Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNUMOZ1)

• DOT Name: Serine/threonine-protein kinase TAO2 (TAOK2)
• Synonyms: EC 2.7.11.1; Kinase from chicken homolog C; hKFC-C; Prostate-derived sterile 20-like kinase 1; PSK-1; PSK1; Prostate-derived STE20-like kinase 1; Thousand and one amino acid protein kinase 2
• Gene Name: TAOK2
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Autism
  Dementia
  Gastric cancer
  Hepatocellular carcinoma
  Inborn error of immunity
  Lung adenocarcinoma
  Neoplasm
  Parkinson disease
  Pervasive developmental disorder
  Psychotic disorder
  Stomach cancer
  Anxiety
  Anxiety disorder
  Autism spectrum disorder
  Immunodeficiency
  Neurodevelopmental disorder
  Schizophrenia
• UniProt ID: TAOK2_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MPAGGRAGSLKDPDVAELFFKDDPEKLFSDLREIGHGSFGAVYFARDVRNSEVVAIKKMS
  YSGKQSNEKWQDIIKEVRFLQKLRHPNTIQYRGCYLREHTAWLVMEYCLGSASDLLEVHK
  KPLQEVEIAAVTHGALQGLAYLHSHNMIHRDVKAGNILLSEPGLVKLGDFGSASIMAPAN
  SFVGTPYWMAPEVILAMDEGQYDGKVDVWSLGITCIELAERKPPLFNMNAMSALYHIAQN
  ESPVLQSGHWSEYFRNFVDSCLQKIPQDRPTSEVLLKHRFVLRERPPTVIMDLIQRTKDA
  VRELDNLQYRKMKKILFQEAPNGPGAEAPEEEEEAEPYMHRAGTLTSLESSHSVPSMSIS
  ASSQSSSVNSLADASDNEEEEEEEEEEEEEEEGPEAREMAMMQEGEHTVTSHSSIIHRLP
  GSDNLYDDPYQPEITPSPLQPPAAPAPTSTTSSARRRAYCRNRDHFATIRTASLVSRQIQ
  EHEQDSALREQLSGYKRMRRQHQKQLLALESRLRGEREEHSARLQRELEAQRAGFGAEAE
  KLARRHQAIGEKEARAAQAEERKFQQHILGQQKKELAALLEAQKRTYKLRKEQLKEELQE
  NPSTPKREKAEWLLRQKEQLQQCQAEEEAGLLRRQRQYFELQCRQYKRKMLLARHSLDQD
  LLREDLNKKQTQKDLECALLLRQHEATRELELRQLQAVQRTRAELTRLQHQTELGNQLEY
  NKRREQELRQKHAAQVRQQPKSLKVRAGQRPPGLPLPIPGALGPPNTGTPIEQQPCSPGQ
  EAVLDQRMLGEEEEAVGERRILGKEGATLEPKQQRILGEESGAPSPSPQKHGSLVDEEVW
  GLPEEIEELRVPSLVPQERSIVGQEEAGTWSLWGKEDESLLDEEFELGWVQGPALTPVPE
  EEEEEEEGAPIGTPRDPGDGCPSPDIPPEPPPTHLRPCPASQLPGLLSHGLLAGLSFAVG
  SSSGLLPLLLLLLLPLLAAQGGGGLQAALLALEVGLVGLGASYLLLCTALHLPSSLFLLL
  AQGTALGAVLGLSWRRGLMGVPLGLGAAWLLAWPGLALPLVAMAAGGRWVRQQGPRVRRG
  ISRLWLRVLLRLSPMAFRALQGCGAVGDRGLFALYPKTNKDGFRSRLPVPGPRRRNPRTT
  QHPLALLARVWVLCKGWNWRLARASQGLASHLPPWAIHTLASWGLLRGERPTRIPRLLPR
  SQRQLGPPASRQPLPGTLAGRRSRTRQSRALPPWR
• Function: Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade. Phosphorylates itself, MBP, activated MAPK8, MAP2K3, MAP2K6 and tubulins. Activates the MAPK14/p38 MAPK signaling pathway through the specific activation and phosphorylation of the upstream MAP2K3 and MAP2K6 kinases. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of upstream MAP2K3 and MAP2K6 kinases. Isoform 1, but not isoform 2, plays a role in apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation. This function, which requires the activation of MAPK8/JNK and nuclear localization of C-terminally truncated isoform 1, may be linked to the mitochondrial CASP9-associated death pathway. Isoform 1 binds to microtubules and affects their organization and stability independently of its kinase activity. Prevents MAP3K7-mediated activation of CHUK, and thus NF-kappa-B activation, but not that of MAPK8/JNK. May play a role in the osmotic stress-MAPK8 pathway. Isoform 2, but not isoform 1, is required for PCDH8 endocytosis. Following homophilic interactions between PCDH8 extracellular domains, isoform 2 phosphorylates and activates MAPK14/p38 MAPK which in turn phosphorylates isoform 2. This process leads to PCDH8 endocytosis and CDH2 cointernalization. Both isoforms are involved in MAPK14 phosphorylation.
• Tissue Specificity: Ubiquitously expressed, with a higher level of expression in testis and brain.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Inborn error of immunity	DISNGCMN	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Parkinson disease	DISQVHKL	Strong	Biomarker	[8]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[9]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Anxiety	DISIJDBA	Limited	Biomarker	[11]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[11]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[12]
Immunodeficiency	DIS093I0	Limited	Autosomal recessive	[12]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[13]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein kinase TAO2 (TAOK2).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Serine/threonine-protein kinase TAO2 (TAOK2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase TAO2 (TAOK2).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase TAO2 (TAOK2).	[26]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[18]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[19]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[25]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein kinase TAO2 (TAOK2).	[27]

