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TLK2 (Tousled Like Kinase 2)

Written2020-09Mustafa Cicek, Esra Cicek, A. Elif Erson-Bensan
Department of Biology, Karamanoglu Mehmetbey University, Karaman/Turkey, mustafacicek@kmu.edu.tr (MC), Department of Biological Sciences, Middle East Technical University, Ankara/Turkey, esyavuz@metu.edu.tr; erson@metu.edu.tr (EC, AEEB)

Abstract Tousled-like kinase 2 (TLK2) gene maps to chromosome 17, to plus strand and consists of 31 exons and 30 introns. Multiple transcript variants are encoded by TLK2 gene due to alternative splicing. TLK2 is a member of Tousled-like kinases family of serine/threonine kinases and composed of a C-terminal protein kinase catalytic domain, a middle region including three putative coiled coil (CC) domains and an N-terminal region carrying a nuclear localization signal. TLK2 has been implicated in DNA replication, regulation of cell cycle progression, development, as well as various diseases including cancer.

Keywords TLK2, Ser/Thr Kinase, Replication, Genome integrity

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)HsHPK (Homo sapiens Hepatoma Protein Kinase)
MRD57 (Mental retardation, autosomal dominant 57)
PKU-ALPHA (Protein Kinase, Ubiquitous-Alpha)
HGNC (Hugo) TLK2
HGNC Alias symbPKU-ALPHA
MGC44450
HGNC Previous nametousled-like kinase 2
LocusID (NCBI) 11011
Atlas_Id 43530
Location 17q23.2  [Link to chromosome band 17q23]
Location_base_pair Starts at 62478825 and ends at 62615480 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping TLK2.png]
Local_order From centromere to telomere: METTL2A, LOC112268200, LOC112268201, TLK2, RPS10P26, LOC112268202, LOC107985020, MRC2, RNU6-446P.
 
  Figure 1. Local order of TLK2 is shown together with leading and subsequent genes on chromosome 17. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note TLK2 gene consists of 31 exons and 30 introns. The gene maps to 17q23.2 and is 144,574 bp long (NCBI Reference Sequence : NC_000017.11 : 62470908-62615481).
 
  Figure 2. The longest transcript encoded by TLK2 gene (ENST00000326270.13) consists of 23 exons and 22 introns. Red boxes represent exons/protein-coding regions and blue boxes represents untranslated regions.
Description TLK2 is 144,574 bp long and is on the plus strand. TLK2 gene has 31 exons (According to NCBI).
Transcription TLK2 produces 10 coding transcripts (3608 bp, 3512 bp, 3449 bp, 3227 bp, 1784 bp, 767 bp, 559 bp, 550 bp, 530 bp and 512 bp), 7 non-protein coding transcripts (578 bp, 513 bp, 3536 bp, 877 bp, 606 bp, 541 bp and 436 bp) and there is also an NMD (non-sense mediated decay) transcript (ENST00000583690.6; 496 bp) generated from the locus. (https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000146872;r=17:62458658-62615481).
Pseudogene There are 2 reported pseudogenes of TLK2 which are: TLK2P1 (tousled like kinase 2 pseudogene 1) on chromosome 17 and TLK2P2 (tousled like kinase pseudogene 2) on chromosome 10 (https://www.ncbi.nlm.nih.gov/, 2020). TLK2P1 and TLK2P2 are ubiquitously expressed in whole blood, white blood cells, lymph node, brain, cortex, cerebellum, spinal cord, tibial nerve, heart, artery, skeletal muscle, small intestine, colon, adipocyte, kidney, liver, lung, spleen, stomach, esophagus, bladder, pancreas, thyroid, salivary gland, adrenal gland, pituitary, breast, skin, ovary, uterus, prostate and testis (https://www.genecards.org/cgi-bin/carddisp.pl?gene=TLK2P1&keywords=tlk2p1; https://www.genecards.org/cgi-bin/carddisp.pl?gene=TLK2P2&keywords=tlk2p2).

