Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC80IMR)

• DOT Name: Secretin receptor (SCTR)
• Synonyms: SCT-R
• Gene Name: SCTR
• Related Disease:
  Carcinoid tumor
  Primary biliary cholangitis
  Adenoma
  Advanced cancer
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cholangiocarcinoma
  Colorectal carcinoma
  Diabetes insipidus, nephrogenic, X-linked
  Gastrinoma
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Pancreatic adenocarcinoma
  Pancreatic tumour
  Prostate cancer
  Prostate carcinoma
  Neoplasm
  Pancreatic cancer
  Kaposi sarcoma
  Adenocarcinoma
  Non-insulin dependent diabetes
  Pheochromocytoma
• UniProt ID: SCTR_HUMAN
• PDB ID: 6WI9; 6WZG; 7D3S
• Pfam ID: PF00002 ; PF02793
• Sequence:
  MRPHLSPPLQQLLLPVLLACAAHSTGALPRLCDVLQVLWEEQDQCLQELSREQTGDLGTE
  QPVPGCEGMWDNISCWPSSVPGRMVEVECPRFLRMLTSRNGSLFRNCTQDGWSETFPRPN
  LACGVNVNDSSNEKRHSYLLKLKVMYTVGYSSSLVMLLVALGILCAFRRLHCTRNYIHMH
  LFVSFILRALSNFIKDAVLFSSDDVTYCDAHRAGCKLVMVLFQYCIMANYSWLLVEGLYL
  HTLLAISFFSERKYLQGFVAFGWGSPAIFVALWAIARHFLEDVGCWDINANASIWWIIRG
  PVILSILINFILFINILRILMRKLRTQETRGNEVSHYKRLARSTLLLIPLFGIHYIVFAF
  SPEDAMEIQLFFELALGSFQGLVVAVLYCFLNGEVQLEVQKKWQQWHLREFPLHPVASFS
  NSTKASHLEQSQGTCRTSII
• Function: Receptor for secretin (SCT), which is involved in different processes such as regulation of the pH of the duodenal content, food intake and water homeostasis. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Upon binding to secretin, regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas. In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation. Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation. Also able to stimulate lipolysis in white adipocytes. Also plays an important role in cellular osmoregulation by regulating renal water reabsorption. Also plays a role in the central nervous system: required for synaptic plasticity.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Glucagon-type ligand receptors (R-HSA-420092)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoid tumor	DISMNRDC	Definitive	Altered Expression	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[7]
Diabetes insipidus, nephrogenic, X-linked	DISHUTO5	Strong	Genetic Variation	[8]
Gastrinoma	DIS4IMNF	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Liver cancer	DISDE4BI	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[11]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[12]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[14]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[7]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[15]
Pheochromocytoma	DIS56IFV	Limited	Altered Expression	[1]

6 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 Secretin receptor (SCTR).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Secretin receptor (SCTR).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Secretin receptor (SCTR).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Secretin receptor (SCTR).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Secretin receptor (SCTR).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Secretin receptor (SCTR).	[21]

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 Secretin receptor (SCTR).	[22]

References

• [1] Secretin receptor promotes the proliferation of endocrine tumor cells via the PI3K/AKT pathway.Mol Endocrinol. 2012 Aug;26(8):1394-405. doi: 10.1210/me.2012-1055. Epub 2012 Jun 12.
• [2] Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.FASEB J. 2019 Sep;33(9):10269-10279. doi: 10.1096/fj.201802606R. Epub 2019 Jun 28.
• [3] Long-range epigenetic silencing at 2q14.2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease.Br J Cancer. 2009 May 19;100(10):1534-9. doi: 10.1038/sj.bjc.6605045. Epub 2009 Apr 21.
• [4] Epigenetic deregulation across chromosome 2q14.2 differentiates normal from prostate cancer and provides a regional panel of novel DNA methylation cancer biomarkers.Cancer Epidemiol Biomarkers Prev. 2011 Jan;20(1):148-59. doi: 10.1158/1055-9965.EPI-10-0719. Epub 2010 Nov 23.
• [5] Secretin receptors in the human liver: expression in biliary tract and cholangiocarcinoma, but not in hepatocytes or hepatocellular carcinoma.J Hepatol. 2006 Dec;45(6):825-35. doi: 10.1016/j.jhep.2006.06.016. Epub 2006 Jul 28.
• [6] Wild-type and splice-variant secretin receptors in lung cancer: overexpression in carcinoid tumors and peritumoral lung tissue.Mod Pathol. 2008 Apr;21(4):387-95. doi: 10.1038/modpathol.3801005. Epub 2008 Jan 25.
• [7] Detection of viral DNA sequences in sporadic colorectal cancers in relation to CpG island methylation and methylator phenotype.Tumour Biol. 2011 Aug;32(4):653-9. doi: 10.1007/s13277-011-0165-6. Epub 2011 Apr 6.
• [8] Signaling Modification by GPCR Heteromer and Its Implication on X-Linked Nephrogenic Diabetes Insipidus.PLoS One. 2016 Sep 20;11(9):e0163086. doi: 10.1371/journal.pone.0163086. eCollection 2016.
• [9] Secretin-receptor and secretin-receptor-variant expression in gastrinomas: correlation with clinical and tumoral features and secretin and calcium provocative test results.J Clin Endocrinol Metab. 2007 Nov;92(11):4394-402. doi: 10.1210/jc.2007-0986. Epub 2007 Aug 21.
• [10] Construction of a prognostic prediction system for pancreatic ductal adenocarcinoma to investigate the key prognostic genes.Mol Med Rep. 2018 Jan;17(1):216-224. doi: 10.3892/mmr.2017.7850. Epub 2017 Oct 20.
• [11] Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors.Clin Exp Metastasis. 2014 Dec;31(8):935-44. doi: 10.1007/s10585-014-9681-2. Epub 2014 Sep 21.
• [12] Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma.Cancer Res. 2002 Sep 15;62(18):5223-9.
• [13] Secretin receptors in normal and diseased human pancreas: marked reduction of receptor binding in ductal neoplasia.Am J Pathol. 2005 Oct;167(4):959-68. doi: 10.1016/S0002-9440(10)61186-8.
• [14] A novel secretin receptor splice variant potentially useful for early diagnosis of pancreatic carcinoma.Gastroenterology. 2007 Sep;133(3):853-61. doi: 10.1053/j.gastro.2007.06.013. Epub 2007 Jun 20.
• [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] 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.
• [17] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [18] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [22] 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.