Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZC1XZ1)

• DOT Name: Linker for activation of T-cells family member 1 (LAT)
• Synonyms: 36 kDa phosphotyrosine adapter protein; pp36; p36-38
• Gene Name: LAT
• Related Disease:
  Hepatocellular carcinoma
  Rheumatoid arthritis
  Adenoma
  Adult glioblastoma
  Advanced cancer
  Allergic asthma
  Amyotrophic lateral sclerosis type 1
  Asthma
  Autoimmune disease
  Brain disease
  Cholangiocarcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epilepsy
  Esophageal squamous cell carcinoma
  Familial amyotrophic lateral sclerosis
  Gastric cancer
  Glioma
  Herpes simplex infection
  Leukemia
  Lung neoplasm
  Lymphoma
  Lysinuric protein intolerance
  Malignant glioma
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Schizophrenia
  Severe combined immunodeficiency due to LAT deficiency
  Stomach cancer
  Systemic lupus erythematosus
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Head-neck squamous cell carcinoma
  Lymphoproliferative syndrome
  Prostate carcinoma
  Squamous cell carcinoma
  Glioblastoma multiforme
  Type-1/2 diabetes
  Adenocarcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Lung adenocarcinoma
  Matthew-Wood syndrome
  Phenylketonuria
  Renal cell carcinoma
  Thyroid gland papillary carcinoma
• UniProt ID: LAT_HUMAN
• Pfam ID: PF15234
• Sequence:
  MEEAILVPCVLGLLLLPILAMLMALCVHCHRLPGSYDSTSSDSLYPRGIQFKRPHTVAPW
  PPAYPPVTSYPPLSQPDLLPIPRSPQPLGGSHRTPSSRRDSDGANSVASYENEGASGIRG
  AQAGWGVWGPSWTRLTPVSLPPEPACEDADEDEDDYHNPGYLVVLPDSTPATSTAAPSAP
  ALSTPGIRDSAFSMESIDDYVNVPESGESAEASLDGSREYVNVSQELHPGAAKTEPAALS
  SQEAEEVEEEGAPDYENLQELN
• Function: Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules.
• Tissue Specificity: Expressed in thymus, T-cells, NK cells, mast cells and, at lower levels, in spleen. Present in T-cells but not B-cells (at protein level).
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  NF-kappa B sig.ling pathway (hsa04064)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Yersinia infection (hsa05135)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  (Name not found)
  Generation of second messenger molecules (R-HSA-202433)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Allergic asthma	DISHF0H3	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[7]
Asthma	DISW9QNS	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[8]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[9]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Posttranslational Modification	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[13]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[13]
Epilepsy	DISBB28L	Strong	Altered Expression	[14]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[15]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[16]
Glioma	DIS5RPEH	Strong	Biomarker	[17]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[18]
Leukemia	DISNAKFL	Strong	Genetic Variation	[19]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[20]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[19]
Lysinuric protein intolerance	DIS5F4A8	Strong	Genetic Variation	[21]
Malignant glioma	DISFXKOV	Strong	Genetic Variation	[22]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[23]
Neoplasm	DISZKGEW	Strong	Biomarker	[24]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[25]
Prostate cancer	DISF190Y	Strong	Altered Expression	[26]
Schizophrenia	DISSRV2N	Strong	Biomarker	[27]
Severe combined immunodeficiency due to LAT deficiency	DISNCL02	Strong	Autosomal recessive	[28]
Stomach cancer	DISKIJSX	Strong	Biomarker	[16]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[29]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[30]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[31]
Lymphoproliferative syndrome	DISMVL8O	moderate	Biomarker	[19]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[26]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[32]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[4]
Type-1/2 diabetes	DISIUHAP	Disputed	Biomarker	[33]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[34]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[35]
Liver cancer	DISDE4BI	Limited	Biomarker	[35]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[36]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[37]
Phenylketonuria	DISCU56J	Limited	Genetic Variation	[38]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[39]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[40]

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 Linker for activation of T-cells family member 1 (LAT).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Linker for activation of T-cells family member 1 (LAT).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Linker for activation of T-cells family member 1 (LAT).	[42]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Linker for activation of T-cells family member 1 (LAT).	[43]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Linker for activation of T-cells family member 1 (LAT).	[44]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Linker for activation of T-cells family member 1 (LAT).	[45]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Linker for activation of T-cells family member 1 (LAT).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Linker for activation of T-cells family member 1 (LAT).	[48]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Linker for activation of T-cells family member 1 (LAT).	[49]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Linker for activation of T-cells family member 1 (LAT).	[50]

References

• [1] PET imaging of hepatocellular carcinoma with anti-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid in comparison with L-[S-methyl-(11)C]methionine.EJNMMI Res. 2019 May 22;9(1):47. doi: 10.1186/s13550-019-0519-4.
