Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7SAT9U)

• DOT Name: Relaxin receptor 2 (RXFP2)
• Synonyms: G-protein coupled receptor 106; G-protein coupled receptor affecting testicular descent; Leucine-rich repeat-containing G-protein coupled receptor 8; Relaxin family peptide receptor 2
• Gene Name: RXFP2
• Related Disease:
  Hypogonadism, male
  Leiomyoma
  Liver cirrhosis
  Medullary thyroid gland carcinoma
  Osteoporosis
  Prostate carcinoma
  Testicular cancer
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Uterine fibroids
  Cryptorchidism
• UniProt ID: RXFP2_HUMAN
• PDB ID: 2M96
• Pfam ID: PF00001 ; PF00057 ; PF13855
• Sequence:
  MIVFLVFKHLFSLRLITMFFLLHFIVLINVKDFALTQGSMITPSCQKGYFPCGNLTKCLP
  RAFHCDGKDDCGNGADEENCGDTSGWATIFGTVHGNANSVALTQECFLKQYPQCCDCKET
  ELECVNGDLKSVPMISNNVTLLSLKKNKIHSLPDKVFIKYTKLKKIFLQHNCIRHISRKA
  FFGLCNLQILYLNHNCITTLRPGIFKDLHQLTWLILDDNPITRISQRLFTGLNSLFFLSM
  VNNYLEALPKQMCAQMPQLNWVDLEGNRIKYLTNSTFLSCDSLTVLFLPRNQIGFVPEKT
  FSSLKNLGELDLSSNTITELSPHLFKDLKLLQKLNLSSNPLMYLHKNQFESLKQLQSLDL
  ERIEIPNINTRMFQPMKNLSHIYFKNFRYCSYAPHVRICMPLTDGISSFEDLLANNILRI
  FVWVIAFITCFGNLFVIGMRSFIKAENTTHAMSIKILCCADCLMGVYLFFVGIFDIKYRG
  QYQKYALLWMESVQCRLMGFLAMLSTEVSVLLLTYLTLEKFLVIVFPFSNIRPGKRQTSV
  ILICIWMAGFLIAVIPFWNKDYFGNFYGKNGVCFPLYYDQTEDIGSKGYSLGIFLGVNLL
  AFLIIVFSYITMFCSIQKTALQTTEVRNCFGREVAVANRFFFIVFSDAICWIPVFVVKIL
  SLFRVEIPDTMTSWIVIFFLPVNSALNPILYTLTTNFFKDKLKQLLHKHQRKSIFKIKKK
  SLSTSIVWIEDSSSLKLGVLNKITLGDSIMKPVS
• Function: Receptor for relaxin. The activity of this receptor is mediated by G proteins leading to stimulation of adenylate cyclase and an increase of cAMP. May also be a receptor for Leydig insulin-like peptide (INSL3).
• Tissue Specificity: Expressed mainly in the brain, kidney, muscle, testis, thyroid, uterus, peripheral blood cells and bone marrow.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Relaxin sig.ling pathway (hsa04926)
• Reactome Pathway:
  Relaxin receptors (R-HSA-444821)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadism, male	DISV1F5R	Strong	Biomarker	[1]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[2]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[3]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Altered Expression	[4]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Testicular cancer	DIS6HNYO	Strong	Genetic Variation	[7]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[8]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[2]
Cryptorchidism	DISYUD2P	Limited	Autosomal recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Relaxin receptor 2 (RXFP2).	[6]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the activity of Relaxin receptor 2 (RXFP2).	[13]

2 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 Relaxin receptor 2 (RXFP2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Relaxin receptor 2 (RXFP2).	[12]

References

• [1] Protective Role of Testicular Hormone INSL3 From Atrophy and Weakness in Skeletal Muscle.Front Endocrinol (Lausanne). 2018 Sep 28;9:562. doi: 10.3389/fendo.2018.00562. eCollection 2018.
• [2] Relaxin signaling in uterine fibroids.Ann N Y Acad Sci. 2009 Apr;1160:374-8. doi: 10.1111/j.1749-6632.2008.03803.x.
• [3] Relaxin receptors in hepatic stellate cells and cirrhotic liver.Biochem Pharmacol. 2007 Apr 1;73(7):1033-40. doi: 10.1016/j.bcp.2006.12.007. Epub 2006 Dec 10.
• [4] Human medullary thyroid carcinoma: a source and potential target for relaxin-like hormones.Ann N Y Acad Sci. 2005 May;1041:449-61. doi: 10.1196/annals.1282.069.
• [5] Mutations in the insulin-like factor 3 receptor are associated with osteoporosis.J Bone Miner Res. 2008 May;23(5):683-93. doi: 10.1359/jbmr.080204.
• [6] INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int J Oncol. 2005 Aug;27(2):307-15.
• [7] Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization.Mol Hum Reprod. 2006 Jun;12(6):401-6. doi: 10.1093/molehr/gal043. Epub 2006 May 10.
• [8] INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes.Int J Oncol. 2003 May;22(5):993-1001.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int J Oncol. 2005 Aug;27(2):307-15.
• [11] 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.
• [12] 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.
• [13] Human amniotic fluid-based exposure levels of phthalates and bisphenol A mixture reduce INSL3/RXFP2 signaling. Environ Int. 2020 May;138:105585. doi: 10.1016/j.envint.2020.105585. Epub 2020 Feb 29.