Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEQN0MA)

• DOT Name: Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1)
• Synonyms: Ral GEF with PH domain and SH3-binding motif 1; Ral guanine nucleotide exchange factor 2; RalGEF 2; RalA exchange factor RalGPS1
• Gene Name: RALGPS1
• Related Disease:
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Parkinsonian disorder
• UniProt ID: RGPS1_HUMAN
• PDB ID: 3QXL
• Pfam ID: PF00169 ; PF00617
• Sequence:
  MYKRNGLMASVLVTSATPQGSSSSDSLEGQSCDYASKSYDAVVFDVLKVTPEEFASQITL
  MDIPVFKAIQPEELASCGWSKKEKHSLAPNVVAFTRRFNQVSFWVVREILTAQTLKIRAE
  ILSHFVKIAKKLLELNNLHSLMSVVSALQSAPIFRLTKTWALLNRKDKTTFEKLDYLMSK
  EDNYKRTREYIRSLKMVPSIPYLGIYLLDLIYIDSAYPASGSIMENEQRSNQMNNILRII
  ADLQVSCSYDHLTTLPHVQKYLKSVRYIEELQKFVEDDNYKLSLRIEPGSSSPRLVSSKE
  DLAGPSAGSGSARFSRRPTCPDTSVAGSLPTPPVPRHRKSHSLGNNMMCQLSVVESKSAT
  FPSEKARHLLDDSVLESRSPRRGLALTSSSAVTNGLSLGSSESSEFSEEMSSGLESPTGP
  CICSLGNSAAVPTMEGPLRRKTLLKEGRKPALSSWTRYWVILSGSTLLYYGAKSLRGTDR
  KHYKSTPGKKVSIVGWMVQLPDDPEHPDIFQLNNPDKGNVYKFQTGSRFHAILWHKHLDD
  ACKSNRPQVPANLMSFE
• Function: Guanine nucleotide exchange factor (GEF) for the small GTPase RALA. May be involved in cytoskeletal organization. Guanine nucleotide exchange factor for.
• Tissue Specificity: Widely expressed (at protein level). Isoform 2 is expressed in brain, colon, kidney, pancreas, prostate, skeletal muscle, small intestine, testis, thymus and uterus. Isoform 1 is expressed at high levels in heart and testis and at lower levels in brain, pancreas, skeletal muscle, small intestine and thymus.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Parkinsonian disorder	DISHGY45	Disputed	Biomarker	[3]

4 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 Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS1 (RALGPS1).	[15]

References

• [1] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [2] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [3] Molecular hypotheses to explain the shared pathways and underlying pathobiological causes in catatonia and in catatonic presentations in neuropsychiatric disorders.Med Hypotheses. 2018 Apr;113:54-64. doi: 10.1016/j.mehy.2018.02.009. Epub 2018 Feb 15.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.