Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3UPQAA)

• DOT Name: Rab-3A-interacting protein (RAB3IP)
• Synonyms: Rab3A-interacting protein; Rabin-3; Rabin8; SSX2-interacting protein
• Gene Name: RAB3IP
• Related Disease:
  Parkinson disease
  Gastric cancer
  Stomach cancer
• UniProt ID: RAB3I_HUMAN
• PDB ID: 4LHX; 4LHY; 4LHZ; 4UJ3; 4UJ4; 4UJ5; 6F6P
• Pfam ID: PF06428
• Sequence:
  MGLKKMKGLSYDEAFAMANDPLEGFHEVNLASPTSPDLLGVYESGTQEQTTSPSVIYRPH
  PSALSSVPIQANALDVSELPTQPVYSSPRRLNCAEISSISFHVTDPAPCSTSGVTAGLTK
  LTTRKDNYNAEREFLQGATITEACDGSDDIFGLSTDSLSRLRSPSVLEVREKGYERLKEE
  LAKAQRELKLKDEECERLSKVRDQLGQELEELTASLFEEAHKMVREANIKQATAEKQLKE
  AQGKIDVLQAEVAALKTLVLSSSPTSPTQEPLPGGKTPFKKGHTRNKSTSSAMSGSHQDL
  SVIQPIVKDCKEADLSLYNEFRLWKDEPTMDRTCPFLDKIYQEDIFPCLTFSKSELASAV
  LEAVENNTLSIEPVGLQPIRFVKASAVECGGPKKCALTGQSKSCKHRIKLGDSSNYYYIS
  PFCRYRITSVCNFFTYIRYIQQGLVKQQDVDQMFWEVMQLRKEMSLAKLGYFKEEL
• Function: Guanine nucleotide exchange factor (GEF) which may activate RAB8A and RAB8B. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. Mediates the release of GDP from RAB8A and RAB8B but not from RAB3A or RAB5. Modulates actin organization and promotes polarized transport of RAB8A-specific vesicles to the cell surface. Together with RAB11A, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Part of the ciliary targeting complex containing Rab11, ASAP1, RAB3IP and RAB11FIP3 and ARF4 that promotes RAB3IP preciliary vesicle trafficking to mother centriole and ciliogenesis initiation.
• Tissue Specificity: Expressed in brain, kidney, heart, pancreas and placenta. Not detected in skeletal muscle or liver.
• Reactome Pathway:
  VxPx cargo-targeting to cilium (R-HSA-5620916)
  BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[2]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Rab-3A-interacting protein (RAB3IP).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rab-3A-interacting protein (RAB3IP).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rab-3A-interacting protein (RAB3IP).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Rab-3A-interacting protein (RAB3IP).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Rab-3A-interacting protein (RAB3IP).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rab-3A-interacting protein (RAB3IP).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Rab-3A-interacting protein (RAB3IP).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Rab-3A-interacting protein (RAB3IP).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rab-3A-interacting protein (RAB3IP).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rab-3A-interacting protein (RAB3IP).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rab-3A-interacting protein (RAB3IP).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Rab-3A-interacting protein (RAB3IP).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rab-3A-interacting protein (RAB3IP).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Rab-3A-interacting protein (RAB3IP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rab-3A-interacting protein (RAB3IP).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Rab-3A-interacting protein (RAB3IP).	[14]

References

• [1] LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson's disease through RAB3IP.Biol Chem. 2019 Aug 27;400(9):1217-1228. doi: 10.1515/hsz-2018-0431.
• [2] Promotion of Cell Proliferation through Inhibition of Cell Autophagy Signalling Pathway by Rab3IP is Restrained by MicroRNA-532-3p in Gastric Cancer.J Cancer. 2018 Oct 22;9(23):4363-4373. doi: 10.7150/jca.27533. eCollection 2018.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.