TLK2_HUMAN
ID TLK2_HUMAN Reviewed; 772 AA.
AC Q86UE8; D3DU07; Q9UKI7; Q9Y4F7;
DT 22-AUG-2003, integrated into UniProtKB/Swiss-Prot.
DT 22-AUG-2003, sequence version 2.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Serine/threonine-protein kinase tousled-like 2;
DE EC=2.7.11.1;
DE AltName: Full=HsHPK;
DE AltName: Full=PKU-alpha;
DE AltName: Full=Tousled-like kinase 2;
GN Name=TLK2;
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] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT ARG-6, FUNCTION,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Placenta {ECO:0000269|PubMed:9427565}, and
RC Testis {ECO:0000269|PubMed:9427565};
RX PubMed=9427565; DOI=10.1016/s0378-1119(97)00495-2;
RA Yamakawa A., Kameoka Y., Hashimoto K., Yoshitake Y., Nishikawa K.,
RA Tanihara K., Date T.;
RT "cDNA cloning and chromosomal mapping of genes encoding novel protein
RT kinases termed PKU-alpha and PKU-beta, which have nuclear localization
RT signal.";
RL Gene 202:193-201(1997).
RN [2] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, MUTAGENESIS OF ASP-613,
RP SUBCELLULAR LOCATION, INTERACTION WITH TLK1, AND ACTIVITY REGULATION.
RC TISSUE=Placenta {ECO:0000269|PubMed:10523312};
RX PubMed=10523312; DOI=10.1093/emboj/18.20.5691;
RA Sillje H.H.W., Takahashi K., Tanaka K., Van Houwe G., Nigg E.A.;
RT "Mammalian homologues of the plant tousled gene code for cell-cycle-
RT regulated kinases with maximal activities linked to ongoing DNA
RT replication.";
RL EMBO J. 18:5691-5702(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000305}
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 189-772 (ISOFORM 2/3), AND TISSUE
RP SPECIFICITY.
RX PubMed=9662073; DOI=10.1007/bf02258367;
RA Huang A.M., Chang T.J., Cho W.L., Chou C.K.;
RT "From mosquito to man: identification of a novel protein kinase, HsHPK,
RT which is highly expressed in human hepatoma tissues.";
RL J. Biomed. Sci. 5:135-140(1998).
RN [6]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH YWHAZ.
RX PubMed=10455159; DOI=10.1074/jbc.274.35.24865;
RA Zhang S., Xing H., Muslin A.J.;
RT "Nuclear localization of protein kinase U-alpha is regulated by 14-3-3.";
RL J. Biol. Chem. 274:24865-24872(1999).
RN [7]
RP FUNCTION, INTERACTION WITH ASF1A AND ASF1B, AND MUTAGENESIS OF ASP-613.
RX PubMed=11470414; DOI=10.1016/s0960-9822(01)00298-6;
RA Sillje H.H.W., Nigg E.A.;
RT "Identification of human Asf1 chromatin assembly factors as substrates of
RT Tousled-like kinases.";
RL Curr. Biol. 11:1068-1073(2001).
RN [8] {ECO:0000305}
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=12660173; DOI=10.1093/emboj/cdg151;
RA Groth A., Lukas J., Nigg E.A., Sillje H.H.W., Wernstedt C., Bartek J.,
RA Hansen K.;
RT "Human tousled like kinases are targeted by an ATM- and Chk1-dependent DNA
RT damage checkpoint.";
RL EMBO J. 22:1676-1687(2003).
RN [9]
RP PHOSPHORYLATION AT SER-750, FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=12955071; DOI=10.1038/sj.onc.1206691;
RA Krause D.R., Jonnalagadda J.C., Gatei M.H., Sillje H.H.W., Zhou B.-B.,
RA Nigg E.A., Khanna K.;
RT "Suppression of tousled-like kinase activity after DNA damage or
RT replication block requires ATM, NBS1 and Chk1.";
RL Oncogene 22:5927-5937(2003).