Protein

Note Tousled-like kinase 2 (TLK2), together with Tousled-like kinase 1 ( TLK1), belongs to Tousled-like kinases family of serine/threonine kinases (Silljé et al., 1999; Mortuza et al., 2018; Segura-Bayona and Stracker, 2019). As a cell cycle regulated enzyme, TLK2 exhibits its highest level of activity during S-phase (Silljé et al., 1999).
TLK2 is composed of an N-Terminal region harboring a nuclear localization signal (NLS), a middle region of helixes containing three putative coiled coil (CC) domains and a C-terminal protein kinase catalytic domain. The C-terminal region of the protein kinase domain is known to carry multiple potential phosphorylation sites in its carboxy-terminus (C-tail) (Groth et al., 2003; Krause et al., 2003; Klimovskaia et al., 2014; Mortuza et al., 2018).
TLK2 is activated through cis-autophosphorylation events in its kinase domain. These autophosphorylation events induce a conformational change which allows further phosphorylation in the C-tail of TLK2 (Mortuza et al., 2018). The monomeric TLK2 exhibits a negligible catalytic activity in comparison to its dimeric form (Mortuza et al., 2018; Segura-Bayona and Stracker, 2019).
Homodimerization of TLK2 or heterodimerization with TLK1 requires the presence of the first coiled coil (CC1) domain. Activated/phosphorylated dimers of TLK2 can display higher orders of oligomerization through further phosphorylation of the phosphor-sites in the loops joining the CC domains (Mortuza et al., 2018). This oligomerization can trigger activation and may also increase the enzymatic activity through recruiting additional TLK2 molecules. While the dimeric/oligomeric constructs of TLK2 are able to phosphorylate a specific substrate, ASF1A, the kinase domain alone do not display this property, suggesting that either the CC domains or their role in oligomerization is crucial for substrate recognition (Mortuza et al., 2018; Segura-Bayona and Stracker, 2019). Mechanism and role of other phosphorylations at the N terminus remain to be further investigated (Hornbeck et al., 2015; Segura-Bayona and Stracker, 2019).
 
