC161600; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS17491.1; -.
DR RefSeq; NP_031738.2; NM_007712.4.
DR AlphaFoldDB; O35491; -.
DR SMR; O35491; -.
DR BioGRID; 198752; 2.
DR STRING; 10090.ENSMUSP00000113390; -.
DR BindingDB; O35491; -.
DR ChEMBL; CHEMBL1075281; -.
DR GuidetoPHARMACOLOGY; 1991; -.
DR iPTMnet; O35491; -.
DR PhosphoSitePlus; O35491; -.
DR EPD; O35491; -.
DR jPOST; O35491; -.
DR MaxQB; O35491; -.
DR PaxDb; O35491; -.
DR PRIDE; O35491; -.
DR ProteomicsDB; 283303; -.
DR Antibodypedia; 34187; 329 antibodies from 31 providers.
DR DNASU; 12748; -.
DR Ensembl; ENSMUST00000121212; ENSMUSP00000113390; ENSMUSG00000068917.
DR GeneID; 12748; -.
DR KEGG; mmu:12748; -.
DR UCSC; uc008pxt.2; mouse.
DR CTD; 1196; -.
DR MGI; MGI:1098669; Clk2.
DR VEuPathDB; HostDB:ENSMUSG00000068917; -.
DR eggNOG; KOG0671; Eukaryota.
DR GeneTree; ENSGT00940000154947; -.
DR InParanoid; O35491; -.
DR TreeFam; TF101041; -.
DR BRENDA; 2.7.12.1; 3474.
DR BioGRID-ORCS; 12748; 3 hits in 75 CRISPR screens.
DR PRO; PR:O35491; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; O35491; protein.
DR Bgee; ENSMUSG00000068917; Expressed in undifferentiated genital tubercle and 261 other tissues.
DR ExpressionAtlas; O35491; baseline and differential.
DR Genevisible; O35491; MM.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
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:MGI.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IMP:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0043484; P:regulation of RNA splicing; ISS:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0010033; P:response to organic substance; IDA:MGI.
DR GO; GO:0032526; P:response to retinoic acid; IDA:MGI.
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 ATP-binding; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Tyrosine-protein kinase.
FT CHAIN 1..499
FT /note="Dual specificity protein kinase CLK2"
FT /id="PRO_0000085869"
FT DOMAIN 163..479
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..65
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 102..142
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..20
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 35..65
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 112..133
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 289
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 168..176
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 192
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 34
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:P49760"
FT MOD_RES 98
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:20074525"
FT MOD_RES 99
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:20074525"
FT MOD_RES 127
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:P49760"
FT MOD_RES 141
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:9852100,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 152
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P49760"
FT MOD_RES 343
FT /note="Phosphothreonine; by PKB/AKT2"
FT /evidence="ECO:0000269|PubMed:20074525"
FT MUTAGEN 141
FT /note="S->A,E: Loss of phosphorylation."
FT /evidence="ECO:0000269|PubMed:9852100"
FT CONFLICT 173
FT /note="F -> S (in Ref. 1; AAB87508)"
FT /evidence="ECO:0000305"
FT CONFLICT 188
FT /note="Q -> R (in Ref. 1; AAB87508)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 499 AA; 59987 MW; 29A7196AFC7797CA CRC64;
MPHPRRYHSS ERGSRGSYHE HYQSRKHKRR RSRSWSSSSD RTRRRRREDS YHVRSRSSYD
DHSSDRRLYD RRYCGSYRRN DYSRDRGEAY YDTDFRQSYE YHRENSSYRS QRSSRRKHRR
RRRRSRTFSR SSSHSSRRAK SVEDDAEGHL IYHVGDWLQE RYEIVSTLGE GTFGRVVQCV
DHRRGGTQVA LKIIKNVEKY KEAARLEINV LEKINEKDPD NKNLCVQMFD WFDYHGHMCI
SFELLGLSTF DFLKDNNYLP YPIHQVRHMA FQLCQAVKFL HDNKLTHTDL KPENILFVNS
DYELTYNLEK KRDERSVKST AVRVVDFGSA TFDHEHHSTI VSTRHYRAPE VILELGWSQP
CDVWSIGCII FEYYVGFTLF QTHDNREHLA MMERILGPVP SRMIRKTRKQ KYFYRGRLDW
DENTSAGRYV RENCKPLRRY LTSEAEDHHQ LFDLIENMLE YEPAKRLTLG EALQHPFFAC
LRTEPPNTKL WDSSRDISR
