Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0GV1HD)

• DOT Name: R-spondin-1 (RSPO1)
• Synonyms: Roof plate-specific spondin-1; hRspo1
• Gene Name: RSPO1
• Related Disease: Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome
• UniProt ID: RSPO1_HUMAN
• PDB ID: 4BSO; 4BSP; 4BSR; 4BSS; 4BST; 4BSU; 4CDK; 4KNG; 4KT1; 4LI2; 4QXF
• Pfam ID: PF15913
• Sequence:
  MRLGLCVVALVLSWTHLTISSRGIKGKRQRRISAEGSQACAKGCELCSEVNGCLKCSPKL
  FILLERNDIRQVGVCLPSCPPGYFDARNPDMNKCIKCKIEHCEACFSHNFCTKCKEGLYL
  HKGRCYPACPEGSSAANGTMECSSPAQCEMSEWSPWGPCSKKQQLCGFRRGSEERTRRVL
  HAPVGDHAACSDTKETRRCTVRRVPCPEGQKRRKGGQGRRENANRNLARKESKEAGAGSR
  RRKGQQQQQQQGTVGPLTSAGPA
• Function: Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. 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. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1-mediated internalization of LRP6 through an interaction with KREM1.
• Tissue Specificity: Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Regulation of FZD by ubiquitination (R-HSA-4641263)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome	DIS3VEZ5	Strong	Autosomal recessive	[1]

4 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-1 (RSPO1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of R-spondin-1 (RSPO1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of R-spondin-1 (RSPO1).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of R-spondin-1 (RSPO1).	[5]

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 R-spondin-1 (RSPO1).	[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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [6] 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.