Details of Drug Off-Target (DOT)

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

• DOT Name: Triggering receptor expressed on myeloid cells 2 (TREM2)
• Synonyms: TREM-2; Triggering receptor expressed on monocytes 2
• Gene Name: TREM2
• Related Disease:
  Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2
  Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly
• UniProt ID: TREM2_HUMAN
• PDB ID: 5ELI; 5UD7; 5UD8; 6B8O; 6XDS; 6Y6C; 6YMQ; 6YYE; 6Z0G; 6Z0H; 6Z0I
• Pfam ID: PF07686
• Sequence:
  MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPC
  QRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSLHGSEADT
  LRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTSILLLLA
  CIFLIKILAASALWAAAWHGQKPGTHPPSELDCGHDPGYQLQTLPGLRDT
• Function: Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding. Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia. Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1. Acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU and enhances their uptake in microglia. Binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin. Regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade. Required for microglial phagocytosis of apoptotic neurons. Also required for microglial activation and phagocytosis of myelin debris after neuronal injury and of neuronal synapses during synapse elimination in the developing brain. Regulates microglial chemotaxis and process outgrowth, and also the microglial response to oxidative stress and lipopolysaccharide. It suppresses PI3K and NF-kappa-B signaling in response to lipopolysaccharide; thus promoting phagocytosis, suppressing pro-inflammatory cytokine and nitric oxide production, inhibiting apoptosis and increasing expression of IL10 and TGFB. During oxidative stress, it promotes anti-apoptotic NF-kappa-B signaling and ERK signaling. Plays a role in microglial MTOR activation and metabolism. Regulates age-related changes in microglial numbers. Triggers activation of the immune responses in macrophages and dendritic cells. Mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages. In dendritic cells, it mediates up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival. Involved in the positive regulation of osteoclast differentiation.
• Tissue Specificity: Expressed in the brain, specifically in microglia and in the fusiform gyrus (at protein level) . Expressed on macrophages and dendritic cells but not on granulocytes or monocytes . In the CNS strongest expression seen in the basal ganglia, corpus callosum, medulla oblongata and spinal cord .
• KEGG Pathway: Osteoclast differentiation (hsa04380)
• Reactome Pathway:
  DAP12 interactions (R-HSA-2172127)
  DAP12 signaling (R-HSA-2424491)
  Other semaphorin interactions (R-HSA-416700)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2	DISMVCY3	Strong	Autosomal recessive	[1]
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly	DIS6AABL	Supportive	Autosomal recessive	[2]

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 Triggering receptor expressed on myeloid cells 2 (TREM2).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Triggering receptor expressed on myeloid cells 2 (TREM2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Triggering receptor expressed on myeloid cells 2 (TREM2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Triggering receptor expressed on myeloid cells 2 (TREM2).	[6]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy. 2002 Jan 24 [updated 2020 Dec 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.