Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW4HC8M)

• DOT Name: Tyrosine-protein kinase ITK/TSK (ITK)
• Synonyms: EC 2.7.10.2; Interleukin-2-inducible T-cell kinase; IL-2-inducible T-cell kinase; Kinase EMT; T-cell-specific kinase; Tyrosine-protein kinase Lyk
• Gene Name: ITK
• Related Disease: Lymphoproliferative syndrome 1
• UniProt ID: ITK_HUMAN
• PDB ID: 1SM2 ; 1SNU ; 1SNX ; 2E6I ; 2LMJ ; 2YUQ ; 3MIY ; 3MJ1 ; 3MJ2 ; 3QGW ; 3QGY ; 3T9T ; 3V5J ; 3V5L ; 3V8T ; 3V8W ; 4HCT ; 4HCU ; 4HCV ; 4KIO ; 4L7S ; 4M0Y ; 4M0Z ; 4M12 ; 4M13 ; 4M14 ; 4M15 ; 4MF0 ; 4MF1 ; 4PP9 ; 4PPA ; 4PPB ; 4PPC ; 4PQN ; 4QD6 ; 4RFM
• EC Number: 2.7.10.2
• Pfam ID: PF00779 ; PF00169 ; PF07714 ; PF00017 ; PF00018
• Sequence:
  MNNFILLEEQLIKKSQQKRRTSPSNFKVRFFVLTKASLAYFEDRHGKKRTLKGSIELSRI
  KCVEIVKSDISIPCHYKYPFQVVHDNYLLYVFAPDRESRQRWVLALKEETRNNNSLVPKY
  HPNFWMDGKWRCCSQLEKLATGCAQYDPTKNASKKPLPPTPEDNRRPLWEPEETVVIALY
  DYQTNDPQELALRRNEEYCLLDSSEIHWWRVQDRNGHEGYVPSSYLVEKSPNNLETYEWY
  NKSISRDKAEKLLLDTGKEGAFMVRDSRTAGTYTVSVFTKAVVSENNPCIKHYHIKETND
  NPKRYYVAEKYVFDSIPLLINYHQHNGGGLVTRLRYPVCFGRQKAPVTAGLRYGKWVIDP
  SELTFVQEIGSGQFGLVHLGYWLNKDKVAIKTIREGAMSEEDFIEEAEVMMKLSHPKLVQ
  LYGVCLEQAPICLVFEFMEHGCLSDYLRTQRGLFAAETLLGMCLDVCEGMAYLEEACVIH
  RDLAARNCLVGENQVIKVSDFGMTRFVLDDQYTSSTGTKFPVKWASPEVFSFSRYSSKSD
  VWSFGVLMWEVFSEGKIPYENRSNSEVVEDISTGFRLYKPRLASTHVYQIMNHCWKERPE
  DRPAFSRLLRQLAEIAESGL
• Function: Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Required for TCR-mediated calcium response in gamma-delta T-cells, may also be involved in the modulation of the transcriptomic signature in the Vgamma2-positive subset of immature gamma-delta T-cells. Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3.
• Tissue Specificity: T-cell lines and natural killer cell lines.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  T cell receptor sig.ling pathway (hsa04660)
  Leukocyte transendothelial migration (hsa04670)
• Reactome Pathway:
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Generation of second messenger molecules (R-HSA-202433)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphoproliferative syndrome 1	DISY2LSN	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Tyrosine-protein kinase ITK/TSK (ITK).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[8]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Tyrosine-protein kinase ITK/TSK (ITK).	[6]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [4] 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.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [7] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.
• [8] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.