Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQTE0GI)

• DOT Name: Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2)
• Synonyms: RGAP-iso; Rab3 GTPase-activating protein 150 kDa subunit; Rab3-GAP p150; Rab3-GAP150; Rab3-GAP regulatory subunit
• Gene Name: RAB3GAP2
• Related Disease:
  Martsolf syndrome 1
  Multiple sclerosis
  Warburg micro syndrome
  Amyotrophic lateral sclerosis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Cervical carcinoma
  Congenital nervous system disorder
  Dyschromatosis symmetrica hereditaria
  Epithelial ovarian cancer
  Frontotemporal dementia
  Gastric cancer
  Martsolf syndrome
  Metastatic malignant neoplasm
  Neoplasm
  Ovarian cancer
  rubella
  Stomach cancer
  Warburg micro syndrome 1
  Warburg micro syndrome 2
  Advanced cancer
  Cataract
  Autosomal recessive spastic paraplegia type 69
  Obsolete cataract-intellectual disability-hypogonadism syndrome
  Parkinsonian disorder
• UniProt ID: RBGPR_HUMAN
• Pfam ID: PF14656 ; PF14655
• Sequence:
  MACSIVQFCYFQDLQAARDFLFPHLREEILSGALRRDPSKSTDWEDDGWGAWEENEPQEP
  EEEGNTCKTQKTSWLQDCVLSLSPTNDLMVIAREQKAVFLVPKWKYSDKGKEEMQFAVGW
  SGSLNVEEGECVTSALCIPLASQKRSSTGRPDWTCIVVGFTSGYVRFYTENGVLLLAQLL
  NEDPVLQLKCRTYEIPRHPGVTEQNEELSILYPAAIVTIDGFSLFQSLRACRNQVAKAAA
  SGNENIQPPPLAYKKWGLQDIDTIIDHASVGIMTLSPFDQMKTASNIGGFNAAIKNSPPA
  MSQYITVGSNPFTGFFYALEGSTQPLLSHVALAVASKLTSALFNAASGWLGWKSKHEEEA
  VQKQKPKVEPATPLAVRFGLPDSRRHGESICLSPCNTLAAVTDDFGRVILLDVARGIAIR
  MWKGYRDAQIGWIQTVEDLHERVPEKADFSPFGNSQGPSRVAQFLVIYAPRRGILEVWST
  QQGPRVGAFNVGKHCRLLYPGYKIMGLNNVTSQSWQPQTYQICLVDPVSGSVKTVNVPFH
  LALSDKKSERAKDMHLVKKLAALLKTKSPNLDLVETEIKELILDIKYPATKKQALESILA
  SERLPFSCLRNITQTLMDTLKSQELESVDEGLLQFCANKLKLLQLYESVSQLNSLDFHLD
  TPFSDNDLALLLRLDEKELLKLQALLEKYKQENTRTNVRFSDDKDGVLPVKTFLEYLEYE
  KDVLNIKKISEEEYVALGSFFFWKCLHGESSTEDMCHTLESAGLSPQLLLSLLLSVWLSK
  EKDILDKPQSICCLHTMLSLLSKMKVAIDETWDSQSVSPWWQQMRTACIQSENNGAALLS
  AHVGHSVAAQISNNMTEKKFSQTVLGADSEALTDSWEALSLDTEYWKLLLKQLEDCLILQ
  TLLHSKGNTQTSKVSSLQAEPLPRLSVKKLLEGGKGGIADSVAKWIFKQDFSPEVLKLAN
  EERDAENPDEPKEGVNRSFLEVSEMEMDLGAIPDLLHLAYEQFPCSLELDVLHAHCCWEY
  VVQWNKDPEEARFFVRSIEHLKQIFNAHVQNGIALMMWNTFLVKRFSAATYLMDKVGKSP
  KDRLCRRDVGMSDTAMTSFLGSCLDLLQILMEADVSRDEIQVPVLDTEDAWLSVEGPISI
  VELALEQKHIHYPLVEHHSILCSILYAVMRFSLKTVKPLSLFDSKGKNAFFKDLTSIQLL
  PSGEMDPNFISVRQQFLLKVVSAAVQAQHSATKVKDPTEEATPTPFGKDQDWPALAVDLA
  HHLQVSEDVVRRHYVGELYNYGVDHLGEEAILQVHDKEVLASQLLVLTGQRLAHALLHTQ
  TKEGMELLARLPPTLCTWLKAMDPQDLQNTEVPIATTAKLVNKVIELLPEKHGQYGLALH
  LIEAVEAISLPSL
• Function: Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and guanine nucleotide exchange factor (GEF) activity towards RAB18. As part of the Rab3GAP complex, acts as a GAP for Rab3 proteins by converting active RAB3-GTP to the inactive form RAB3-GDP. Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones. The Rab3GAP complex, acts as a GEF for RAB18 by promoting the conversion of inactive RAB18-GDP to the active form RAB18-GTP. Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure. Required for normal eye and brain development. May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Martsolf syndrome 1	DISVTV3N	Definitive	Autosomal recessive	[1]
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[2]
Warburg micro syndrome	DISSEZ2V	Definitive	Autosomal recessive	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[2]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Congenital nervous system disorder	DIS2BIP8	Strong	Genetic Variation	[1]
Dyschromatosis symmetrica hereditaria	DIS9HI9T	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Posttranslational Modification	[7]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Martsolf syndrome	DISF77WN	Strong	Genetic Variation	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Posttranslational Modification	[7]
rubella	DISXUI9P	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Warburg micro syndrome 1	DIS90EI2	Strong	Genetic Variation	[1]
Warburg micro syndrome 2	DISVYHF3	Strong	Autosomal recessive	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[10]
Cataract	DISUD7SL	moderate	Genetic Variation	[11]
Autosomal recessive spastic paraplegia type 69	DISCI1YC	Supportive	Autosomal recessive	[12]
Obsolete cataract-intellectual disability-hypogonadism syndrome	DISBWVTW	Supportive	Autosomal recessive	[13]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[14]