  Figure 3. The longest isoform of TLK2 is encoded by 772 amino acids and consists of a regulatory domain and a kinase domain. Regulatory domain contains NLS region and coiled coil domains. Kinase domain has an ATP binding region and a catalytic loop.
Description TLK2 longest transcript encodes for 772 amino acids. Molecular weight is 87,661 Da.
Expression TLK2 transcript is mostly expressed in testis but also in brain, eye, endocrine tissues, lung, proximal digestive tract, gastrointestinal tract, liver and gallbladder, pancreas, kidney, urinary bladder, female tissues, muscle tissues, adipose and soft tissue, skin, bone marrow, lymphoid tissues and blood. (https://www.proteinatlas.org/ENSG00000146872-TLK2/tissue).
Localisation TLK2 is a nuclear protein but its subcellular localization may change depending on the cell cycle. TLK2 colocalizes to cytoplasmic intermediate filaments during G1 phase and to the perinuclear region at S phase (Yamakawa et.al., 1997; Zhang et.al., 1999).
Function Cell Cycle and DNA Damage
Following its identification as a mammalian homologue of A. thaliana Tousled kinase, TLK2 has been linked to a wide-range of cellular functions (Sillje et al., 1999). TLK2 exhibits a constitutive expression pattern throughout the cell cycle whereas its kinase activity fluctuates during the cell cycle and peaking in the S-phase (Sillje et al., 1999). Inhibition of DNA-replication and induction of DNA-damage in mid-S phase cells with various agents (e.g. aphidicolin, hydroxyurea, cisplatin, bleomycin, topoisomerase inhibitors, ionizing radiation) substantially decrease TLK2 kinase activity (Sillje et al., 1999; Groth et al., 2003). These results suggest that there is a direct link between TLK2 activity and ongoing DNA-replication and this activity is inhibited as a result of stalled replication fork on damaged DNA. In support, TLK2 activity is associated with maintenance of replication fork integrity and chromatin assembly (Lee et al., 2018). siRNA-mediated knockdown of TLK2 reduces the rate of DNA replication fork progression, disrupt replication-coupled nucleosome assembly and result in accumulation of replication-dependent single-stranded DNA. Moreover, sustained depletion of TLK2 result in accumulation of replication-dependent DNA-damage which in turn cause a TP53 -mediated G1-S checkpoint arrest (Lee et al., 2018). However, how TLK2 promotes genome stability and its role in DNA damage response (DDR) remain to be fully elucidated. One possible mechanism to associate TLK2 activity with DDR is based on the fact that H3/H4 histone chaperone ASF1 is an interacting partner of TLKs (Sillje and Nigg, 2001). TLK-mediated phosphorylation of ASF1 positively regulates ASF1a protein levels, hinders its proteasomal degradation (Pilyugin et al., 2009) and stimulates its association with soluble histones and downstream chaperones, CAF-1 and HIRA (Klimovskaia et al., 2014). In yeast, ASF1 is implicated in maintenance of genome stability and checkpoint recovery through its direct interaction with CHEK2 (RAD53) (Emili et al., 2001; Hu et al., 2001), but in mammalian cells it is indirectly regulated by checkpoint kinases through activities of TLKs (Segura-Bayona and Stracker, 2019). Although a direct interaction of Checkpoint kinase 1 ( CHEK1) with TLK2 has not been demonstrated in proteomics studies (Segura-Bayona et al., 2017), its paralog TLK1 has been reported as a substrate of CHEK1. Phosphorylation of TLK1 at serine 695 (S695) in response to DNA-damage results in transient inhibition of TLK1 activity (Groth et al., 2003; Krause et al., 2003). This modulation of TLK1 activity by CHEK1 may be a key event for regulating histone binding capacity of ASF1 and to allow chromatin restoration during DNA-repair.
Interestingly, overexpression of TLK2 in T47D cells disrupt the CHEK1/2-mediated DDR signaling, resulting in a delayed DNA repair process, impaired G2/M checkpoint and an enhanced chromosome instability (Kim et al., 2016a). However, it has not yet been fully elucidated whether TLK2 is also directly regulated by CHEK1 or by heterodimerization with C-terminally phosphorylated TLK1 (Segura-Bayona and Stracker, 2019).
On the other hand, TLK2 controls chromatin restoration after DNA-damage during G2 arrest through histone chaperone ASF1A. In the absence of TLK2, improper chromatin restoration results in decreases expression of pro-mitotic genes such as; CCNB1 (Cyclin B1) and PLK1 which in turn compromised cellular competence to recover from cell cycle arrests induced by DNA-damage (Bruinsma et al., 2016).