RN [10]
RP INTERACTION WITH FEZ1 AND FEZ2.
RX PubMed=16484223; DOI=10.1074/jbc.m513280200;
RA Assmann E.M., Alborghetti M.R., Camargo M.E.R., Kobarg J.;
RT "FEZ1 dimerization and interaction with transcription regulatory proteins
RT involves its coiled-coil region.";
RL J. Biol. Chem. 281:9869-9881(2006).
RN [11]
RP IDENTIFICATION BY 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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, AND IDENTIFICATION BY
RP 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-94 AND SER-134, AND
RP IDENTIFICATION BY 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 [15]
RP FUNCTION AS ASF1A AND ASF1B KINASE, AND ACTIVITY REGULATION.
RX PubMed=20016786; DOI=10.1371/journal.pone.0008328;
RA Pilyugin M., Demmers J., Verrijzer C.P., Karch F., Moshkin Y.M.;
RT "Phosphorylation-mediated control of histone chaperone ASF1 levels by
RT Tousled-like kinases.";
RL PLoS ONE 4:E8328-E8328(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-99, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP FUNCTION.
RX PubMed=22354037; DOI=10.1038/emboj.2012.36;
RA McKnight N.C., Jefferies H.B., Alemu E.A., Saunders R.E., Howell M.,
RA Johansen T., Tooze S.A.;
RT "Genome-wide siRNA screen reveals amino acid starvation-induced autophagy
RT requires SCOC and WAC.";
RL EMBO J. 31:1931-1946(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-73; SER-94; SER-99; SER-115;
RP SER-117 AND SER-134, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [22]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-6; ASP-54; GLY-95; GLY-108; LEU-109;
RP LEU-173 AND GLN-262.
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).
RN [23]
RP VARIANT MRD57 720-ARG--ASN-772 DEL, AND INVOLVEMENT IN MRD57.
RX PubMed=27479843; DOI=10.1038/nn.4352;
RA Lelieveld S.H., Reijnders M.R., Pfundt R., Yntema H.G., Kamsteeg E.J.,
RA de Vries P., de Vries B.B., Willemsen M.H., Kleefstra T., Loehner K.,
RA Vreeburg M., Stevens S.J., van der Burgt I., Bongers E.M., Stegmann A.P.,
RA Rump P., Rinne T., Nelen M.R., Veltman J.A., Vissers L.E., Brunner H.G.,
RA Gilissen C.;
RT "Meta-analysis of 2,104 trios provides support for 10 new genes for
RT intellectual disability.";
RL Nat. Neurosci. 19:1194-1196(2016).
RN [24]
RP VARIANTS MRD57 13-GLN--ASN-772 DEL; 61-ARG--ASN-772 DEL; 68-GLU--ASN-772
RP DEL; 259-TYR--ASN-772 DEL; 262-ARG--ASN-772 DEL; ASP-297; 303-ARG--ASN-772
RP DEL; 330-SER--ASN-772 DEL; GLN-339; TRP-339; LYS-447; ARG-493; ARG-518;
RP TRP-568; 573-GLN--ASN-772 DEL; ASN-629; ARG-680; 720-ARG--ASN-772 DEL AND
RP 746-ARG--ASN-772 DEL, AND INVOLVEMENT IN MRD57.