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 Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[24]

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 Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[26]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Rab3 GTPase-activating protein non-catalytic subunit (RAB3GAP2).	[27]

References

• [1] Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome?. Ophthalmic Genet. 2018 Jun;39(3):391-395. doi: 10.1080/13816810.2018.1432065. Epub 2018 Feb 8.
• [2] The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis.Acta Neurol Scand. 2007 Oct;116(4):231-4. doi: 10.1111/j.1600-0404.2007.00884.x.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1041-6. doi: 10.1073/pnas.1213021110. Epub 2012 Dec 28.
• [5] p150 overexpression in gastric carcinoma: the association with p53, apoptosis and cell proliferation.Int J Cancer. 2004 Nov 10;112(3):393-8. doi: 10.1002/ijc.20443.
• [6] The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria.Br J Dermatol. 2013 Sep;169(3):637-44. doi: 10.1111/bjd.12401.
• [7] Promoter methylation of the SALL2 tumor suppressor gene in ovarian cancers.Mol Oncol. 2013 Jun;7(3):419-27. doi: 10.1016/j.molonc.2012.11.005. Epub 2012 Dec 12.
• [8] Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology.PLoS One. 2017 Nov 16;12(11):e0188149. doi: 10.1371/journal.pone.0188149. eCollection 2017.
• [9] Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet. 2006 Apr;78(4):702-7. doi: 10.1086/502681. Epub 2006 Feb 14.
• [10] Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer.Biochem Biophys Res Commun. 2014 Jun 27;449(2):208-15. doi: 10.1016/j.bbrc.2014.05.006. Epub 2014 May 15.
• [11] Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013 Dec 5;93(6):1001-14. doi: 10.1016/j.ajhg.2013.10.011. Epub 2013 Nov 14.
• [12] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [13] Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome. Hum Mutat. 2013 May;34(5):686-96. doi: 10.1002/humu.22296.
• [14] The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian syndromes.J Neural Transm (Vienna). 2013 May;120(5):785-98. doi: 10.1007/s00702-012-0910-z. Epub 2012 Nov 11.
• [15] 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.
• [16] 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.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [27] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.