The Drosophila genome includes a single Tousled-like kinase gene and the encoded Tlk plays dual function to prolong the G2-phase and to promote the G2 recovery via modulating the "p38a" (symbol provided by Flybase for Drosophila genes) activity. According to the proposed model, Tlk remains in an inactive form when its cellular level is low. Alternatively, Tlk kinase activity can be inactivated as a consequence of dATM/DCHEK1 activity triggered by a stress-induced DNA and/or histone damage. This inactive Tlk associates with "Tak1", "Hsc70-5" (Flybase) and EEF1A1. The resulting protein complex elevates p38a activity, which in turn causes a delay in G2 phase. On the other hand, under conditions where TLK activity is high, active Tlk promotes G2 recovery by decreasing p38a activity and increasing ASF1 activity (Liaw and Chian, 2019).
Cancer
TLK2 function has been linked to patient outcomes in a variety of human cancers including breast cancer, glioblastoma, uveal melanoma, cervical squamous cell carcinoma and endocervical adenocarcinoma (Kim et al., 2016b; Lin et al., 2018; Lee et al., 2018). Analysis of copy number, RNA-seq and survival data sets for breast tumors from The Cancer Genome Atlas Project (TCGA) showed that TLK2 is amplified in nearly 10% of ER-positive breast cancers and its resulting overexpression correlates with worse clinical outcome (Kim et al., 2016b). A phosphoproteomic analyses of TCGA breast cancer samples performed by The Clinical Proteomic Tumor Analysis Consortium (CPTAC) independently identified TLK2 as an amplicon-associated, highly phosphorylated kinase in luminal breast cancers (Mertins et al., 2016). Ectopic expression of TLK2 in T47D luminal breast cancer cell line, which normally possesses low TLK2 levels, results in increased invasion and cell migration and this aggressiveness reversed upon withdrawal of TLK2 expression (Kim et al., 2016b). The TLK2 overexpression-mediated invasiveness of breast cancer cells may be attributed to EGFR / SRC / PTK2 (FAK) signaling axis as TLK2 overexpression increases phosphorylation of EGFR, SRC and FAK. Conversely, siRNA-mediated knockdown of SRC, FAK or EGFR decreased the migration ability of TLK2-overexpressing T47D cells (Kim et al., 2016b).
shRNA targeting of TLK2 suppresses ESR1 (ERα), BCL2 and SKP2 protein levels, upregulates CDKN1B (p27), impairs cell cycle progression through G1/S border, decreases colony-forming ability, induces apoptosis and significantly improves progression-free survival in vivo (Kim et al., 2016b). Activation of SRC signaling axis by TLK2 and effects of this relation on cancer progression was also proved by studies performed with glioblastoma cells (Lin et al., 2018). TLK2 is upregulated in invasive glioblastoma samples in comparison to normal tissues and non-invasive glioblastoma samples, and this upregulation is associated with worse patient outcomes. Overexpression of TLK2 in glioblastoma cells increased cell growth, invasion and migration, while silencing TLK2 result in cell cycle arrest at G2/M checkpoint and ultimately induction of apoptosis. Expression analysis for markers of epithelial-to-mesenchymal transition indicated that TLK2 overexpression is associated with decreased levels of epithelial markers CDH1 (E-cadherin) and TJP1 (ZO-1), whereas mesenchymal marker vimentin is increased. On the other hand, TLK2 knockdown resulted in an opposite effect (Lin et al., 2018). In vivo analysis of TLK2 activity on cancer progression created a link between TLK2 knockdown and reduction in tumor growth and metastasis (Lin et al., 2018).
Development
In addition to its roles in replication, cell cycle regulation and maintenance of genome stability TLK2 function also implicated in mammalian development. The characterization studies performed with TLK2-defficient mice suggested that TLK2 is required for normal differentiation of trophoblast lineages. TLK2 deficiency in mice resulted in late embryonic lethality due to placental failure. Histological examination of the labyrinths of TLK2 deficient mice placenta indicate a disorganized structure composed of less mature and less differentiated trophoblasts. Taken together, these data suggest a requirement to TLK2 for proper placental development and function (Segura-Bayona et al., 2017).
This effect of TLK2 may be a consequence of its roles in transcriptional regulation (Bruinsma et al., 2016). TLK2 loss was also correlated with decreased histone chaperon ASF1 (Anti-Silencing Function 1) phosphorylation (Segura-Bayona et al., 2017).
Homology TLK2 is conserved among species such as chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, C. elegans and frog (https://www.ncbi.nlm.nih.gov/).

