Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX6XLLM)

• DOT Name: Receptor activity-modifying protein 3 (RAMP3)
• Synonyms: Calcitonin-receptor-like receptor activity-modifying protein 3; CRLR activity-modifying protein 3
• Gene Name: RAMP3
• Related Disease:
  Metastatic malignant neoplasm
  Adrenal gland neoplasm
  Cardiac disease
  Colorectal carcinoma
  Metabolic disorder
  Obesity
  Carcinoma
  Coronary heart disease
  Fetal growth restriction
  High blood pressure
  Neoplasm
  Adult glioblastoma
  Amyotrophic lateral sclerosis
  Carcinoma of liver and intrahepatic biliary tract
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Liver cancer
  Malignant pleural mesothelioma
• UniProt ID: RAMP3_HUMAN
• PDB ID: 6UUS; 6UVA; 7TZF; 8F0K; 8F2A; 8F2B
• Pfam ID: PF04901
• Sequence:
  METGALRRPQLLPLLLLLCGGCPRAGGCNETGMLERLPLCGKAFADMMGKVDVWKWCNLS
  EFIVYYESFTNCTEMEANVVGCYWPNPLAQGFITGIHRQFFSNCTVDRVHLEDPPDEVLI
  PLIVIPVVLTVAMAGLVVWRSKRTDTLL
• Function: Plays a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a GPER1-dependent manner. Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) and GPER1 to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.
• Tissue Specificity: Strongly expressed in lung, breast, immune system and fetal tissues.
• KEGG Pathway: Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway:
  Calcitonin-like ligand receptors (R-HSA-419812)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[1]
Adrenal gland neoplasm	DISFK7RF	Strong	Altered Expression	[2]
Cardiac disease	DISVO1I5	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Biomarker	[6]
Coronary heart disease	DIS5OIP1	moderate	Altered Expression	[7]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[8]
High blood pressure	DISY2OHH	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[11]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[12]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[13]
Liver cancer	DISDE4BI	Limited	Biomarker	[13]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[14]

3 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 Receptor activity-modifying protein 3 (RAMP3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Receptor activity-modifying protein 3 (RAMP3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Receptor activity-modifying protein 3 (RAMP3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Receptor activity-modifying protein 3 (RAMP3).	[16]

References

• [1] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts.Oncogene. 2020 Feb;39(9):1914-1930. doi: 10.1038/s41388-019-1112-z. Epub 2019 Nov 21.
• [2] Expression of adrenomedullin 2/intermedin in human adrenal tumors and attached non-neoplastic adrenal tissues.J Endocrinol. 2008 Jul;198(1):175-83. doi: 10.1677/JOE-08-0103. Epub 2008 May 6.
• [3] G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection.J Mol Endocrinol. 2013 Jul 3;51(1):191-202. doi: 10.1530/JME-13-0021. Print 2013.
• [4] Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo.Cancer Med. 2013 Apr;2(2):196-207. doi: 10.1002/cam4.51. Epub 2013 Jan 29.
• [5] RAMP3 deficiency enhances postmenopausal obesity and metabolic disorders.Peptides. 2018 Dec;110:10-18. doi: 10.1016/j.peptides.2018.10.006. Epub 2018 Oct 29.
• [6] Receptor activity modifying protein-3 mediates the protumorigenic activity of lysyl oxidase-like protein-2.FASEB J. 2011 Jan;25(1):55-65. doi: 10.1096/fj.10-162677. Epub 2010 Aug 27.
• [7] Expression of adrenomedullin in human epicardial adipose tissue: role of coronary status.Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1443-50. doi: 10.1152/ajpendo.00273.2007. Epub 2007 Sep 18.
• [8] Impaired Vasodilatory Responses of Omental Arteries to CGRP Family Peptides in Pregnancies Complicated by Fetal Growth Restriction.J Clin Endocrinol Metab. 2016 Aug;101(8):2984-93. doi: 10.1210/jc.2016-1798. Epub 2016 Jun 3.
• [9] Cerebellar Adrenomedullinergic System. Role in Cardiovascular Regulation.Adv Exp Med Biol. 2017;956:541-560. doi: 10.1007/5584_2016_48.
• [10] IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo.Nature. 2015 Jan 29;517(7536):626-30. doi: 10.1038/nature13910. Epub 2014 Nov 17.
• [11] Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo.Am J Pathol. 2002 Apr;160(4):1279-92. doi: 10.1016/S0002-9440(10)62555-2.
• [12] Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression.Sci Rep. 2019 Jun 4;9(1):8254. doi: 10.1038/s41598-019-44765-4.
• [13] RAMP3 is a prognostic indicator of liver cancer and might reduce the adverse effect of TP53 mutation on survival.Future Oncol. 2018 Oct;14(25):2615-2625. doi: 10.2217/fon-2018-0296. Epub 2018 Jun 8.
• [14] Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma.J Thorac Oncol. 2016 Jan;11(1):94-107. doi: 10.1016/j.jtho.2015.09.004.
• [15] 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.
• [16] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [17] 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.
• [18] 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.