Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOYS0SD)

• DOT Name: Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2)
• Synonyms: Ral GEF with PH domain and SH3-binding motif 2; RalA exchange factor RalGPS2
• Gene Name: RALGPS2
• Related Disease:
  Bladder cancer
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: RGPS2_HUMAN
• Pfam ID: PF00169 ; PF00617
• Sequence:
  MDLMNGQASSVNIAATASEKSSSSESLSDKGSELKKSFDAVVFDVLKVTPEEYAGQITLM
  DVPVFKAIQPDELSSCGWNKKEKYSSAPNAVAFTRRFNHVSFWVVREILHAQTLKIRAEV
  LSHYIKTAKKLYELNNLHALMAVVSGLQSAPIFRLTKTWALLSRKDKTTFEKLEYVMSKE
  DNYKRLRDYISSLKMTPCIPYLGIYLSDLTYIDSAYPSTGSILENEQRSNLMNNILRIIS
  DLQQSCEYDIPMLPHVQKYLNSVQYIEELQKFVEDDNYKLSLKIEPGTSTPRSAASREDL
  VGPEVGASPQSGRKSVAAEGALLPQTPPSPRNLIPHGHRKCHSLGYNFIHKMNTAEFKSA
  TFPNAGPRHLLDDSVMEPHAPSRGQAESSTLSSGISIGSSDGSELSEETSWPAFERNRLY
  HSLGPVTRVARNGYRSHMKASSSAESEDLAVHLYPGAVTIQGVLRRKTLLKEGKKPTVAS
  WTKYWAALCGTQLFYYAAKSLKATERKHFKSTSNKNVSVIGWMVMMADDPEHPDLFLLTD
  SEKGNSYKFQAGNRMNAMLWFKHLSAACQSNKQQVPTNLMTFE
• Function: Guanine nucleotide exchange factor for the small GTPase RALA. May be involved in cytoskeletal organization. May also be involved in the stimulation of transcription in a Ras-independent fashion.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]

5 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 Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-specific guanine nucleotide-releasing factor RalGPS2 (RALGPS2).	[17]

References

• [1] RalGPS2 is involved in tunneling nanotubes formation in 5637 bladder cancer cells.Exp Cell Res. 2018 Jan 15;362(2):349-361. doi: 10.1016/j.yexcr.2017.11.036. Epub 2017 Dec 6.
• [2] RalGPS2 Is Essential for Survival and Cell Cycle Progression of Lung Cancer Cells Independently of Its Established Substrates Ral GTPases.PLoS One. 2016 May 5;11(5):e0154840. doi: 10.1371/journal.pone.0154840. eCollection 2016.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [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] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.