Mutations

Note Copy number variations and mutations are reported for TLK2.
Germinal De novo loss of function mutations are detected in patients with facial dysmorphisms and microcephaly (Lelieveld et al., 2016). De novo mutations (DNM) also detected in Autism spectrum disorders (ASD) (O'Roak et al., 2011; Takata et al., 2018) and schizophrenia (Gulsuner et al., 2013). DNMs on the serine/threonin catalytic subunit of TLK2 are substitutions and listed as; p.(H493R), p.(H518R), p.(D629N), p.(R270) and c.(1786+1G>T) were detected in Intellectual Disability (ID) patients (Lelieveld et al., 2016).
Somatic Copy number increases (CNI) are seen in breast cancer patients (Kelemen et al., 2009; Kim et al., 2016b). Mutations of TLK2 are also reported for adenocortical carcinoma, bladder urothelial carcinoma, oligoastrocytoma, astrocytoma, breast invasive mixed mucinous carcinoma, breast invasive lobular carcinoma, breast invasive ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma of the colon and rectum, glioblastoma mutiforme, head and neck squamous cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, serous ovarian cancer, pancreatic adenocarcinoma, prostate adenocarcinoma, dedifferentiated liposarcoma, cutaneous melanoma, stomach adenocarcinoma, mucinous stomach adenocarcinoma, uterine carcinosarcoma / uterine malignant mixed mullerian tumor, uterine endometrioid carcinoma, uterine serous carcinoma/uterine papillary serous carcinoma, uterine mixed endometrial carcinoma (cBioPortal database) (Cerami et al., 2012; Gao et al., 2013).

Implicated in

  
Entity Breast Cancer
Note TLK2 SNPs rs2245092 and rs733025 were found to be associated with hormone-receptor positive breast cancer (Kelemen et al., 2009; Stevens et al., 2011). TLK2 was found to be among highly phosphorylated kinases in basal luminal breast cancers most probably because amplification of 17q23 region (Mertins et al., 2016). TLK2 overexpression and amplification weaken CHEK1/2-induced DNA-damage checkpoint signaling and leads G2/M checkpoint defect, retardation of DNA repair process and chromosomal instability increase in aggressive estrogen (ER) positive breast cancers (Kim et al., 2016a). Moreover, TLK2 overexpression correlate with tumor aggressiveness and worse clinical outcome in breast cancer cells. TLK2 inhibition caused ER-alpha, BCL2 and SKP2 downregulation, weak G1/S cell cycle progression, increased apoptosis and better progression free survival (Kim et al., 2016b).
  
  
Entity Colorectal Cancer
Note TLK2 is overexpressed in mCRC (metastatic colorectal carcinoma) patients with KRAS mutation compared to cetuximab plus irinotecan (CI) treated patients. TLK2 has a significant correlation to prolonged Progression Free Survival (PFS) (Kim et al., 2015).
  
  
Entity
Note Copy number alterations (CNAs) that includes amplification of a segment which contains TLK2 have been predicted to effect GBM patient survival and chemotherapy response. (Lee et al., 2012). TLK2 upregulation in GBM, also caused increased cell proliferation, migration, EMT, metastasis, cell cycle arrest and enhanced SRC signaling. TLK2 silencing reverses these effects (Lin et al., 2018).
  
  
Entity Intellectual Disability (ID)
Note In a study which meta-analysis performed on de novo mutations (DNMs) identified from the exomes of patient-parent trios, TLK2 was identified among new candidate genes for intellectual disability. additional DNMs of TLK2 was found in patients which have autism spectrum disorder, schizophrenia and facial dysmorphisms (Lelieveld et al., 2016).
  
  
Entity Autism Spectrum Disorder (ASD)
Note TLK2 de novo mutations which are loss of function or consensus-damaging missense mutations were reported for ASD via integrative bioinformatics analyses (Takata et al., 2018).
  
  
Entity Neurodevelopmental Disorder (ND)
Note De novo and inherited TLK2 mutations were reported for a distinct neurodevelopmental disease identified by developmental delay, diverse behavioural disorders, gastro-intestinal complications and facial dysmorphism (Reijnders et al., 2018). a TLK2 homozygous missense variant was also identified in a patient who has cerebellar vermis hypoplasia and West syndrome using Whole Exome Sequencing studies (Töpf et al., 2019).
  
  
Entity Developmental Disorders
Note Reciprocal translocations, inversions, insertions and other complex chromosomal rearrangements for TLK2 were reported in association with intellectual disabilities and/or congenital anomalies (Schluth-Bolard et al., 2019).
  