• [2] Fibroblast-like synoviocyte migration is enhanced by IL-17-mediated overexpression of L-type amino acid transporter 1 (LAT1) via the mTOR/4E-BP1 pathway.Amino Acids. 2018 Feb;50(2):331-340. doi: 10.1007/s00726-017-2520-4. Epub 2017 Dec 2.
• [3] Endoscopic Transsphenoidal Surgery of Microprolactinomas: A Reappraisal of Cure Rate Based on Radiological Criteria.Neurosurgery. 2019 Oct 1;85(4):508-515. doi: 10.1093/neuros/nyy385.
• [4] New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma.Sci Rep. 2019 Feb 27;9(1):2878. doi: 10.1038/s41598-019-40013-x.
• [5] Xenopus slc7a5 is essential for notochord function and eye development.Mech Dev. 2019 Feb;155:48-59. doi: 10.1016/j.mod.2019.01.001. Epub 2019 Jan 6.
• [6] LAT alleviates Th2/Treg imbalance in an OVA-induced allergic asthma mouse model through LAT-PLC-1 interaction.Int Immunopharmacol. 2017 Mar;44:9-15. doi: 10.1016/j.intimp.2016.12.029. Epub 2017 Jan 4.
• [7] Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
• [8] Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. J Exp Med. 2016 Jun 27;213(7):1185-99. doi: 10.1084/jem.20151110. Epub 2016 May 30.
• [9] l-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of l-histidine and l-tryptophan. Bioorg Med Chem Lett. 2019 Aug 15; 29(16):2254-2258.
• [10] High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas.Cancer Med. 2014 Oct;3(5):1246-55. doi: 10.1002/cam4.272. Epub 2014 Jun 2.
• [11] LAT, HOXD3 and NFE2L3 identified as novel DNA methylation-driven genes and prognostic markers in human clear cell renal cell carcinoma by integrative bioinformatics approaches.J Cancer. 2019 Oct 22;10(26):6726-6737. doi: 10.7150/jca.35641. eCollection 2019.
• [12] Role of Amino Acid Transporter Expression as a Prognostic Marker in Patients With Surgically Resected Colorectal Cancer.Anticancer Res. 2019 May;39(5):2535-2543. doi: 10.21873/anticanres.13375.
• [13] LAT1 is a putative therapeutic target in endometrioid endometrial carcinoma.Int J Cancer. 2016 Dec 1;139(11):2529-39. doi: 10.1002/ijc.30371. Epub 2016 Aug 16.
• [14] Increased expression of L-amino acid transporters in balloon cells of tuberous sclerosis.Childs Nerv Syst. 2011 Jan;27(1):63-70. doi: 10.1007/s00381-010-1239-2. Epub 2010 Aug 3.
• [15] Clinical Significance and Phenotype of MTA1 Expression in Esophageal Squamous Cell Carcinoma.Anticancer Res. 2017 Aug;37(8):4147-4155. doi: 10.21873/anticanres.11802.
• [16] LAT-1 functions as a promotor in gastric cancer associated with clinicopathologic features.Biomed Pharmacother. 2013 Oct;67(8):693-9. doi: 10.1016/j.biopha.2013.05.003. Epub 2013 Jun 14.
• [17] Methylmercury-l-Cysteine targeting L-type amino acid transporter conjugate cytotoxicity on C6 glioma cells.J Biol Regul Homeost Agents. 2018 Jan-Feb;32(1):147-151.
• [18] In Vivo Knockdown of the Herpes Simplex Virus 1 Latency-Associated Transcript Reduces Reactivation from Latency.J Virol. 2018 Jul 31;92(16):e00812-18. doi: 10.1128/JVI.00812-18. Print 2018 Aug 15.
• [19] miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways.PLoS One. 2015 Jun 29;10(6):e0131823. doi: 10.1371/journal.pone.0131823. eCollection 2015.
