Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSNYG0D)

• DOT Name: GTP-binding protein Rit2 (RIT2)
• Synonyms: EC 3.6.5.2; Ras-like protein expressed in neurons; Ras-like without CAAX protein 2
• Gene Name: RIT2
• Related Disease:
  B-cell neoplasm
  Adenoma
  Autism spectrum disorder
  Bipolar disorder
  Carcinoma
  Cryohydrocytosis
  Dermatomyositis
  Familial hyperinsulinism
  Hepatitis
  Hepatitis A virus infection
  Hyperinsulinemic hypoglycemia
  Hypoglycemia
  Multiple endocrine neoplasia type 1
  Narcolepsy
  Pervasive developmental disorder
  Polymyositis
  Renal carcinoma
  Renal cell carcinoma
  Rheumatoid arthritis
  Insulinoma
  Autism
  Mental disorder
  Nervous system disease
  Non-insulin dependent diabetes
  Schizophrenia
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: RIT2_HUMAN
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MEVENEASCSPGSASGGSREYKVVMLGAGGVGKSAMTMQFISHQFPDYHDPTIEDAYKTQ
  VRIDNEPAYLDILDTAGQAEFTAMREQYMRGGEGFIICYSVTDRQSFQEAAKFKELIFQV
  RHTYEIPLVLVGNKIDLEQFRQVSTEEGLSLAQEYNCGFFETSAALRFCIDDAFHGLVRE
  IRKKESMPSLMEKKLKRKDSLWKKLKGSLKKKRENMT
• Function: Binds and exchanges GTP and GDP. Binds and modulates the activation of POU4F1 as gene expression regulator.
• Tissue Specificity: Neuron-specific.
• Reactome Pathway: Signalling to p38 via RIT and RIN (R-HSA-187706)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Cryohydrocytosis	DISMQHL3	Strong	Genetic Variation	[5]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[6]
Familial hyperinsulinism	DISHQKQE	Strong	Biomarker	[7]
Hepatitis	DISXXX35	Strong	Biomarker	[8]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[8]
Hyperinsulinemic hypoglycemia	DIS3KP5D	Strong	Biomarker	[7]
Hypoglycemia	DISRCKR7	Strong	Genetic Variation	[7]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[7]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[9]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[3]
Polymyositis	DIS5DHFP	Strong	Biomarker	[6]
Renal carcinoma	DISER9XT	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[10]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[11]
Insulinoma	DISIU1JS	moderate	Biomarker	[12]
Autism	DISV4V1Z	Limited	Genetic Variation	[13]
Mental disorder	DIS3J5R8	Limited	Biomarker	[13]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[14]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[4]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[15]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[16]

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 GTP-binding protein Rit2 (RIT2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GTP-binding protein Rit2 (RIT2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP-binding protein Rit2 (RIT2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of GTP-binding protein Rit2 (RIT2).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of GTP-binding protein Rit2 (RIT2).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of GTP-binding protein Rit2 (RIT2).	[19]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of GTP-binding protein Rit2 (RIT2).	[21]

References

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• [2] Improvement of tissue preparation for laser capture microdissection: application for cell type-specific miRNA expression profiling in colorectal tumors.BMC Genomics. 2010 Mar 10;11:163. doi: 10.1186/1471-2164-11-163.
• [3] Ras-like without CAAX 2 (RIT2): a susceptibility gene for autism spectrum disorder.Metab Brain Dis. 2017 Jun;32(3):751-755. doi: 10.1007/s11011-017-9969-4. Epub 2017 Feb 11.
• [4] RIT2 Polymorphisms: Is There a Differential Association?.Mol Neurobiol. 2017 Apr;54(3):2234-2240. doi: 10.1007/s12035-016-9815-4. Epub 2016 Mar 3.
• [5] A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects.Liver Int. 2014 Jul;34(6):e89-95. doi: 10.1111/liv.12334. Epub 2013 Oct 16.
• [6] T-cell transcriptomics from peripheral blood highlights differences between polymyositis and dermatomyositis patients.Arthritis Res Ther. 2018 Aug 29;20(1):188. doi: 10.1186/s13075-018-1688-7.
• [7] O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human.Nucl Med Biol. 2017 Oct;53:21-28. doi: 10.1016/j.nucmedbio.2017.07.005. Epub 2017 Jul 12.
• [8] Clinical significance of hepatitis C virus (HCV) infection in liver transplant recipients. Role of serology and HCV RNA detection.Dig Dis Sci. 1994 May;39(5):965-9. doi: 10.1007/BF02087545.
• [9] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [10] Parathyroid hormone-related protein. Evidence for secretion of a novel mid-region fragment by three different cell types.J Biol Chem. 1992 Sep 5;267(25):18236-43.
• [11] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [12] Effect of Carbidopa on 18F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging.J Nucl Med. 2017 Jan;58(1):36-41. doi: 10.2967/jnumed.116.180588. Epub 2016 Sep 8.
• [13] RIT2: responsible and susceptible gene for neurological and psychiatric disorders.Mol Genet Genomics. 2018 Aug;293(4):785-792. doi: 10.1007/s00438-018-1451-4. Epub 2018 Jun 2.
• [14] Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells.Br J Pharmacol. 2007 Nov;152(5):676-90. doi: 10.1038/sj.bjp.0707424. Epub 2007 Aug 20.
• [15] Effect of Catha edulis (khat) on pancreatic functions in streptozotocin-induced diabetes in male Sprague-Dawley rats.Exp Anim. 2018 Nov 1;67(4):517-526. doi: 10.1538/expanim.18-0057. Epub 2018 Jul 3.
• [16] Attenuation of high glucose induced apoptotic and inflammatory signaling pathways in RIN-m5F pancreatic cell lines by Hibiscus rosa sinensis L. petals and its phytoconstituents.J Ethnopharmacol. 2018 Dec 5;227:8-17. doi: 10.1016/j.jep.2018.08.022. Epub 2018 Aug 16.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [21] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [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.