RX PubMed=29861108; DOI=10.1016/j.ajhg.2018.04.014;
RG Deciphering Developmental Disorders Study;
RA Reijnders M.R.F., Miller K.A., Alvi M., Goos J.A.C., Lees M.M.,
RA de Burca A., Henderson A., Kraus A., Mikat B., de Vries B.B.A., Isidor B.,
RA Kerr B., Marcelis C., Schluth-Bolard C., Deshpande C., Ruivenkamp C.A.L.,
RA Wieczorek D., Baralle D., Blair E.M., Engels H., Luedecke H.J., Eason J.,
RA Santen G.W.E., Clayton-Smith J., Chandler K., Tatton-Brown K., Payne K.,
RA Helbig K., Radtke K., Nugent K.M., Cremer K., Strom T.M., Bird L.M.,
RA Sinnema M., Bitner-Glindzicz M., van Dooren M.F., Alders M., Koopmans M.,
RA Brick L., Kozenko M., Harline M.L., Klaassens M., Steinraths M.,
RA Cooper N.S., Edery P., Yap P., Terhal P.A., van der Spek P.J., Lakeman P.,
RA Taylor R.L., Littlejohn R.O., Pfundt R., Mercimek-Andrews S.,
RA Stegmann A.P.A., Kant S.G., McLean S., Joss S., Swagemakers S.M.A.,
RA Douzgou S., Wall S.A., Kuery S., Calpena E., Koelling N., McGowan S.J.,
RA Twigg S.R.F., Mathijssen I.M.J., Nellaker C., Brunner H.G., Wilkie A.O.M.;
RT "De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and
RT Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.";
RL Am. J. Hum. Genet. 102:1195-1203(2018).
CC -!- FUNCTION: Serine/threonine-protein kinase involved in the process of
CC chromatin assembly and probably also DNA replication, transcription,
CC repair, and chromosome segregation. Phosphorylates the chromatin
CC assembly factors ASF1A AND ASF1B. Phosphorylation of ASF1A prevents its
CC proteasome-mediated degradation, thereby enhancing chromatin assembly.
CC Negative regulator of amino acid starvation-induced autophagy.
CC {ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:11470414,
CC ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:12955071,
CC ECO:0000269|PubMed:20016786, ECO:0000269|PubMed:22354037,
CC ECO:0000269|PubMed:9427565}.
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=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:12660173,
CC ECO:0000269|PubMed:9427565};
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=2.7.11.1; Evidence={ECO:0000269|PubMed:10523312,
CC ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:9427565};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10523312, ECO:0000269|PubMed:12660173,
CC ECO:0000269|PubMed:9427565};
CC -!- ACTIVITY REGULATION: Cell cycle-regulated, with maximal activity in the
CC S-phase. Rapidly and transiently inhibited by phosphorylation following
CC the generation of DNA double-stranded breaks during S-phase, probably
CC by CHEK1, possibly at Ser-750. This inhibition is cell cycle
CC checkpoint- and ATM-dependent. {ECO:0000269|PubMed:10523312,
CC ECO:0000269|PubMed:12660173, ECO:0000269|PubMed:12955071,
CC ECO:0000269|PubMed:20016786}.
CC -!- SUBUNIT: Monomer and heterodimer with TLK1. Interacts with ASF1A and
CC ASF1B. Association with 14-3-3 proteins such as YWHAZ regulates
CC subcellular location. May also interact with FEZ1/LZTS1 and FEZ2.
CC {ECO:0000269|PubMed:10455159, ECO:0000269|PubMed:10523312,
CC ECO:0000269|PubMed:11470414, ECO:0000269|PubMed:16484223}.
CC -!- INTERACTION:
CC Q86UE8; Q8NHQ1: CEP70; NbExp=3; IntAct=EBI-1047967, EBI-739624;
CC Q86UE8; Q9NPF5: DMAP1; NbExp=3; IntAct=EBI-1047967, EBI-399105;
CC Q86UE8; Q96NE9-2: FRMD6; NbExp=3; IntAct=EBI-1047967, EBI-13213391;
CC Q86UE8; Q96IK5: GMCL1; NbExp=3; IntAct=EBI-1047967, EBI-2548508;
CC Q86UE8; Q15306: IRF4; NbExp=2; IntAct=EBI-1047967, EBI-751345;
CC Q86UE8; Q92985: IRF7; NbExp=2; IntAct=EBI-1047967, EBI-968267;
CC Q86UE8; Q02548: PAX5; NbExp=3; IntAct=EBI-1047967, EBI-296331;
CC Q86UE8; P26367: PAX6; NbExp=3; IntAct=EBI-1047967, EBI-747278;
CC Q86UE8; Q86UE8: TLK2; NbExp=3; IntAct=EBI-1047967, EBI-1047967;
CC Q86UE8; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-1047967, EBI-10180829;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm, perinuclear region.
