Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3HHXU0)

DOT Name	R-spondin-2 (RSPO2)
Synonyms	Roof plate-specific spondin-2; hRspo2
Gene Name	RSPO2
Related Disease	Parkinson disease ( ) Adenocarcinoma ( ) Advanced cancer ( ) Aerodigestive tract cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Colitis ( ) Colonic neoplasm ( ) Colorectal carcinoma ( ) Crohn disease ( ) Fibrosarcoma ( ) Functioning pituitary gland adenoma ( ) Gastric cancer ( ) Hepatocellular carcinoma ( ) Inflammatory bowel disease ( ) Lung adenocarcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Malignant peripheral nerve sheath tumor ( ) Neoplasm ( ) Osteoarthritis ( ) Pancreatic cancer ( ) Sigmoid colon cancer ( ) Stomach cancer ( ) Tetraamelia syndrome 2 ( ) Thyroid cancer ( ) Thyroid gland carcinoma ( ) Thyroid gland papillary carcinoma ( ) Thyroid tumor ( ) Female hypogonadism ( ) Metastatic malignant neoplasm ( ) Tetraamelia-multiple malformations syndrome ( ) Alopecia ( ) Androgenetic alopecia ( ) Baldness, male pattern ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Colon cancer ( ) Colon carcinoma ( ) Glioblastoma multiforme ( ) Liver cancer ( ) Rheumatoid arthritis ( )
UniProt ID	RSPO2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF15913
Sequence	MQFRLFSFALIILNCMDYSHCQGNRWRRSKRASYVSNPICKGCLSCSKDNGCSRCQQKLF FFLRREGMRQYGECLHSCPSGYYGHRAPDMNRCARCRIENCDSCFSKDFCTKCKVGFYLH RGRCFDECPDGFAPLEETMECVEGCEVGHWSEWGTCSRNNRTCGFKWGLETRTRQIVKKP VKDTILCPTIAESRRCKMTMRHCPGGKRTPKAKEKRNKKKKRKLIERAQEQHSVFLATDR ANQ
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. During embryonic development, plays a crucial role in limb specification, amplifying the Wnt signaling pathway independently of LGR4-6 receptors, possibly by acting as a direct antagonistic ligand to RNF43 and ZNRF3, hence governing the number of limbs an embryo should form.
KEGG Pathway	Wnt sig.ling pathway (hsa04310 )
Reactome Pathway	Regulation of FZD by ubiquitination (R-HSA-4641263 )

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Aerodigestive tract cancer	DIS3AOQ7	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[3]
Functioning pituitary gland adenoma	DISS1Q4V	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Biomarker	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[16]
Sigmoid colon cancer	DISVZMTQ	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Tetraamelia syndrome 2	DIS84O7L	Strong	Autosomal recessive	[17]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[18]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[18]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[18]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[18]
Female hypogonadism	DISWASB4	moderate	Altered Expression	[19]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[14]
Tetraamelia-multiple malformations syndrome	DISTTV0J	Supportive	Autosomal recessive	[20]
Alopecia	DIS37HU4	Limited	Genetic Variation	[21]
Androgenetic alopecia	DISSJR1P	Limited	Genetic Variation	[22]
Baldness, male pattern	DIS9C9RO	Limited	Genetic Variation	[22]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[23]
Colon cancer	DISVC52G	Limited	Biomarker	[23]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[23]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[24]
Liver cancer	DISDE4BI	Limited	Biomarker	[23]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[25]
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⏷ Show the Full List of 41 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of R-spondin-2 (RSPO2).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of R-spondin-2 (RSPO2).	[33]
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9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of R-spondin-2 (RSPO2).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of R-spondin-2 (RSPO2).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of R-spondin-2 (RSPO2).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of R-spondin-2 (RSPO2).	[29]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of R-spondin-2 (RSPO2).	[30]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of R-spondin-2 (RSPO2).	[31]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of R-spondin-2 (RSPO2).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of R-spondin-2 (RSPO2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of R-spondin-2 (RSPO2).	[34]
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⏷ Show the Full List of 9 Drug(s)

