Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZK8GDS)

• DOT Name: R-spondin-3 (RSPO3)
• Synonyms: Protein with TSP type-1 repeat; hPWTSR; Roof plate-specific spondin-3; hRspo3; Thrombospondin type-1 domain-containing protein 2
• Gene Name: RSPO3
• UniProt ID: RSPO3_HUMAN
• Pfam ID: PF15913 ; PF19028
• Sequence:
  MHLRLISWLFIILNFMEYIGSQNASRGRRQRRMHPNVSQGCQGGCATCSDYNGCLSCKPR
  LFFALERIGMKQIGVCLSSCPSGYYGTRYPDINKCTKCKADCDTCFNKNFCTKCKSGFYL
  HLGKCLDNCPEGLEANNHTMECVSIVHCEVSEWNPWSPCTKKGKTCGFKRGTETRVREII
  QHPSAKGNLCPPTNETRKCTVQRKKCQKGERGKKGRERKRKKPNKGESKEAIPDSKSLES
  SKEIPEQRENKQQQKKRKVQDKQKSVSVSTVH
• Function: Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors, which acts as a key regulator of angiogenesis. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Acts as a key regulator of angiogenesis by controlling vascular stability and pruning: acts by activating the non-canonical Wnt signaling pathway in endothelial cells. Can also amplify Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3.
• Tissue Specificity: Ubiquitously expressed. Expressed at higher level in placenta, small intestine, fetal thymus and lymph node . Highly expressed in endothelial cells .
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  RUNX1 regulates transcription of genes involved in WNT signaling (R-HSA-8939256)
  Regulation of FZD by ubiquitination (R-HSA-4641263)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of R-spondin-3 (RSPO3).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of R-spondin-3 (RSPO3).	[2]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of R-spondin-3 (RSPO3).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of R-spondin-3 (RSPO3).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of R-spondin-3 (RSPO3).	[5]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of R-spondin-3 (RSPO3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of R-spondin-3 (RSPO3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of R-spondin-3 (RSPO3).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of R-spondin-3 (RSPO3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of R-spondin-3 (RSPO3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of R-spondin-3 (RSPO3).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] 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.
• [5] 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.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [7] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [8] 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.
• [9] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [10] 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.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.