  
Entity Alzheimer's Disease
Note Array analysis and quantitative trait loci (QTL) mapping studies showed TLK2 to be one of the AD-related and APP (Amyloid precursor protein) coregulated gene in mice (Wang et al., 2010). Virally encoded Abeta42, found in the amyloid plaques of AD, was shown to inhibit serine/threonine kinase, TLK2, phosphorylation in human (Suhara et al., 2003).
  
  
Entity Systemic Lupus Erythematosus
Note The genome-wide gene expression analysis of CD4+ T lymphocytes, isolated from a systemic lupus erythematosus (SLE) patient during disease active state and non-active state, revealed that TLK2 expression was higher at active state of the disease. The differential expression of TLK2, along with other genes, might be responsible for the SLE autoimmunity through generation of immature CD4+ T lymphocytes (Deng et al., 2006).
  
  
Entity Respiratory Syncytial Virus (RSV) Infection
Note TLK2 expression is higher in RSV-infected BEAS-2B cells samples compared to controls determined by microarray analysis. TLK2 could be considered as a possible biomarker in early infection (Gardinassi, 2016).
  
  
Entity Osteochondrosis (OC)
Note TLK2 mRNA was upregulated in OC samples, possibly because of increased DNA replication during tissue damage and recovery. (Austbø et al., 2010).
  

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Schluth-Bolard C, Diguet F, Chatron N, Rollat-Farnier PA, Bardel C, Afenjar A, Amblard F, Amiel J, Blesson S, Callier P, Capri Y, Collignon P, Cordier MP, Coubes C, Demeer B, Chaussenot A, Demurger F, Devillard F, Doco-Fenzy M, Dupont C, Dupont JM, Dupuis-Girod S, Faivre L, Gilbert-Dussardier B, Guerrot AM, Houlier M, Isidor B, Jaillard S, Joly-Hélas G, Kremer V, Lacombe D, Le Caignec C, Lebbar A, Lebrun M, Lesca G, Lespinasse J, Levy J, Malan V, Mathieu-Dramard M, Masson J, Masurel-Paulet A, Mignot C, Missirian C, Morice-Picard F, Moutton S, Nadeau G, Pebrel-Richard C, Odent S, Paquis-Flucklinger V, Pasquier L, Philip N, Plutino M, Pons L, Portnoï MF, Prieur F, Puechberty J, Putoux A, Rio M, Rooryck-Thambo C, Rossi M, Sarret C, Satre V, Siffroi JP, Till M, Touraine R, Toutain A, Toutain J, Valence S, Verloes A, Whalen S, Edery P, Tabet AC, Sanlaville D
J Med Genet 2019 Aug;56(8):526-535.
PMID 30923172
 
Differential requirements for Tousled-like kinases 1 and 2 in mammalian development
Segura-Bayona S, Knobel PA, González-Burón H, Youssef SA, Peña-Blanco A, Coyaud , López-Rovira T, Rein K, Palenzuela L, Colombelli J, Forrow S, Raught B, Groth A, de Bruin A, Stracker TH
Cell Death Differ 2017 Nov;24(11):1872-1885.
PMID 28708136
 
Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases
Silljé HH, Nigg EA
Curr Biol 2001 Jul 10;11(13):1068-73.
PMID 11470414
 
Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer
Stevens KN, Wang X, Fredericksen Z, Pankratz VS, Cerhan J, Vachon CM, Olson JE, Couch FJ
Breast Cancer Res Treat 2011 Sep;129(2):617-22.
PMID 21607584
 
Abeta42 generation is toxic to endothelial cells and inhibits eNOS function through an Akt/GSK-3beta signaling-dependent mechanism
Suhara T, Magrané J, Rosen K, Christensen R, Kim HS, Zheng B, McPhie DL, Walsh K, Querfurth H
Neurobiol Aging May-Jun 2003;24(3):437-51.
PMID 12600720
 
Severe neurodevelopmental disease caused by a homozygous TLK2 variant
Töpf A, Oktay Y, Balaraju S, Yilmaz E, Sonmezler E, Yis U, Laurie S, Thompson R, Roos A, MacArthur DG, Yaramis A, Güngör S, Lochmüller H, Hiz S, Horvath R
Eur J Hum Genet 2020 Mar;28(3):383-387.
PMID 31558842
 
