Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGMMX6W)

• DOT Name: Ras GTPase-activating protein nGAP (RASAL2)
• Synonyms: RAS protein activator-like 2
• Gene Name: RASAL2
• Related Disease:
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Neoplasm
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bipolar disorder
  Clear cell renal carcinoma
  Hepatocellular carcinoma
  Renal cell carcinoma
  Triple negative breast cancer
  Pancreatic ductal carcinoma
  Advanced cancer
  Pancreatic cancer
  Patent ductus arteriosus
• UniProt ID: NGAP_HUMAN
• Pfam ID: PF00168 ; PF12004 ; PF00616
• Sequence:
  MQTPEVPAERSPRRRSISGTSTSEKPNSMDTANTSPFKVPGFFSKRLKGSIKRTKSQSKL
  DRNTSFRLPSLRSTDDRSRGLPKLKESRSHESLLSPCSTVECLDLGRGEPVSVKPLHSSI
  LGQDFCFEVTYLSGSKCFSCNSASERDKWMENLRRTVQPNKDNCRRAENVLRLWIIEAKD
  LAPKKKYFCELCLDDTLFARTTSKTKADNIFWGEHFEFFSLPPLHSITVHIYKDVEKKKK
  KDKNNYVGLVNIPTASVTGRQFVEKWYPVSTPTPNKGKTGGPSIRIKSRFQTITILPMEQ
  YKEFAEFVTSNYTMLCSVLEPVISVRNKEELACALVHILQSTGRAKDFLTDLVMSEVDRC
  GEHDVLIFRENTIATKSIEEYLKLVGQQYLHDALGEFIKALYESDENCEVDPSKCSSSEL
  IDHQSNLKMCCELAFCKIINSYCVFPRELKEVFASWKQQCLNRGKQDISERLISASLFLR
  FLCPAIMSPSLFNLMQEYPDDRTSRTLTLIAKVIQNLANFAKFGNKEEYMAFMNDFLEHE
  WGGMKRFLLEISNPDTISNTPGFDGYIDLGRELSVLHSLLWEVVSQLDKGENSFLQATVA
  KLGPLPRVLADITKSLTNPTPIQQQLRRFTEHNSSPNVSGSLSSGLQKIFEDPTDSDLHK
  LKSPSQDNTDSYFRGKTLLLVQQASSQSMTYSEKDERESSLPNGRSVSLMDLQDTHAAQV
  EHASVMLDVPIRLTGSQLSITQVASIKQLRETQSTPQSAPQVRRPLHPALNQPGGLQPLS
  FQNPVYHLNNPIPAMPKASIDSSLENLSTASSRSQSNSEDFKLSGPSNSSMEDFTKRSTQ
  SEDFSRRHTVPDRHIPLALPRQNSTGQAQIRKVDQGGLGARAKAPPSLPHSASLRSTGSM
  SVVSAALVAEPVQNGSRSRQQSSSSRESPVPKVRAIQRQQTQQVQSPVDSATMSPVERTA
  AWVLNNGQYEEDVEETEQNLDEAKHAEKYEQEITKLKERLRVSSRRLEEYERRLLVQEQQ
  MQKLLLEYKARLEDSEERLRRQQEEKDSQMKSIISRLMAVEEELKKDHAEMQAVIDAKQK
  IIDAQEKRIVSLDSANTRLMSALTQVKERYSMQVRNGISPTNPTKLSITENGEFKNSSC
• Function: Inhibitory regulator of the Ras-cyclic AMP pathway.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway:
  RND3 GTPase cycle (R-HSA-9696264)
  RND1 GTPase cycle (R-HSA-9696273)
  Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[8]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[9]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[11]
Pancreatic ductal carcinoma	DIS26F9Q	Disputed	Biomarker	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Pancreatic cancer	DISJC981	Limited	Biomarker	[12]
Patent ductus arteriosus	DIS9P8YS	Limited	Biomarker	[12]

13 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 Ras GTPase-activating protein nGAP (RASAL2).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras GTPase-activating protein nGAP (RASAL2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[22]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Ras GTPase-activating protein nGAP (RASAL2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras GTPase-activating protein nGAP (RASAL2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ras GTPase-activating protein nGAP (RASAL2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ras GTPase-activating protein nGAP (RASAL2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ras GTPase-activating protein nGAP (RASAL2).	[23]

References

• [1] RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis.Oncotarget. 2014 Aug 30;5(16):6734-45. doi: 10.18632/oncotarget.2244.
• [2] RASAL2 inhibits tumor angiogenesis via p-AKT/ETS1 signaling in bladder cancer.Cell Signal. 2018 Aug;48:38-44. doi: 10.1016/j.cellsig.2018.04.006. Epub 2018 Apr 24.
• [3] Rasal2 suppresses breast cancer cell proliferation modulated by secretory autophagy.Mol Cell Biochem. 2019 Dec;462(1-2):115-122. doi: 10.1007/s11010-019-03615-7. Epub 2019 Aug 31.
• [4] RASAL2 activates RAC1 to promote triple-negative breast cancer progression.J Clin Invest. 2014 Dec;124(12):5291-304. doi: 10.1172/JCI76711. Epub 2014 Nov 10.
• [5] RASAL2 Plays Inconsistent Roles in Different Cancers.Front Oncol. 2019 Nov 13;9:1235. doi: 10.3389/fonc.2019.01235. eCollection 2019.
• [6] Phosphorylated Rasal2 facilitates breast cancer progression.EBioMedicine. 2019 Dec;50:144-155. doi: 10.1016/j.ebiom.2019.11.019. Epub 2019 Nov 21.
• [7] Reduced expression of RAS protein activator like-1 in gastric cancer.Int J Cancer. 2011 Mar 15;128(6):1293-302. doi: 10.1002/ijc.25459.
• [8] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.Mol Psychiatry. 2018 Mar;23(3):639-647. doi: 10.1038/mp.2016.259. Epub 2017 Jan 24.
• [9] The expression and function of RASAL2 in renal cell carcinoma angiogenesis.Cell Death Dis. 2018 Aug 29;9(9):881. doi: 10.1038/s41419-018-0898-x.
• [10] Upregulation of RASAL2 promotes proliferation and metastasis, and is targeted by miR-203 in hepatocellular carcinoma.Mol Med Rep. 2017 May;15(5):2720-2726. doi: 10.3892/mmr.2017.6320. Epub 2017 Mar 14.
• [11] miR-136 suppresses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer.Oncol Rep. 2016 Jul;36(1):65-71. doi: 10.3892/or.2016.4767. Epub 2016 Apr 25.
• [12] Sulforaphane Induces miR135b-5p and Its Target Gene, RASAL2, thereby Inhibiting the Progression of Pancreatic Cancer.Mol Ther Oncolytics. 2019 Apr 6;14:74-81. doi: 10.1016/j.omto.2019.03.011. eCollection 2019 Sep 27.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.