CLK4_MOUSE
ID CLK4_MOUSE Reviewed; 481 AA.
AC O35493; O35721; Q8CEU9; Q99LU6;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 160.
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 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] (ISOFORM 1), FUNCTION, PHOSPHORYLATION, AND
RP SUBCELLULAR 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 MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=Czech II; TISSUE=Mammary tumor;
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 1-219.
RX PubMed=9339371; DOI=10.1006/geno.1997.4931;
RA Watkins-Chow D.E., Douglas K.R., Buckwalter M.S., Probst F.J., Camper S.A.;
RT "Construction of a 3-Mb contig and partial transcript map of the central
RT region of mouse chromosome 11.";
RL Genomics 45:147-157(1997).
RN [5]
RP FUNCTION.
RX PubMed=11461155; DOI=10.1006/mcne.2001.1000;
RA Hartmann A.M., Rujescu D., Giannakouros T., Nikolakaki E., Goedert M.,
RA Mandelkow E.-M., Gao Q.S., Andreadis A., Stamm S.;
RT "Regulation of alternative splicing of human tau exon 10 by phosphorylation
RT of splicing factors.";
RL Mol. Cell. Neurosci. 18:80-90(2001).
RN [6]
RP TISSUE SPECIFICITY, AND MUTAGENESIS OF LYS-189.
RX PubMed=12169693; DOI=10.1074/jbc.m206504200;
RA Katsu R., Onogi H., Wada K., Kawaguchi Y., Hagiwara M.;
RT "Novel SR-rich-related protein Clasp specifically interacts with
RT inactivated Clk4 and induces the exon EB inclusion of Clk.";
RL J. Biol. Chem. 277:44220-44228(2002).
RN [7]
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Liver, Lung, Pancreas, Spleen, and Testis;
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).
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:11461155, 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: TG003 inhibits its kinase activity and affects the
CC regulation of alternative splicing mediated by phosphorylation of SR
CC proteins. {ECO:0000269|PubMed:15010457}.
CC -!- SUBUNIT: Interacts with UBL5. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9307018}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O35493-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O35493-2; Sequence=VSP_008205;
CC -!- TISSUE SPECIFICITY: Expressed in the hippocampus, the cerebellum and
CC the olfactory bulb. {ECO:0000269|PubMed:12169693}.
CC -!- PTM: Autophosphorylates on all three types of residues.
CC {ECO:0000269|PubMed:9307018}.
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; AF033566; AAB87510.1; -; mRNA.
DR EMBL; AK013974; BAC25420.1; -; mRNA.
DR EMBL; BC002220; AAH02220.1; -; mRNA.
DR EMBL; BC012675; AAH12675.1; -; mRNA.
DR EMBL; U94846; AAB62179.1; -; mRNA.
DR CCDS; CCDS24651.1; -. [O35493-1]
DR CCDS; CCDS78942.1; -. [O35493-2]
DR RefSeq; NP_001291673.1; NM_001304744.1. [O35493-2]
DR RefSeq; NP_031740.1; NM_007714.6. [O35493-1]
DR RefSeq; XP_006532177.1; XM_006532114.3. [O35493-2]
DR RefSeq; XP_006532178.1; XM_006532115.3.
DR RefSeq; XP_006532179.1; XM_006532116.2.
DR RefSeq; XP_006532181.1; XM_006532118.2. [O35493-2]
DR RefSeq; XP_017169733.1; XM_017314244.1.
DR AlphaFoldDB; O35493; -.
DR SMR; O35493; -.
DR IntAct; O35493; 1.
DR MINT; O35493; -.
DR STRING; 10090.ENSMUSP00000090820; -.
DR BindingDB; O35493; -.
DR ChEMBL; CHEMBL1075283; -.
DR GuidetoPHARMACOLOGY; 1993; -.
DR iPTMnet; O35493; -.
DR PhosphoSitePlus; O35493; -.
DR EPD; O35493; -.
DR jPOST; O35493; -.
DR MaxQB; O35493; -.
