Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGQXLH5)

DOT Name	Receptor activity-modifying protein 2 (RAMP2)
Synonyms	Calcitonin-receptor-like receptor activity-modifying protein 2; CRLR activity-modifying protein 2
Gene Name	RAMP2
Related Disease	Cardiac failure ( ) Congestive heart failure ( ) Metastatic malignant neoplasm ( ) OPTN-related open angle glaucoma ( ) Adenocarcinoma ( ) Adult respiratory distress syndrome ( ) Alzheimer disease ( ) Carcinoma ( ) Central retinal vein occlusion ( ) Cerebral infarction ( ) High blood pressure ( ) Hypertension, pregnancy-induced ( ) Lung carcinoma ( ) Marinesco-Sjogren syndrome ( ) Myocardial ischemia ( ) Neoplasm ( ) Nephropathy ( ) Non-insulin dependent diabetes ( ) Obesity ( ) Pheochromocytoma ( ) Pulmonary fibrosis ( ) Pulmonary hypertension ( ) Vascular disease ( ) Bone osteosarcoma ( ) Coronary heart disease ( ) Diabetic kidney disease ( ) Fetal growth restriction ( ) Lung neoplasm ( ) Osteosarcoma ( ) Stroke ( ) Type-1 diabetes ( ) Lung cancer ( ) Malignant pleural mesothelioma ( ) Open-angle glaucoma ( )
UniProt ID	RAMP2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2XVT; 3AQE; 3AQF; 4RWF; 6UUN; 6V2E; 7TYH; 7TYX; 7TYY
Pfam ID	PF04901
Sequence	MASLRVERAGGPRLPRTRVGRPAALRLLLLLGAVLNPHEALAQPLPTTGTPGSEGGTVKN YETAVQFCWNHYKDQMDPIEKDWCDWAMISRPYSTLRDCLEHFAELFDLGFPNPLAERII FETHQIHFANCSLVQPTFSDPPEDVLLAMIIAPICLIPFLITLVVWRSKDSEAQA
Function	Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) 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

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[2]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Central retinal vein occlusion	DIS5ICKE	Strong	Biomarker	[8]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Biomarker	[10]
Hypertension, pregnancy-induced	DISHNU25	Strong	Altered Expression	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Biomarker	[7]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nephropathy	DISXWP4P	Strong	Biomarker	[14]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[15]
Obesity	DIS47Y1K	Strong	Altered Expression	[16]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[17]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[18]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[19]
Vascular disease	DISVS67S	Strong	Biomarker	[20]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[21]
Coronary heart disease	DIS5OIP1	moderate	Altered Expression	[22]
Diabetic kidney disease	DISJMWEY	moderate	Biomarker	[23]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[24]
Lung neoplasm	DISVARNB	moderate	Posttranslational Modification	[4]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[21]
Stroke	DISX6UHX	moderate	Genetic Variation	[25]
Type-1 diabetes	DIS7HLUB	moderate	Altered Expression	[23]
Lung cancer	DISCM4YA	Disputed	Biomarker	[12]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[26]
Open-angle glaucoma	DISSZEE8	Limited	Autosomal dominant	[27]
------------------------------------------------------------------------------------


⏷ Show the Full List of 34 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[31]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[34]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor activity-modifying protein 2 (RAMP2).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Receptor activity-modifying protein 2 (RAMP2).	[38]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Receptor activity-modifying protein 2 (RAMP2).	[39]
------------------------------------------------------------------------------------


⏷ Show the Full List of 11 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Receptor activity-modifying protein 2 (RAMP2).	[4]
------------------------------------------------------------------------------------

References

1	Ventricular adrenomedullin system in the transition from LVH to heart failure in rats.Hypertension. 2003 Mar;41(3):512-8. doi: 10.1161/01.HYP.0000053447.64213.C4. Epub 2003 Feb 3.
2	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.
3	Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis.Genet Med. 2019 Oct;21(10):2345-2354. doi: 10.1038/s41436-019-0507-0. Epub 2019 Apr 19.
4	Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4336-44. doi: 10.1158/1078-0432.CCR-07-0015.
5	MicroRNA and mRNA expression profiling in rat acute respiratory distress syndrome.BMC Med Genomics. 2014 Jul 28;7:46. doi: 10.1186/1755-8794-7-46.
6	Adrenomedullin Expression in Alzheimer's Brain.Curr Alzheimer Res. 2016;13(4):428-38. doi: 10.2174/1567205013666160229112725.
7	Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas.Int J Cancer. 2011 Dec 15;129(12):2855-66. doi: 10.1002/ijc.25951. Epub 2011 Apr 1.
8	Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin-Receptor Activity-Modifying Protein 2 System.Am J Pathol. 2019 Feb;189(2):449-466. doi: 10.1016/j.ajpath.2018.10.021. Epub 2019 Jan 15.
9	Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia.Peptides. 2014 Dec;62:21-31. doi: 10.1016/j.peptides.2014.08.013. Epub 2014 Sep 22.
10	Cerebellar Adrenomedullinergic System. Role in Cardiovascular Regulation.Adv Exp Med Biol. 2017;956:541-560. doi: 10.1007/5584_2016_48.
11	Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension.J Clin Endocrinol Metab. 2001 Oct;86(10):5079-82. doi: 10.1210/jcem.86.10.8099.
12	Network analysis of differentially expressed smoking-associated mRNAs, lncRNAs and miRNAs reveals key regulators in smoking-associated lung cancer.Exp Ther Med. 2018 Dec;16(6):4991-5002. doi: 10.3892/etm.2018.6891. Epub 2018 Oct 23.
13	Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats.Eur J Pharmacol. 2006 Nov 7;549(1-3):117-23. doi: 10.1016/j.ejphar.2006.07.054. Epub 2006 Aug 17.
14	Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection.PLoS One. 2014 Feb 5;9(2):e87667. doi: 10.1371/journal.pone.0087667. eCollection 2014.
15	Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
16	Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues.Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E56-62. doi: 10.1152/ajpendo.00586.2003. Epub 2004 Aug 17.
17	Expression and effect of adrenomedullin in pheochromocytoma.Ann N Y Acad Sci. 2006 Aug;1073:270-6. doi: 10.1196/annals.1353.030.
18	Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin.Am J Physiol Lung Cell Mol Physiol. 2013 Jun 1;304(11):L757-64. doi: 10.1152/ajplung.00262.2012. Epub 2013 Apr 12.
19	[Changes of intermedin/adrenomedullin 2 and its receptors in the right ventricle of rats with chronic hypoxic pulmonary hypertension].Sheng Li Xue Bao. 2007 Apr 25;59(2):210-4.
20	Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells.Endocrinology. 2017 May 1;158(5):1359-1372. doi: 10.1210/en.2016-1531.
21	Hypoxia-induced apoptosis is blocked by adrenomedullin via upregulation of Bcl-2 in human osteosarcoma cells.Oncol Rep. 2015 Aug;34(2):787-94. doi: 10.3892/or.2015.4011. Epub 2015 May 28.
22	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.
23	The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats.Kidney Int. 2004 Feb;65(2):540-50. doi: 10.1111/j.1523-1755.2004.00407.x.
24	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.
25	Genetic Variants of RAMP2 and CLR are Associated with Stroke.J Atheroscler Thromb. 2017 Dec 1;24(12):1267-1281. doi: 10.5551/jat.41517. Epub 2017 Sep 14.
26	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.
27	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.
28	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
29	Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
30	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
31	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
32	The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
33	Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4336-44. doi: 10.1158/1078-0432.CCR-07-0015.
34	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
35	Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
36	Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
37	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
38	Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
39	3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.