Details of Drug Off-Target (DOT)

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

• DOT Name: Megakaryocyte-associated tyrosine-protein kinase (MATK)
• Synonyms: EC 2.7.10.2; CSK homologous kinase; CHK; Hematopoietic consensus tyrosine-lacking kinase; Protein kinase HYL; Tyrosine-protein kinase CTK
• Gene Name: MATK
• Related Disease:
  Neuroblastoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adenovirus infection
  Adult glioblastoma
  Astrocytoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colonic neoplasm
  Dengue
  Glioblastoma multiforme
  Hepatitis C virus infection
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Pancreatic cancer
  T-cell acute lymphoblastic leukaemia
  T-cell lymphoma
  Visceral leishmaniasis
  Advanced cancer
  Hemolytic-uremic syndrome
• UniProt ID: MATK_HUMAN
• PDB ID: 1JWO; 1X6G; 3US4
• EC Number: 2.7.10.2
• Pfam ID: PF07714 ; PF00017 ; PF00018
• Sequence:
  MAGRGSLVSWRAFHGCDSAEELPRVSPRFLRAWHPPPVSARMPTRRWAPGTQCITKCEHT
  RPKPGELAFRKGDVVTILEACENKSWYRVKHHTSGQEGLLAAGALREREALSADPKLSLM
  PWFHGKISGQEAVQQLQPPEDGLFLVRESARHPGDYVLCVSFGRDVIHYRVLHRDGHLTI
  DEAVFFCNLMDMVEHYSKDKGAICTKLVRPKRKHGTKSAEEELARAGWLLNLQHLTLGAQ
  IGEGEFGAVLQGEYLGQKVAVKNIKCDVTAQAFLDETAVMTKMQHENLVRLLGVILHQGL
  YIVMEHVSKGNLVNFLRTRGRALVNTAQLLQFSLHVAEGMEYLESKKLVHRDLAARNILV
  SEDLVAKVSDFGLAKAERKGLDSSRLPVKWTAPEALKHGKFTSKSDVWSFGVLLWEVFSY
  GRAPYPKMSLKEVSEAVEKGYRMEPPEGCPGPVHVLMSSCWEAEPARRPPFRKLAEKLAR
  ELRSAGAPASVSGQDADGSTSPRSQEP
• Function: Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation.
• Tissue Specificity: Expressed in various myeloid cell lines, detected in brain and lung.
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway: Downregulation of ERBB2 signaling (R-HSA-8863795)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Adenovirus infection	DISUYSBZ	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Dengue	DISKH221	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[9]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[10]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[11]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[12]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[13]
Visceral leishmaniasis	DISTKEYK	Strong	Altered Expression	[14]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[15]
Hemolytic-uremic syndrome	DISSCBGW	Limited	Genetic Variation	[16]

2 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 Megakaryocyte-associated tyrosine-protein kinase (MATK).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[21]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[22]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Megakaryocyte-associated tyrosine-protein kinase (MATK).	[26]

References

• [1] Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma.Int J Oncol. 2008 Mar;32(3):619-23.
• [2] Transcriptional memory of cells of origin overrides -catenin requirement of MLL cancer stem cells.EMBO J. 2017 Nov 2;36(21):3139-3155. doi: 10.15252/embj.201797994. Epub 2017 Oct 4.
• [3] Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors.Cancer. 2004 Sep 1;101(5):1018-27. doi: 10.1002/cncr.20442.
• [4] Csk homologous kinase (CHK) and ErbB-2 interactions are directly coupled with CHK negative growth regulatory function in breast cancer.J Biol Chem. 2002 Sep 27;277(39):36465-70. doi: 10.1074/jbc.M206018200. Epub 2002 Jul 16.
• [5] Decreased CHK protein levels are associated with Src activation in colon cancer cells.Oncogene. 2008 Mar 27;27(14):2027-34. doi: 10.1038/sj.onc.1210838. Epub 2007 Oct 15.
• [6] Host plant forensics and olfactory-based detection in Afro-tropical mosquito disease vectors.PLoS Negl Trop Dis. 2018 Feb 20;12(2):e0006185. doi: 10.1371/journal.pntd.0006185. eCollection 2018 Feb.
• [7] Evaluation of Three Rapid Screening Tests for Detection of Hepatitis C Antibodies on Mass Scale.Crit Rev Eukaryot Gene Expr. 2019;29(1):25-28. doi: 10.1615/CritRevEukaryotGeneExpr.2018025062.
• [8] Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.Cancer Cell. 2008 May;13(5):432-40. doi: 10.1016/j.ccr.2008.03.005.
• [9] Genetic polymorphism of xenobiotic metabolizing enzymes among Chinese lung cancer patients.Int J Cancer. 1999 May 5;81(3):325-9. doi: 10.1002/(sici)1097-0215(19990505)81:3<325::aid-ijc2>3.0.co;2-s.
• [10] Beneficial Effects of the Calcium Channel Blocker CTK 01512-2 in a Mouse Model of Multiple Sclerosis.Mol Neurobiol. 2018 Dec;55(12):9307-9327. doi: 10.1007/s12035-018-1049-1. Epub 2018 Apr 17.
• [11] CHK negatively regulates Lyn kinase and suppresses pancreatic cancer cell invasion.Int J Oncol. 2006 Dec;29(6):1453-8.
• [12] Enhancement of Quercetin-Induced Apoptosis by Cotreatment with Autophagy Inhibitor Is Associated with Augmentation of BAK-Dependent Mitochondrial Pathway in Jurkat T Cells.Oxid Med Cell Longev. 2019 Nov 15;2019:7989276. doi: 10.1155/2019/7989276. eCollection 2019.
• [13] Occult recurrence of monomorphic epitheliotropic intestinal T-cell lymphoma and the role of MATK gene expression in diagnosis.Hematol Oncol. 2017 Dec;35(4):852-855. doi: 10.1002/hon.2288. Epub 2016 Mar 7.
• [14] TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis.PLoS Pathog. 2017 Jul 3;13(7):e1006465. doi: 10.1371/journal.ppat.1006465. eCollection 2017 Jul.
• [15] CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition.Cancer Res. 2018 Feb 1;78(3):781-797. doi: 10.1158/0008-5472.CAN-17-2802. Epub 2017 Dec 11.
• [16] Wild ungulates as disseminators of Shiga toxin-producing Escherichia coli in urban areas.PLoS One. 2013 Dec 11;8(12):e81512. doi: 10.1371/journal.pone.0081512. eCollection 2013.
• [17] 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.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [21] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] Progesterone increases csk homologous kinase in HMC-1560 human mast cells and reduces cell proliferation. J Cell Biochem. 2007 Dec 1;102(5):1271-80. doi: 10.1002/jcb.21357.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] 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.
• [26] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.