Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRTJF29)

• DOT Name: Sphingosine 1-phosphate receptor 2 (S1PR2)
• Synonyms: S1P receptor 2; S1P2; Endothelial differentiation G-protein coupled receptor 5; Sphingosine 1-phosphate receptor Edg-5; S1P receptor Edg-5
• Gene Name: S1PR2
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 68
  Nonsyndromic genetic hearing loss
  Hearing loss, autosomal recessive
• UniProt ID: S1PR2_HUMAN
• PDB ID: 7T6B
• Pfam ID: PF00001
• Sequence:
  MGSLYSEYLNPNKVQEHYNYTKETLETQETTSRQVASAFIVILCCAIVVENLLVLIAVAR
  NSKFHSAMYLFLGNLAASDLLAGVAFVANTLLSGSVTLRLTPVQWFAREGSAFITLSASV
  FSLLAIAIERHVAIAKVKLYGSDKSCRMLLLIGASWLISLVLGGLPILGWNCLGHLEACS
  TVLPLYAKHYVLCVVTIFSIILLAIVALYVRIYCVVRSSHADMAAPQTLALLKTVTIVLG
  VFIVCWLPAFSILLLDYACPVHSCPILYKAHYFFAVSTLNSLLNPVIYTWRSRDLRREVL
  RPLQCWRPGVGVQGRRRGGTPGHHLLPLRSSSSLERGMHMPTSPTFLEGNTVV
• Function: Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effects on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis. Receptor for the chemokine-like protein FAM19A5. Mediates the inhibitory effect of FAM19A5 on vascular smooth muscle cell proliferation and migration.
• KEGG Pathway:
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Lysosphingolipid and LPA receptors (R-HSA-419408)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 68	DISYES6B	Strong	Autosomal recessive	[1]
Nonsyndromic genetic hearing loss	DISZX61P	Strong	Autosomal recessive	[2]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[1]

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 Sphingosine 1-phosphate receptor 2 (S1PR2).	[3]

7 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 Sphingosine 1-phosphate receptor 2 (S1PR2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[6]
Cantharidin	DMBP5N3	Approved	Cantharidin increases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sphingosine 1-phosphate receptor 2 (S1PR2).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine-1-Phosphate increases the uptake of Sphingosine 1-phosphate receptor 2 (S1PR2).	[11]

References

• [1] Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2. Am J Hum Genet. 2016 Feb 4;98(2):331-8. doi: 10.1016/j.ajhg.2015.12.004. Epub 2016 Jan 21.
• [2] 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.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] Hepatoxicity mechanism of cantharidin-induced liver LO2 cells by LC-MS metabolomics combined traditional approaches. Toxicol Lett. 2020 Oct 15;333:49-61. doi: 10.1016/j.toxlet.2020.07.024. Epub 2020 Jul 26.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Taurocholate induces cyclooxygenase-2 expression via the sphingosine 1-phosphate receptor 2 in a human cholangiocarcinoma cell line. J Biol Chem. 2015 Dec 25;290(52):30988-1002.