Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTV150J)

• DOT Name: Lysosomal-associated transmembrane protein 4B (LAPTM4B)
• Synonyms: Lysosome-associated transmembrane protein 4-beta
• Gene Name: LAPTM4B
• UniProt ID: LAP4B_HUMAN
• Pfam ID: PF03821
• Sequence:
  MTSRTRVTWPSPPRPLPVPAAAAVAFGAKGTDPAEARSSRGIEEAGPRAHGRAGREPERR
  RSRQQRRGGLQARRSTLLKTCARARATAPGAMKMVAPWTRFYSNSCCLCCHVRTGTILLG
  VWYLIINAVVLLILLSALADPDQYNFSSSELGGDFEFMDDANMCIAIAISLLMILICAMA
  TYGAYKQRAAWIIPFFCYQIFDFALNMLVAITVLIYPNSIQEYIRQLPPNFPYRDDVMSV
  NPTCLVLIILLFISIILTFKGYLISCVWNCYRYINGRNSSDVLVYVTSNDTTVLLPPYDD
  ATVNGAAKEPPPPYVSA
• Function: Required for optimal lysosomal function. Blocks EGF-stimulated EGFR intraluminal sorting and degradation. Conversely by binding with the phosphatidylinositol 4,5-bisphosphate, regulates its PIP5K1C interaction, inhibits HGS ubiquitination and relieves LAPTM4B inhibition of EGFR degradation. Recruits SLC3A2 and SLC7A5 (the Leu transporter) to the lysosome, promoting entry of leucine and other essential amino acid (EAA) into the lysosome, stimulating activation of proton-transporting vacuolar (V)-ATPase protein pump (V-ATPase) and hence mTORC1 activation. Plays a role as negative regulator of TGFB1 production in regulatory T cells. Binds ceramide and facilitates its exit from late endosome in order to control cell death pathways.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysosomal-associated transmembrane protein 4B (LAPTM4B).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.