CC Cytoplasm, cytoskeleton. Note=Colocalizes with the cytoplasmic
CC intermediate filament system during the G1 phase of the cell cycle.
CC Present in the perinuclear region at S phase and in the nucleus at late
CC G2.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1 {ECO:0000305};
CC IsoId=Q86UE8-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:10523312};
CC IsoId=Q86UE8-2; Sequence=VSP_050573;
CC Name=3 {ECO:0000269|PubMed:9427565};
CC IsoId=Q86UE8-3; Sequence=VSP_050572, VSP_050573;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Detected in placenta, fetal liver,
CC kidney, pancreas, heart and skeletal muscle. Highly expressed in
CC testis. Detected in spleen, thymus, colon, ovary, small intestine,
CC prostate and peripheral blood leukocytes. {ECO:0000269|PubMed:9427565,
CC ECO:0000269|PubMed:9662073}.
CC -!- PTM: Phosphorylated at Ser-750, probably by CHEK1.
CC {ECO:0000269|PubMed:12955071}.
CC -!- DISEASE: Intellectual developmental disorder, autosomal dominant 57
CC (MRD57) [MIM:618050]: A disorder characterized by significantly below
CC average general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period. MRD57
CC is characterized by delayed psychomotor development apparent in infancy
CC or early childhood, and a variety of behavioral abnormalities. Affected
CC individuals may have severe gastro-intestinal problems, and facial
CC dysmorphism. {ECO:0000269|PubMed:27479843,
CC ECO:0000269|PubMed:29861108}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF03095.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAH44925.2; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAA20561.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AB004884; BAA20561.1; ALT_INIT; mRNA.
DR EMBL; AF162667; AAF03095.1; ALT_INIT; mRNA.
DR EMBL; CH471109; EAW94346.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94348.1; -; Genomic_DNA.
DR EMBL; BC044925; AAH44925.2; ALT_INIT; mRNA.
DR CCDS; CCDS11633.1; -. [Q86UE8-2]
DR CCDS; CCDS45753.1; -. [Q86UE8-3]
DR CCDS; CCDS62283.1; -. [Q86UE8-1]
DR RefSeq; NP_001271262.1; NM_001284333.1. [Q86UE8-1]
DR RefSeq; NP_001271292.1; NM_001284363.1. [Q86UE8-3]
DR RefSeq; NP_006843.2; NM_006852.3. [Q86UE8-2]
DR RefSeq; XP_011522518.1; XM_011524216.2. [Q86UE8-1]
DR RefSeq; XP_011522519.1; XM_011524217.2. [Q86UE8-1]
DR RefSeq; XP_011522524.1; XM_011524222.2. [Q86UE8-1]
DR RefSeq; XP_016879533.1; XM_017024044.1. [Q86UE8-2]
DR RefSeq; XP_016879535.1; XM_017024046.1.
DR RefSeq; XP_016879536.1; XM_017024047.1.
DR RefSeq; XP_016879540.1; XM_017024051.1. [Q86UE8-3]
DR RefSeq; XP_016879541.1; XM_017024052.1.
DR RefSeq; XP_016879542.1; XM_017024053.1. [Q86UE8-3]
DR PDB; 5O0Y; X-ray; 2.86 A; A=191-755.
DR PDB; 7LO0; X-ray; 2.71 A; I/J/K/L/M/N/O/P/Q/R/T/U/V/W/X/Y=3-23.
DR PDBsum; 5O0Y; -.
DR PDBsum; 7LO0; -.
