Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMRMJ8N)

• DOT Name: Proteinase-activated receptor 2 (F2RL1)
• Synonyms: PAR-2; Coagulation factor II receptor-like 1; G-protein coupled receptor 11; Thrombin receptor-like 1
• Gene Name: F2RL1
• UniProt ID: PAR2_HUMAN
• PDB ID: 5NDD; 5NDZ; 5NJ6
• Pfam ID: PF00001
• Sequence:
  MRSPSAAWLLGAAILLAASLSCSGTIQGTNRSSKGRSLIGKVDGTSHVTGKGVTVETVFS
  VDEFSASVLTGKLTTVFLPIVYTIVFVVGLPSNGMALWVFLFRTKKKHPAVIYMANLALA
  DLLSVIWFPLKIAYHIHGNNWIYGEALCNVLIGFFYGNMYCSILFMTCLSVQRYWVIVNP
  MGHSRKKANIAIGISLAIWLLILLVTIPLYVVKQTIFIPALNITTCHDVLPEQLLVGDMF
  NYFLSLAIGVFLFPAFLTASAYVLMIRMLRSSAMDENSEKKRKRAIKLIVTVLAMYLICF
  TPSNLLLVVHYFLIKSQGQSHVYALYIVALCLSTLNSCIDPFVYYFVSHDFRDHAKNALL
  CRSVRTVKQMQVSLTSKKHSRKSSSYSSSSTTVKTSY
• Function: Receptor for trypsin and trypsin-like enzymes coupled to G proteins. Its function is mediated through the activation of several signaling pathways including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB and Rho. Can also be transactivated by cleaved F2R/PAR1. Involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, and acts as a sensor for proteolytic enzymes generated during infection. Generally is promoting inflammation. Can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. Has a protective role in establishing the endothelial barrier; the activity involves coagulation factor X. Regulates endothelial cell barrier integrity during neutrophil extravasation, probably following proteolytic cleavage by PRTN3. Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. Involved in the regulation of vascular tone; activation results in hypotension presumably mediated by vasodilation. Associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12 and GNA13, but probably not with G(o)-alpha, G(i) subunit alpha-1 and G(i) subunit alpha-2. However, according to PubMed:21627585 can signal through G(i) subunit alpha. Believed to be a class B receptor which internalizes as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptor, for extended periods of time. Mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to GNAQ and GNA11; the function involves dissociation of RIPK1 and TRADD from TNFR1. Mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536'; the function involves IKBKB and is predominantly independent of G proteins. Involved in cellular migration. Involved in cytoskeletal rearrangement and chemotaxis through beta-arrestin-promoted scaffolds; the function is independent of GNAQ and GNA11 and involves promotion of cofilin dephosphorylation and actin filament severing. Induces redistribution of COPS5 from the plasma membrane to the cytosol and activation of the JNK cascade is mediated by COPS5. Involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function such as pro-inflammatory cytokine secretion, superoxide production and degranulation. During inflammation promotes dendritic cell maturation, trafficking to the lymph nodes and subsequent T-cell activation. Involved in antimicrobial response of innate immune cells; activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. Acts synergistically with interferon-gamma in enhancing antiviral responses. Implicated in a number of acute and chronic inflammatory diseases such as of the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, and in autoimmune disorders.
• Tissue Specificity: Widely expressed in tissues with especially high levels in pancreas, liver, kidney, small intestine, and colon . Moderate expression is detected in many organs, but none in brain or skeletal muscle . Expressed in endothelial cells .
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  African trypanosomiasis (hsa05143)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	Proteinase-activated receptor 2 (F2RL1) increases the transport of Chloride.	[27]

28 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 Proteinase-activated receptor 2 (F2RL1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proteinase-activated receptor 2 (F2RL1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Proteinase-activated receptor 2 (F2RL1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Proteinase-activated receptor 2 (F2RL1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proteinase-activated receptor 2 (F2RL1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Proteinase-activated receptor 2 (F2RL1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Proteinase-activated receptor 2 (F2RL1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Proteinase-activated receptor 2 (F2RL1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Proteinase-activated receptor 2 (F2RL1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Proteinase-activated receptor 2 (F2RL1).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Proteinase-activated receptor 2 (F2RL1).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Proteinase-activated receptor 2 (F2RL1).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Proteinase-activated receptor 2 (F2RL1).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Proteinase-activated receptor 2 (F2RL1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Proteinase-activated receptor 2 (F2RL1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Proteinase-activated receptor 2 (F2RL1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Proteinase-activated receptor 2 (F2RL1).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Proteinase-activated receptor 2 (F2RL1).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Proteinase-activated receptor 2 (F2RL1).	[25]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Proteinase-activated receptor 2 (F2RL1).	[26]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [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.
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• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [7] 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.
• [8] 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.
• [9] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [10] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [25] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [26] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [27] Activation of ion secretion via proteinase-activated receptor-2 in human colon. Am J Physiol Gastrointest Liver Physiol. 2002 Feb;282(2):G200-10. doi: 10.1152/ajpgi.00137.2001.