• [20] Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2.EMBO J. 2015 Jul 2;34(13):1773-85. doi: 10.15252/embj.201488166. Epub 2015 May 15.
• [21] Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease.Int J Mol Sci. 2019 Oct 24;20(21):5294. doi: 10.3390/ijms20215294.
• [22] Neurosarcoidosis Mimics High-Grade Glioma in Dynamic 18F-FET PET Due to LAT Expression.Clin Nucl Med. 2018 Nov;43(11):840-841. doi: 10.1097/RLU.0000000000002266.
• [23] (18)F-Branched-Chain Amino Acids: Structure-Activity Relationships and PET Imaging Potential.J Nucl Med. 2019 Jul;60(7):1003-1009. doi: 10.2967/jnumed.118.220483. Epub 2019 Jan 25.
• [24] Distribution of LAT1-targeting PET tracer was independent of the tumor blood flow in rat xenograft models of C6 glioma and MIA PaCa-2.Ann Nucl Med. 2019 Jun;33(6):394-403. doi: 10.1007/s12149-019-01346-9. Epub 2019 Feb 28.
• [25] Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach.Metabolites. 2019 Mar 13;9(3):50. doi: 10.3390/metabo9030050.
• [26] Up-Regulation of LAT1 during Antiandrogen Therapy Contributes to Progression in Prostate Cancer Cells.J Urol. 2016 May;195(5):1588-1597. doi: 10.1016/j.juro.2015.11.071. Epub 2015 Dec 9.
• [27] Implementing the Latvian Early Intervention Program (LAT-EIP) for Patients With Schizophrenia Spectrum First-Episode Psychosis: Study Protocol.Front Psychiatry. 2019 Nov 13;10:829. doi: 10.3389/fpsyt.2019.00829. eCollection 2019.
• [28] 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.
• [29] Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus.Clin Rheumatol. 2008 Jan;27(1):21-7. doi: 10.1007/s10067-007-0644-8. Epub 2007 May 11.
• [30] A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1.Sci Rep. 2019 Oct 10;9(1):14616. doi: 10.1038/s41598-019-51144-6.
• [31] The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity.Clin Cancer Res. 2019 May 15;25(10):3152-3163. doi: 10.1158/1078-0432.CCR-18-2951. Epub 2019 Jan 22.
• [32] L-type amino acid transporters LAT1 and LAT4 in cancer: uptake of 3-O-methyl-6-18F-fluoro-L-dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo.J Nucl Med. 2007 Dec;48(12):2063-71. doi: 10.2967/jnumed.107.043620.
• [33] CD44 variant inhibits insulin secretion in pancreatic cells by attenuating LAT1-mediated amino acid uptake.Sci Rep. 2018 Feb 12;8(1):2785. doi: 10.1038/s41598-018-20973-2.
• [34] Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma.Hum Pathol. 2019 Feb;84:142-149. doi: 10.1016/j.humpath.2018.09.020. Epub 2018 Oct 6.
• [35] Targeted Suppression and Knockout of ASCT2 or LAT1 in Epithelial and Mesenchymal Human Liver Cancer Cells Fail to Inhibit Growth.Int J Mol Sci. 2018 Jul 19;19(7):2093. doi: 10.3390/ijms19072093.
• [36] LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung.Virchows Arch. 2006 Feb;448(2):142-50. doi: 10.1007/s00428-005-0063-7. Epub 2005 Sep 21.
• [37] Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma.Cancer Chemother Pharmacol. 2018 Jan;81(1):141-153. doi: 10.1007/s00280-017-3477-4. Epub 2017 Nov 17.
• [38] LAT1 gene variants--potential factors influencing the clinical course of phenylketonuria.J Inherit Metab Dis. 2006 Oct;29(5):684. doi: 10.1007/s10545-006-0285-0. Epub 2006 Aug 5.
• [39] Characterization of the expression of LAT1 as a prognostic indicator and a therapeutic target in renal cell carcinoma.Sci Rep. 2019 Nov 20;9(1):16776. doi: 10.1038/s41598-019-53397-7.
• [40] The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model.J Exp Clin Cancer Res. 2018 Sep 21;37(1):234. doi: 10.1186/s13046-018-0907-z.
• [41] 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.
• [42] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [43] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [44] 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.
• [45] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [46] 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.
• [47] 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.
• [48] 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.
• [49] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [50] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.