DR AlphaFoldDB; Q86UE8; -.
DR SMR; Q86UE8; -.
DR BioGRID; 116201; 83.
DR IntAct; Q86UE8; 32.
DR MINT; Q86UE8; -.
DR STRING; 9606.ENSP00000316512; -.
DR BindingDB; Q86UE8; -.
DR ChEMBL; CHEMBL5404; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q86UE8; -.
DR iPTMnet; Q86UE8; -.
DR PhosphoSitePlus; Q86UE8; -.
DR BioMuta; TLK2; -.
DR DMDM; 34222826; -.
DR EPD; Q86UE8; -.
DR jPOST; Q86UE8; -.
DR MassIVE; Q86UE8; -.
DR MaxQB; Q86UE8; -.
DR PaxDb; Q86UE8; -.
DR PeptideAtlas; Q86UE8; -.
DR PRIDE; Q86UE8; -.
DR ProteomicsDB; 69811; -. [Q86UE8-1]
DR ProteomicsDB; 69812; -. [Q86UE8-2]
DR ProteomicsDB; 69813; -. [Q86UE8-3]
DR Antibodypedia; 31236; 373 antibodies from 31 providers.
DR DNASU; 11011; -.
DR Ensembl; ENST00000326270.13; ENSP00000316512.9; ENSG00000146872.19. [Q86UE8-1]
DR Ensembl; ENST00000343388.11; ENSP00000340800.7; ENSG00000146872.19. [Q86UE8-3]
DR Ensembl; ENST00000346027.10; ENSP00000275780.7; ENSG00000146872.19. [Q86UE8-2]
DR Ensembl; ENST00000682085.1; ENSP00000506744.1; ENSG00000146872.19. [Q86UE8-2]
DR Ensembl; ENST00000683104.1; ENSP00000508242.1; ENSG00000146872.19. [Q86UE8-3]
DR GeneID; 11011; -.
DR KEGG; hsa:11011; -.
DR MANE-Select; ENST00000346027.10; ENSP00000275780.7; NM_006852.6; NP_006843.2. [Q86UE8-2]
DR UCSC; uc002izz.5; human. [Q86UE8-1]
DR CTD; 11011; -.
DR DisGeNET; 11011; -.
DR GeneCards; TLK2; -.
DR HGNC; HGNC:11842; TLK2.
DR HPA; ENSG00000146872; Low tissue specificity.
DR MalaCards; TLK2; -.
DR MIM; 608439; gene.
DR MIM; 618050; phenotype.
DR neXtProt; NX_Q86UE8; -.
DR OpenTargets; ENSG00000146872; -.
DR PharmGKB; PA36544; -.
DR VEuPathDB; HostDB:ENSG00000146872; -.
DR eggNOG; KOG1151; Eukaryota.
DR GeneTree; ENSGT00950000182984; -.
DR InParanoid; Q86UE8; -.
DR OMA; FETQASS; -.
DR OrthoDB; 693214at2759; -.
DR PhylomeDB; Q86UE8; -.
DR TreeFam; TF315233; -.
DR PathwayCommons; Q86UE8; -.
DR SignaLink; Q86UE8; -.
DR SIGNOR; Q86UE8; -.
DR BioGRID-ORCS; 11011; 238 hits in 1077 CRISPR screens.
DR ChiTaRS; TLK2; human.
DR GeneWiki; TLK2; -.
DR GenomeRNAi; 11011; -.
DR Pharos; Q86UE8; Tchem.
DR PRO; PR:Q86UE8; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q86UE8; protein.
DR Bgee; ENSG00000146872; Expressed in calcaneal tendon and 113 other tissues.
DR ExpressionAtlas; Q86UE8; baseline and differential.
DR Genevisible; Q86UE8; HS.
