Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMLXQZ0)

• DOT Name: Ras-related protein Rab-31 (RAB31)
• Synonyms: Ras-related protein Rab-22B
• Gene Name: RAB31
• Related Disease:
  Alzheimer disease
  Atopic dermatitis
  Bone osteosarcoma
  Breast neoplasm
  Esophageal squamous cell carcinoma
  Estrogen-receptor positive breast cancer
  Familial acne inversa
  Gastric cancer
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Osteoporosis
  Osteosarcoma
  Pancreatic cancer
  Stomach cancer
  Uveal Melanoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Lung adenocarcinoma
  Neoplasm
• UniProt ID: RAB31_HUMAN
• PDB ID: 2FG5
• Pfam ID: PF00071
• Sequence:
  MMAIRELKVCLLGDTGVGKSSIVCRFVQDHFDHNISPTIGASFMTKTVPCGNELHKFLIW
  DTAGQERFHSLAPMYYRGSAAAVIVYDITKQDSFYTLKKWVKELKEHGPENIVMAIAGNK
  CDLSDIREVPLKDAKEYAESIGAIVVETSAKNAINIEELFQGISRQIPPLDPHENGNNGT
  IKVEKPTMQASRRCC
• Function: The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Required for the integrity and for normal function of the Golgi apparatus and the trans-Golgi network. Plays a role in insulin-stimulated translocation of GLUT4 to the cell membrane. Plays a role in M6PR transport from the trans-Golgi network to endosomes. Plays a role in the internalization of EGFR from the cell membrane into endosomes. Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis.
• Tissue Specificity: Highest expression in placenta and brain with lower levels in heart and lung. Not detected in liver, skeletal muscle, kidney or pancreas.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[6]
Familial acne inversa	DIS7DVKA	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[11]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[12]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[13]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[13]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Ras-related protein Rab-31 (RAB31) decreases the response to substance of Arsenic.	[37]
Irinotecan	DMP6SC2	Approved	Ras-related protein Rab-31 (RAB31) decreases the response to substance of Irinotecan.	[38]

2 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-related protein Rab-31 (RAB31).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ras-related protein Rab-31 (RAB31).	[31]

28 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-related protein Rab-31 (RAB31).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related protein Rab-31 (RAB31).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras-related protein Rab-31 (RAB31).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras-related protein Rab-31 (RAB31).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-31 (RAB31).	[20]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ras-related protein Rab-31 (RAB31).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras-related protein Rab-31 (RAB31).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ras-related protein Rab-31 (RAB31).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ras-related protein Rab-31 (RAB31).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related protein Rab-31 (RAB31).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related protein Rab-31 (RAB31).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ras-related protein Rab-31 (RAB31).	[23]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Ras-related protein Rab-31 (RAB31).	[18]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Ras-related protein Rab-31 (RAB31).	[18]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Ras-related protein Rab-31 (RAB31).	[18]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Ras-related protein Rab-31 (RAB31).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rab-31 (RAB31).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras-related protein Rab-31 (RAB31).	[23]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Ras-related protein Rab-31 (RAB31).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ras-related protein Rab-31 (RAB31).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ras-related protein Rab-31 (RAB31).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related protein Rab-31 (RAB31).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ras-related protein Rab-31 (RAB31).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-31 (RAB31).	[33]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-related protein Rab-31 (RAB31).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-related protein Rab-31 (RAB31).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ras-related protein Rab-31 (RAB31).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ras-related protein Rab-31 (RAB31).	[36]

References

• [1] Application of Weighted Gene Co-Expression Network Analysis to Explore the Key Genes in Alzheimer's Disease.J Alzheimers Dis. 2018;65(4):1353-1364. doi: 10.3233/JAD-180400.
• [2] Mechanisms of IFN--induced apoptosis of human skin keratinocytes in patients with atopic dermatitis.J Allergy Clin Immunol. 2012 May;129(5):1297-306. doi: 10.1016/j.jaci.2012.02.020. Epub 2012 Mar 24.
• [3] Effect of RAB31 silencing on osteosarcoma cell proliferation and migration through the Hedgehog signaling pathway.J Bone Miner Metab. 2019 Jul;37(4):594-606. doi: 10.1007/s00774-018-0961-9. Epub 2018 Nov 23.
• [4] Cooperative interaction between the MUC1-C oncoprotein and the Rab31 GTPase in estrogen receptor-positive breast cancer cells.PLoS One. 2012;7(7):e39432. doi: 10.1371/journal.pone.0039432. Epub 2012 Jul 9.
• [5] Inhibitory effect of microRNA-455-5p on biological functions of esophageal squamous cell carcinoma Eca109 cells via Rab31.Exp Ther Med. 2018 Dec;16(6):4959-4966. doi: 10.3892/etm.2018.6820. Epub 2018 Oct 2.
• [6] Inverse association of rab31 and mucin-1 (CA15-3) antigen levels in estrogen receptor-positive (ER+) breast cancer tissues with clinicopathological parameters and patients' prognosis.Am J Cancer Res. 2017 Sep 1;7(9):1959-1970. eCollection 2017.
• [7] Nicastrin/miR-30a-3p/RAB31 Axis Regulates Keratinocyte Differentiation by Impairing EGFR Signaling in Familial Acne Inversa.J Invest Dermatol. 2019 Jan;139(1):124-134. doi: 10.1016/j.jid.2018.07.020. Epub 2018 Aug 16.
• [8] RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis.Front Oncol. 2018 Nov 26;8:554. doi: 10.3389/fonc.2018.00554. eCollection 2018.
• [9] Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway.Tumour Biol. 2015 Nov;36(11):8661-70. doi: 10.1007/s13277-015-3626-5. Epub 2015 Jun 6.
• [10] SRPX2 and RAB31 are effective prognostic biomarkers in pancreatic cancer.J Cancer. 2019 Jun 2;10(12):2670-2678. doi: 10.7150/jca.32072. eCollection 2019.
• [11] A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women.Bone Rep. 2016 Aug 27;5:233-242. doi: 10.1016/j.bonr.2016.08.005. eCollection 2016 Dec.
• [12] DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders.Sci Rep. 2017 Sep 18;7(1):11762. doi: 10.1038/s41598-017-12084-1.
• [13] Integrative functional genomics identifies regulatory genetic variant modulating RAB31 expression and altering susceptibility to breast cancer.Mol Carcinog. 2018 Dec;57(12):1845-1854. doi: 10.1002/mc.22902. Epub 2018 Sep 19.
• [14] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [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] 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.
• [17] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [18] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [22] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [23] 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.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] 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.
• [26] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] 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.
• [29] 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.
• [30] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [31] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [32] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [33] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [34] 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.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [37] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.
• [38] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.