Details of Drug Off-Target (DOT)

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

• DOT Name: Linker for activation of T-cells family member 2 (LAT2)
• Synonyms: Linker for activation of B-cells; Membrane-associated adapter molecule; Non-T-cell activation linker; Williams-Beuren syndrome chromosomal region 15 protein; Williams-Beuren syndrome chromosomal region 5 protein
• Gene Name: LAT2
• Related Disease:
  Acute lymphocytic leukaemia
  Adenocarcinoma
  Advanced cancer
  Candidiasis
  Cataract
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Leiomyoma
  Mantle cell lymphoma
  Neoplasm
  Obesity
  Type-1/2 diabetes
  Uterine fibroids
  Acute diarrhea
  High blood pressure
  Acute myelogenous leukaemia
  Anxiety
  Anxiety disorder
  Castration-resistant prostate carcinoma
  Pancreatic cancer
• UniProt ID: NTAL_HUMAN
• PDB ID: 3MAZ
• Pfam ID: PF15703
• Sequence:
  MSSGTELLWPGAALLVLLGVAASLCVRCSRPGAKRSEKIYQQRSLREDQQSFTGSRTYSL
  VGQAWPGPLADMAPTRKDKLLQFYPSLEDPASSRYQNFSKGSRHGSEEAYIDPIAMEYYN
  WGRFSKPPEDDDANSYENVLICKQKTTETGAQQEGIGGLCRGDLSLSLALKTGPTSGLCP
  SASPEEDEESEDYQNSASIHQWRESRKVMGQLQREASPGPVGSPDEEDGEPDYVNGEVAA
  TEA
• Function: Involved in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. May also be involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and FCGR1 (high affinity immunoglobulin gamma Fc receptor I)-mediated signaling in myeloid cells. Couples activation of these receptors and their associated kinases with distal intracellular events through the recruitment of GRB2.
• Tissue Specificity: Highly expressed in spleen, peripheral blood lymphocytes, and germinal centers of lymph nodes. Also expressed in placenta, lung, pancreas and small intestine. Present in B-cells, NK cells and monocytes. Absent from T-cells (at protein level).
• KEGG Pathway: .tural killer cell mediated cytotoxicity (hsa04650)
• Reactome Pathway: Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Candidiasis	DISIRYMU	Strong	Biomarker	[4]
Cataract	DISUD7SL	Strong	Genetic Variation	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Leiomyoma	DISLDDFN	Strong	Biomarker	[8]
Mantle cell lymphoma	DISFREOV	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[11]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[8]
Acute diarrhea	DISVH6GQ	moderate	Biomarker	[12]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[14]
Anxiety	DISIJDBA	Limited	Biomarker	[15]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[16]
Pancreatic cancer	DISJC981	Limited	Biomarker	[17]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloroquine	DMSI5CB	Phase 3 Trial	Linker for activation of T-cells family member 2 (LAT2) increases the response to substance of Chloroquine.	[30]
Perifosine	DMVYRH2	Phase 1	Linker for activation of T-cells family member 2 (LAT2) decreases the response to substance of Perifosine.	[3]
Chlorpyrifos	DMKPUI6	Investigative	Linker for activation of T-cells family member 2 (LAT2) decreases the response to substance of Chlorpyrifos.	[32]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Linker for activation of T-cells family member 2 (LAT2) increases the response to substance of Rapamycin Immunosuppressant Drug.	[30]

1 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 Linker for activation of T-cells family member 2 (LAT2).	[18]

12 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 Linker for activation of T-cells family member 2 (LAT2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Linker for activation of T-cells family member 2 (LAT2).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Linker for activation of T-cells family member 2 (LAT2).	[23]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Linker for activation of T-cells family member 2 (LAT2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[25]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Linker for activation of T-cells family member 2 (LAT2).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Linker for activation of T-cells family member 2 (LAT2).	[28]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Linker for activation of T-cells family member 2 (LAT2).	[29]

References

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• [4] Development of a personalized diagnostic model for kidney stone disease tailored to acute care by integrating large clinical, demographics and laboratory data: the diagnostic acute care algorithm - kidney stones (DACA-KS).BMC Med Inform Decis Mak. 2018 Aug 17;18(1):72. doi: 10.1186/s12911-018-0652-4.
• [5] Dysfunctional LAT2 Amino Acid Transporter Is Associated With Cataract in Mouse and Humans.Front Physiol. 2019 Jun 4;10:688. doi: 10.3389/fphys.2019.00688. eCollection 2019.
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• [7] Anti-cancer effect of lactic acid bacteria expressing antioxidant enzymes or IL-10 in a colorectal cancer mouse model.Int Immunopharmacol. 2017 Jan;42:122-129. doi: 10.1016/j.intimp.2016.11.017. Epub 2016 Nov 29.
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• [10] Biased signaling at neural melanocortin receptors in regulation of energy homeostasis.Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt A):2486-2495. doi: 10.1016/j.bbadis.2017.04.010. Epub 2017 Apr 19.
• [11] The Prevalence of Osteoporosis Tested by Quantitative Computed Tomography in Patients With Different Glucose Tolerances.J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz036. doi: 10.1210/clinem/dgz036.
• [12] A prospective, interventional, randomized, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of Bacillus coagulans LBSC in the treatment of acute diarrhea with abdominal discomfort.Eur J Clin Pharmacol. 2019 Jan;75(1):21-31. doi: 10.1007/s00228-018-2562-x. Epub 2018 Sep 28.
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• [15] The involvement of the vasopressin system in stress-related disorders.CNS Neurol Disord Drug Targets. 2006 Apr;5(2):167-79. doi: 10.2174/187152706776359664.
• [16] Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters.Prostate. 2017 Feb;77(2):222-233. doi: 10.1002/pros.23263. Epub 2016 Oct 3.
• [17] Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer.J Hematol Oncol. 2019 Sep 12;12(1):97. doi: 10.1186/s13045-019-0777-7.
• [18] 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.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [23] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [24] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [25] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [26] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [29] Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci. 2014 Jan 9;15(1):905-26. doi: 10.3390/ijms15010905.
• [30] NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia. Sci Rep. 2020 Jun 25;10(1):10315. doi: 10.1038/s41598-020-66223-2.
• [31] Linker for activation of T-cell family member2 (LAT2) a lipid raft adaptor protein for AKT signaling, is an early mediator of alkylphospholipid anti-leukemic activity. Mol Cell Proteomics. 2012 Dec;11(12):1898-912. doi: 10.1074/mcp.M112.019661. Epub 2012 Sep 22.
• [32] Application of human haploid cell genetic screening model in identifying the genes required for resistance to environmental toxicants: Chlorpyrifos as a case study. J Pharmacol Toxicol Methods. 2015 Nov-Dec;76:76-82. doi: 10.1016/j.vascn.2015.08.154. Epub 2015 Aug 20.