DR GO; GO:0005882; C:intermediate filament; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
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:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0071480; P:cellular response to gamma radiation; IDA:UniProtKB.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0007059; P:chromosome segregation; IMP:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR GO; GO:0010507; P:negative regulation of autophagy; NAS:BHF-UCL.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:1902275; P:regulation of chromatin organization; IDA:UniProtKB.
DR DisProt; DP02475; -.
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 InterPro; IPR027086; TLK2.
DR PANTHER; PTHR22974:SF20; PTHR22974:SF20; 1.
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; Alternative splicing; ATP-binding; Cell cycle;
KW Chromatin regulator; Coiled coil; Cytoplasm; Cytoskeleton; Disease variant;
KW DNA damage; Intellectual disability; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..772
FT /note="Serine/threonine-protein kinase tousled-like 2"
FT /id="PRO_0000086754"
FT DOMAIN 462..741
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 24..126
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 180..208
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 342..385
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 225..276
FT /evidence="ECO:0000255"
FT COILED 317..347
FT /evidence="ECO:0000255"
FT COILED 403..451
FT /evidence="ECO:0000255"
FT COMPBIAS 27..45
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 48..71
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 104..120
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 355..383
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 592
FT /note="Proton acceptor"
FT BINDING 468..476
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 491
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 73
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 94
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 99
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT MOD_RES 115
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 117
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 134
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 750
FT /note="Phosphoserine; by CHEK1"
FT /evidence="ECO:0000305|PubMed:12955071"
FT VAR_SEQ 90..121
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9427565"
FT /id="VSP_050572"
FT VAR_SEQ 375..396
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10523312,
FT ECO:0000303|PubMed:9427565"
FT /id="VSP_050573"
FT VARIANT 6
FT /note="H -> R (in dbSNP:rs45550140)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:9427565"
FT /id="VAR_041216"
FT VARIANT 13..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081017"
FT VARIANT 54
FT /note="E -> D"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041217"
FT VARIANT 61..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081018"
FT VARIANT 68..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081019"
FT VARIANT 95
FT /note="A -> G (in dbSNP:rs2598147)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041218"
FT VARIANT 108
FT /note="A -> G"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041219"
FT VARIANT 109
FT /note="R -> L (in dbSNP:rs1555617262)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041220"
FT VARIANT 173
FT /note="F -> L (in a gastric adenocarcinoma sample; somatic
FT mutation; dbSNP:rs1331331651)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041221"
FT VARIANT 259..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081020"
FT VARIANT 262..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081021"
FT VARIANT 262
FT /note="R -> Q (in dbSNP:rs762409144)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041222"
FT VARIANT 297
FT /note="G -> D (in MRD57; unknown pathological significance;
FT dbSNP:rs1555639254)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081022"
FT VARIANT 303..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081023"
FT VARIANT 330..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081024"
FT VARIANT 339
FT /note="R -> Q (in MRD57; unknown pathological significance;
FT dbSNP:rs1567948287)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081025"
FT VARIANT 339
FT /note="R -> W (in MRD57; unknown pathological significance;
FT dbSNP:rs1567948262)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081026"