References

• [1] Arsenic trioxide-dependent activation of thousand-and-one amino acid kinase 2 and transforming growth factor-beta-activated kinase 1.Mol Pharmacol. 2010 May;77(5):828-35. doi: 10.1124/mol.109.061507. Epub 2010 Feb 16.
• [2] Napsin A, a member of the aspartic protease family, is abundantly expressed in normal lung and kidney tissue and is expressed in lung adenocarcinomas.FEBS Lett. 1999 Nov 26;462(1-2):129-34. doi: 10.1016/s0014-5793(99)01493-3.
• [3] Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.J Biol Chem. 2013 May 24;288(21):15418-29. doi: 10.1074/jbc.M112.448183. Epub 2013 Apr 12.
• [4] TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation.Neuron. 2017 Jan 18;93(2):379-393. doi: 10.1016/j.neuron.2016.12.006. Epub 2017 Jan 5.
• [5] A protein-bound polysaccharide, PSK, enhances tumor suppression induced by docetaxel in a gastric cancer xenograft model.Anticancer Res. 2009 Mar;29(3):843-50.
• [6] An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma.Oncogene. 2005 May 26;24(23):3737-47. doi: 10.1038/sj.onc.1208479.
• [7] RETRACTED: Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.J Dermatol Sci. 2017 Aug;87(2):123-129. doi: 10.1016/j.jdermsci.2017.03.018. Epub 2017 Mar 27.
• [8] Kinases in synaptic development and neurological diseases.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt B):343-352. doi: 10.1016/j.pnpbp.2017.12.006. Epub 2017 Dec 11.
• [9] Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex.Nat Neurosci. 2012 Jun 10;15(7):1022-31. doi: 10.1038/nn.3141.
• [10] Common variant at 16p11.2 conferring risk of psychosis.Mol Psychiatry. 2014 Jan;19(1):108-14. doi: 10.1038/mp.2012.157. Epub 2012 Nov 20.
• [11] Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling.Mol Psychiatry. 2019 Sep;24(9):1329-1350. doi: 10.1038/s41380-018-0025-5. Epub 2018 Feb 21.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [14] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [18] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [19] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [20] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [23] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.