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder
Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, Ishizuka K, Nakamura K, Tsujii M, Yoshikawa T, Toyota T, Okamoto N, Hiraki Y, Hashimoto R, Yasuda Y, Saitoh S, Ohashi K, Sakai Y, Ohga S, Hara T, Kato M, Nakamura K, Ito A, Seiwa C, Shirahata E, Osaka H, Matsumoto A, Takeshita S, Tohyama J, Saikusa T, Matsuishi T, Nakamura T, Tsuboi T, Kato T, Suzuki T, Saitsu H, Nakashima M, Mizuguchi T, Tanaka F, Mori N, Ozaki N, Matsumoto N
Cell Rep 2018 Jan 16;22(3):734-747.
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Genetic regulatory network analysis for app based on genetical genomics approach
Wang X, Chen Y, Wang X, Lu L
Exp Aging Res Jan-Mar 2010;36(1):79-93.
PMID 20054728
 
cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal
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Gene 1997 Nov 20;202(1-2):193-201.
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Nuclear localization of protein kinase U-alpha is regulated by 14-3-3
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Citation

This paper should be referenced as such :
Cicek M, Cicek E, Erson-Bensan AE.
TLK2 (Tousled Like Kinase 2);
Atlas Genet Cytogenet Oncol Haematol. in press


External links

 