References

1	The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation.Stem Cell Reports. 2018 Sep 11;11(3):651-664. doi: 10.1016/j.stemcr.2018.07.014. Epub 2018 Aug 23.
2	Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma.Virchows Arch. 2019 Nov;475(5):659-663. doi: 10.1007/s00428-019-02604-x. Epub 2019 Jun 17.
3	Cmannosylation of Rspondin2 activates Wnt/catenin signaling and migration activity in human tumor cells.Int J Oncol. 2019 Jun;54(6):2127-2138. doi: 10.3892/ijo.2019.4767. Epub 2019 Apr 1.
4	Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor.Sci Rep. 2018 Sep 24;8(1):14244. doi: 10.1038/s41598-018-32652-3.
5	Clinical value of R-spondins in triple-negative and metaplastic breast cancers.Br J Cancer. 2017 Jun 6;116(12):1595-1603. doi: 10.1038/bjc.2017.131. Epub 2017 May 4.
6	R-Spondins Are Expressed by the Intestinal Stroma and are Differentially Regulated during Citrobacter rodentium- and DSS-Induced Colitis in Mice.PLoS One. 2016 Apr 5;11(4):e0152859. doi: 10.1371/journal.pone.0152859. eCollection 2016.
7	Recurrent R-spondin fusions in colon cancer.Nature. 2012 Aug 30;488(7413):660-4. doi: 10.1038/nature11282.
8	EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma.Histopathology. 2019 Aug;75(2):266-273. doi: 10.1111/his.13867. Epub 2019 Jun 20.
9	T5224, RSPO2 and AZD5363 are novel drugs against functional pituitary adenoma.Aging (Albany NY). 2019 Oct 26;11(20):9043-9059. doi: 10.18632/aging.102372. Epub 2019 Oct 26.
10	RSPO2 enhances cell invasion and migration via the WNT/-catenin pathway in human gastric cancer.J Cell Biochem. 2019 Apr;120(4):5813-5824. doi: 10.1002/jcb.27867. Epub 2018 Oct 26.
11	MicroRNA-493 suppresses hepatocellular carcinoma tumorigenesis through down-regulation of anthrax toxin receptor 1 (ANTXR1) and R-Spondin 2 (RSPO2).Biomed Pharmacother. 2017 Sep;93:334-343. doi: 10.1016/j.biopha.2017.06.047. Epub 2017 Jun 24.
12	R-spondin family members as novel biomarkers and prognostic factors in lung cancer.Oncol Lett. 2019 Oct;18(4):4008-4015. doi: 10.3892/ol.2019.10778. Epub 2019 Aug 22.
13	Canonical Wnt/-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance.Cancer Discov. 2013 Jun;3(6):674-89. doi: 10.1158/2159-8290.CD-13-0081. Epub 2013 Mar 27.
14	RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway.Cancer Lett. 2017 Aug 28;402:153-165. doi: 10.1016/j.canlet.2017.05.024. Epub 2017 Jun 6.
15	Mianserin suppresses R-spondin 2-induced activation of Wnt/-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis.Sci Rep. 2019 Feb 26;9(1):2808. doi: 10.1038/s41598-019-39393-x.
16	RSPO2 Enhances Canonical Wnt Signaling to Confer Stemness-Associated Traits to Susceptible Pancreatic Cancer Cells.Cancer Res. 2015 May 1;75(9):1883-96. doi: 10.1158/0008-5472.CAN-14-1327. Epub 2015 Mar 13.
17	[Anthroposophic medicine]. Tidsskr Nor Laegeforen. 1986 Feb 20;106(5):426-31.
18	Upregulation of RSPO2-GPR48/LGR4 signaling in papillary thyroid carcinoma contributes to tumor progression.Oncotarget. 2017 Nov 25;8(70):114980-114994. doi: 10.18632/oncotarget.22692. eCollection 2017 Dec 29.
19	R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency.J Ovarian Res. 2017 Jul 25;10(1):51. doi: 10.1186/s13048-017-0345-0.
20	RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature. 2018 May;557(7706):564-569. doi: 10.1038/s41586-018-0118-y. Epub 2018 May 16.
21	Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
22	GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk.Nat Commun. 2017 Nov 17;8(1):1584. doi: 10.1038/s41467-017-01490-8.
23	R-spondin 2 promotes proliferation and migration via the Wnt/-catenin pathway in human hepatocellular carcinoma.Oncol Lett. 2017 Aug;14(2):1757-1765. doi: 10.3892/ol.2017.6339. Epub 2017 Jun 7.
24	R-spodin2 enhances canonical Wnt signaling to maintain the stemness of glioblastoma cells.Cancer Cell Int. 2018 Oct 11;18:156. doi: 10.1186/s12935-018-0655-3. eCollection 2018.
25	Wnt signaling genes of murine chromosome 15 are involved in sex-affected pathways of inflammatory arthritis.Arthritis Rheum. 2012 Apr;64(4):1057-68. doi: 10.1002/art.33414. Epub 2011 Oct 17.
26	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.
27	Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
28	Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
29	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.
30	Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
31	Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
32	Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
33	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.
34	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.