DR PaxDb; O35493; -.
DR PeptideAtlas; O35493; -.
DR PRIDE; O35493; -.
DR ProteomicsDB; 281686; -. [O35493-1]
DR ProteomicsDB; 281687; -. [O35493-2]
DR Antibodypedia; 29447; 116 antibodies from 25 providers.
DR DNASU; 12750; -.
DR Ensembl; ENSMUST00000093132; ENSMUSP00000090820; ENSMUSG00000020385. [O35493-1]
DR Ensembl; ENSMUST00000109111; ENSMUSP00000104739; ENSMUSG00000020385. [O35493-2]
DR Ensembl; ENSMUST00000109113; ENSMUSP00000104741; ENSMUSG00000020385. [O35493-2]
DR GeneID; 12750; -.
DR KEGG; mmu:12750; -.
DR UCSC; uc007itr.2; mouse. [O35493-1]
DR CTD; 57396; -.
DR MGI; MGI:1098551; Clk4.
DR VEuPathDB; HostDB:ENSMUSG00000020385; -.
DR eggNOG; KOG0671; Eukaryota.
DR GeneTree; ENSGT00940000160245; -.
DR HOGENOM; CLU_000288_5_16_1; -.
DR InParanoid; O35493; -.
DR OMA; SSNFRCV; -.
DR OrthoDB; 915778at2759; -.
DR PhylomeDB; O35493; -.
DR TreeFam; TF101041; -.
DR BRENDA; 2.7.12.1; 3474.
DR BioGRID-ORCS; 12750; 1 hit in 64 CRISPR screens.
DR ChiTaRS; Clk4; mouse.
DR PRO; PR:O35493; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; O35493; protein.
DR Bgee; ENSMUSG00000020385; Expressed in undifferentiated genital tubercle and 260 other tissues.
DR ExpressionAtlas; O35493; baseline and differential.
DR Genevisible; O35493; MM.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
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; 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:0018108; P:peptidyl-tyrosine phosphorylation; IDA:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0043484; P:regulation of RNA splicing; ISO: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 Alternative splicing; 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_0000085874"
FT DOMAIN 159..475
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..47
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..24
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:0000250|UniProtKB:Q9HAZ1"
FT MOD_RES 138
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1..180
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_008205"
FT MUTAGEN 189
FT /note="K->R: Loss of function."
FT /evidence="ECO:0000269|PubMed:12169693"
FT CONFLICT 58
FT /note="E -> Q (in Ref. 4; AAB62179)"
FT /evidence="ECO:0000305"
FT CONFLICT 141
FT /note="D -> N (in Ref. 4; AAB62179)"
FT /evidence="ECO:0000305"
FT CONFLICT 344
FT /note="R -> K (in Ref. 2; BAC25420)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 481 AA; 57345 MW; F2C56965900C12AA CRC64;
MRHSKRTHCP DWDSRESWGH ESYSGSHKRK RRSHSSTQEN RHCKPHHQFK DSDCHYLEAR
CLNERDYRDR RYIDEYRNDY CEGYVPRHYH RDVESTYRIH CSKSSVRSRR SSPKRKRNRP
CASHQSHSKS HRRKRSRSIE DDEEGHLICQ SGDVLRARYE IVDTLGEGAF GKVVECIDHG
MDGLHVAVKI VKNVGRYREA ARSEIQVLEH LNSTDPNSVF RCVQMLEWFD HHGHVCIVFE
LLGLSTYDFI KENSFLPFQI DHIRQMAYQI CQSINFLHHN KLTHTDLKPE NILFVKSDYV
VKYNSKMKRD ERTLKNTDIK VVDFGSATYD DEHHSTLVST RHYRAPEVIL ALGWSQPCDV
WSIGCILIEY YLGFTVFQTH DSKEHLAMME RILGPIPAHM IQKTRKRKYF HHNQLDWDEH
SSAGRYVRRR CKPLKEFMLC HDEEHEKLFD LVRRMLEYDP ARRITLDEAL QHPFFDLLKR
K