Nomenclature
HGNC (Hugo)TLK2   11842
Cards
AtlasTLK2ID43530ch17q23
Entrez_Gene (NCBI)TLK2    tousled like kinase 2
AliasesHsHPK; MRD57; PKU-ALPHA
GeneCards (Weizmann)TLK2
Ensembl hg19 (Hinxton)ENSG00000146872 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000146872 [Gene_View]  ENSG00000146872 [Sequence]  chr17:62478825-62615480 [Contig_View]  TLK2 [Vega]
ICGC DataPortalENSG00000146872
TCGA cBioPortalTLK2
AceView (NCBI)TLK2
Genatlas (Paris)TLK2
SOURCE (Princeton)TLK2
Genetics Home Reference (NIH)TLK2
Genomic and cartography
GoldenPath hg38 (UCSC)TLK2  -     chr17:62478825-62615480 +  17q23.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)TLK2  -     17q23.2   [Description]    (hg19-Feb_2009)
GoldenPathTLK2 - 17q23.2 [CytoView hg19]  TLK2 - 17q23.2 [CytoView hg38]
ImmunoBaseENSG00000146872
Genome Data Viewer NCBITLK2 [Mapview hg19]  
OMIM608439   618050   
Gene and transcription
Genbank (Entrez)AA430024 AB004884 AF162667 AI381985 AI621235
RefSeq transcript (Entrez)NM_001112707 NM_001284333 NM_001284363 NM_001330418 NM_001375269 NM_001375270 NM_001375271 NM_001375272 NM_001375273 NM_006852
Consensus coding sequences : CCDS (NCBI)TLK2
Gene ExpressionTLK2 [ NCBI-GEO ]   TLK2 [ EBI - ARRAY_EXPRESS ]   TLK2 [ SEEK ]   TLK2 [ MEM ]
Gene Expression Viewer (FireBrowse)TLK2 [ Firebrowse - Broad ]
GenevisibleExpression of TLK2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)11011
GTEX Portal (Tissue expression)TLK2
Human Protein AtlasENSG00000146872-TLK2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ86UE8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ86UE8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ86UE8
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   [ MEROPS ]
PhosPhoSitePlusQ86UE8
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom_sf    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS    TLK2   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
Conserved Domain (NCBI)TLK2
PDB (RSDB)5O0Y   
PDB Europe5O0Y   
PDB (PDBSum)5O0Y   
PDB (IMB)5O0Y   
Structural Biology KnowledgeBase5O0Y   
SCOP (Structural Classification of Proteins)5O0Y   
CATH (Classification of proteins structures)5O0Y   
SuperfamilyQ86UE8
AlphaFold pdb e-kbQ86UE8   
Human Protein Atlas [tissue]ENSG00000146872-TLK2 [tissue]
HPRD10527
Protein Interaction databases
DIP (DOE-UCLA)Q86UE8
IntAct (EBI)Q86UE8
BioGRIDTLK2
STRING (EMBL)TLK2
ZODIACTLK2
Ontologies - Pathways
QuickGOQ86UE8
Ontology : AmiGOregulation of chromatin assembly or disassembly  regulation of chromatin assembly or disassembly  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  intermediate filament  chromatin organization  protein phosphorylation  cellular response to DNA damage stimulus  cell cycle  chromosome segregation  chromosome segregation  negative regulation of autophagy  peptidyl-serine phosphorylation  peptidyl-serine phosphorylation  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  intracellular signal transduction  intracellular signal transduction  identical protein binding  perinuclear region of cytoplasm  cellular response to gamma radiation  protein serine kinase activity  protein threonine kinase activity  
Ontology : EGO-EBIregulation of chromatin assembly or disassembly  regulation of chromatin assembly or disassembly  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  intermediate filament  chromatin organization  protein phosphorylation  cellular response to DNA damage stimulus  cell cycle  chromosome segregation  chromosome segregation  negative regulation of autophagy  peptidyl-serine phosphorylation  peptidyl-serine phosphorylation  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  intracellular signal transduction  intracellular signal transduction  identical protein binding  perinuclear region of cytoplasm  cellular response to gamma radiation  protein serine kinase activity  protein threonine kinase activity  
NDEx NetworkTLK2
Atlas of Cancer Signalling NetworkTLK2
Wikipedia pathwaysTLK2
Orthology - Evolution
OrthoDB11011
GeneTree (enSembl)ENSG00000146872
Phylogenetic Trees/Animal Genes : TreeFamTLK2
Homologs : HomoloGeneTLK2
Homology/Alignments : Family Browser (UCSC)TLK2
Gene fusions - Rearrangements
Fusion : MitelmanFBXL20::TLK2 [17q12/17q23.2]  
Fusion Cancer (Beijing)TLK2 [17q23.2]  -  LOC731275 [FUSC000028]  [FUSC000028]  [FUSC000028]  [FUSC000028]
Fusion : FusionGDB2.7.11.1   
Fusion : QuiverTLK2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTLK2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TLK2
dbVarTLK2
ClinVarTLK2
MonarchTLK2
1000_GenomesTLK2 
Exome Variant ServerTLK2
GNOMAD BrowserENSG00000146872
Varsome BrowserTLK2
ACMGTLK2 variants
VarityQ86UE8
Genomic Variants (DGV)TLK2 [DGVbeta]
DECIPHERTLK2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTLK2 
Mutations
ICGC Data PortalTLK2 
TCGA Data PortalTLK2 
Broad Tumor PortalTLK2
OASIS PortalTLK2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTLK2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DTLK2
Mutations and Diseases : HGMDTLK2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaTLK2
DgiDB (Drug Gene Interaction Database)TLK2
DoCM (Curated mutations)TLK2
CIViC (Clinical Interpretations of Variants in Cancer)TLK2
NCG (London)TLK2
Cancer3DTLK2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608439    618050   
Orphanet
DisGeNETTLK2
MedgenTLK2
Genetic Testing Registry TLK2
NextProtQ86UE8 [Medical]
GENETestsTLK2
Target ValidationTLK2
Huge Navigator TLK2 [HugePedia]
ClinGenTLK2
Clinical trials, drugs, therapy
MyCancerGenomeTLK2
Protein Interactions : CTDTLK2
Pharm GKB GenePA36544
PharosQ86UE8
Clinical trialTLK2
Miscellaneous
canSAR (ICR)TLK2
HarmonizomeTLK2
DataMed IndexTLK2
Probes
Litterature
PubMed46 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXTLK2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:29:37 CEST 2021

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