FT VARIANT 447
FT /note="E -> K (in MRD57; unknown pathological significance;
FT dbSNP:rs1567959483)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081027"
FT VARIANT 493
FT /note="H -> R (in MRD57; dbSNP:rs1567974030)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081028"
FT VARIANT 518
FT /note="H -> R (in MRD57; dbSNP:rs1567995650)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081029"
FT VARIANT 568
FT /note="R -> W (in MRD57; dbSNP:rs1283838287)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081030"
FT VARIANT 573..772
FT /note="Missing (in MRD57)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081031"
FT VARIANT 629
FT /note="D -> N (in MRD57; dbSNP:rs1568006217)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081032"
FT VARIANT 680
FT /note="P -> R (in MRD57; dbSNP:rs1568018905)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081033"
FT VARIANT 720..772
FT /note="Missing (in MRD57; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27479843,
FT ECO:0000269|PubMed:29861108"
FT /id="VAR_081034"
FT VARIANT 746..772
FT /note="Missing (in MRD57; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29861108"
FT /id="VAR_081035"
FT MUTAGEN 613
FT /note="D->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:10523312,
FT ECO:0000269|PubMed:11470414"
FT CONFLICT 1
FT /note="M -> I (in Ref. 1; BAA20561)"
FT /evidence="ECO:0000305"
FT CONFLICT 161
FT /note="T -> P (in Ref. 1; BAA20561)"
FT /evidence="ECO:0000305"
FT CONFLICT 207
FT /note="Q -> R (in Ref. 2; AAF03095)"
FT /evidence="ECO:0000305"
FT CONFLICT 562
FT /note="M -> I (in Ref. 1; BAA20561)"
FT /evidence="ECO:0000305"
FT CONFLICT 727
FT /note="E -> R (in Ref. 2; AAF03095)"
FT /evidence="ECO:0000305"
FT STRAND 463..470
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 472..481
FT /evidence="ECO:0007829|PDB:5O0Y"
FT TURN 482..485
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 486..494
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 497..499
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 502..519
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 529..534
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 539..545
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 549..551
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 552..559
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 564..581
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 584..586
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 595..597
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 598..600
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 603..607
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 609..611
FT /evidence="ECO:0007829|PDB:5O0Y"
FT TURN 622..624
FT /evidence="ECO:0007829|PDB:5O0Y"
FT TURN 627..629
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 641..643
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 646..649
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 652..654
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 661..676
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 680..682
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 687..693
FT /evidence="ECO:0007829|PDB:5O0Y"
FT TURN 694..698
FT /evidence="ECO:0007829|PDB:5O0Y"
FT STRAND 706..708
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 712..721
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 726..728
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 732..735
FT /evidence="ECO:0007829|PDB:5O0Y"
FT HELIX 739..741
FT /evidence="ECO:0007829|PDB:5O0Y"
SQ SEQUENCE 772 AA; 87661 MW; 765EE37ED4A4ADEC CRC64;
MMEELHSLDP RRQELLEARF TGVGVSKGPL NSESSNQSLC SVGSLSDKEV ETPEKKQNDQ
RNRKRKAEPY ETSQGKGTPR GHKISDYFEF AGGSAPGTSP GRSVPPVARS SPQHSLSNPL
PRRVEQPLYG LDGSAAKEAT EEQSALPTLM SVMLAKPRLD TEQLAQRGAG LCFTFVSAQQ
NSPSSTGSGN TEHSCSSQKQ ISIQHRQTQS DLTIEKISAL ENSKNSDLEK KEGRIDDLLR
ANCDLRRQID EQQKMLEKYK ERLNRCVTMS KKLLIEKSKQ EKMACRDKSM QDRLRLGHFT
TVRHGASFTE QWTDGYAFQN LIKQQERINS QREEIERQRK MLAKRKPPAM GQAPPATNEQ
KQRKSKTNGA ENETPSSGNT ELKDTAPALG AHSLLRLTLA EYHEQEEIFK LRLGHLKKEE
AEIQAELERL ERVRNLHIRE LKRIHNEDNS QFKDHPTLND RYLLLHLLGR GGFSEVYKAF
DLTEQRYVAV KIHQLNKNWR DEKKENYHKH ACREYRIHKE LDHPRIVKLY DYFSLDTDSF
CTVLEYCEGN DLDFYLKQHK LMSEKEARSI IMQIVNALKY LNEIKPPIIH YDLKPGNILL
VNGTACGEIK ITDFGLSKIM DDDSYNSVDG MELTSQGAGT YWYLPPECFV VGKEPPKISN
KVDVWSVGVI FYQCLYGRKP FGHNQSQQDI LQENTILKAT EVQFPPKPVV TPEAKAFIRR
CLAYRKEDRI DVQQLACDPY LLPHIRKSVS TSSPAGAAIA STSGASNNSS SN
