Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7BL9WW)

• DOT Name: Ras-related protein Rab-4A (RAB4A)
• Synonyms: EC 3.6.5.2
• Gene Name: RAB4A
• Related Disease:
  Adult T-cell leukemia/lymphoma
  Alzheimer disease
  Autoimmune disease
  HIV infectious disease
  Large granular lymphocytic leukemia
  Lupus
  Multiple sclerosis
  Myelopathy
  Non-insulin dependent diabetes
  Sjogren syndrome
  Spastic paralysis
  Nephropathy
  Phospholipid syndrome
  Hashimoto thyroiditis
  Systemic lupus erythematosus
• UniProt ID: RAB4A_HUMAN
• PDB ID: 1YU9; 1Z0K; 2BMD; 2BME
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MSQTAMSETYDFLFKFLVIGNAGTGKSCLLHQFIEKKFKDDSNHTIGVEFGSKIINVGGK
  YVKLQIWDTAGQERFRSVTRSYYRGAAGALLVYDITSRETYNALTNWLTDARMLASQNIV
  IILCGNKKDLDADREVTFLEASRFAQENELMFLETSALTGENVEEAFVQCARKILNKIES
  GELDPERMGSGIQYGDAALRQLRSPRRAQAPNAQECGC
• Function: Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Involved in protein transport. Plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling. Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
  TBC/RABGAPs (R-HSA-8854214)
  RAB geranylgeranylation (R-HSA-8873719)
  MET receptor recycling (R-HSA-8875656)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[4]
Large granular lymphocytic leukemia	DISHOPPI	Strong	Genetic Variation	[5]
Lupus	DISOKJWA	Strong	Genetic Variation	[6]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Myelopathy	DISXV8FG	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[7]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[8]
Spastic paralysis	DISVQ6I2	Strong	Biomarker	[5]
Nephropathy	DISXWP4P	Disputed	Genetic Variation	[9]
Phospholipid syndrome	DISPI49U	Disputed	Genetic Variation	[9]
Hashimoto thyroiditis	DIS77CDF	Limited	Biomarker	[10]
Systemic lupus erythematosus	DISI1SZ7	Limited	Posttranslational Modification	[6]

4 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-related protein Rab-4A (RAB4A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ras-related protein Rab-4A (RAB4A).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras-related protein Rab-4A (RAB4A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ras-related protein Rab-4A (RAB4A).	[21]

9 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-4A (RAB4A).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-4A (RAB4A).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related protein Rab-4A (RAB4A).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-4A (RAB4A).	[15]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Ras-related protein Rab-4A (RAB4A).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ras-related protein Rab-4A (RAB4A).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Ras-related protein Rab-4A (RAB4A).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-4A (RAB4A).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-related protein Rab-4A (RAB4A).	[22]

References

• [1] Possible association between multiple sclerosis and the human T cell leukemia virus (HTLV)-related endogenous element, HRES-1.Mult Scler. 1996 Oct;2(3):133-6. doi: 10.1177/135245859600200303.
• [2] App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome.J Neurosci. 2003 Jul 30;23(17):6788-92. doi: 10.1523/JNEUROSCI.23-17-06788.2003.
• [3] Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.Immunogenetics. 1999 Sep;49(10):829-34. doi: 10.1007/s002510050561.
• [4] Regulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection.J Biol Chem. 2006 Nov 10;281(45):34574-91. doi: 10.1074/jbc.M606301200. Epub 2006 Aug 24.
• [5] Increased seroreactivity to human T cell lymphoma/leukemia virus-related endogenous sequence-1 Gag peptides in patients with human T cell lymphoma/leukemia virus myelopathy.AIDS Res Hum Retroviruses. 2015 Feb;31(2):242-9. doi: 10.1089/AID.2014.0171. Epub 2014 Nov 19.
• [6] Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting promote HRES-1/RAB4 expression and mTOR activation.JCI Insight. 2020 Jan 16;5(1):e134010. doi: 10.1172/jci.insight.134010.
• [7] Cloning of Rab GTPases expressed in human skeletal muscle: studies in insulin-resistant subjects.Horm Metab Res. 1998 Nov;30(11):656-62. doi: 10.1055/s-2007-978953.
• [8] The immune response to and expression of cross-reactive retroviral gag sequences in autoimmune disease.Br J Rheumatol. 1992 Nov;31(11):735-42. doi: 10.1093/rheumatology/31.11.735.
• [9] Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus.Arthritis Rheum. 2008 Feb;58(2):532-40. doi: 10.1002/art.23161.
• [10] Serotonin improves glucose metabolism by Serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells.Diabetol Metab Syndr. 2017 Jan 3;9:1. doi: 10.1186/s13098-016-0201-1. eCollection 2017.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Calcineurin is an important factor involved in glucose uptake in human adipocytes. Mol Cell Biochem. 2018 Aug;445(1-2):157-168. doi: 10.1007/s11010-017-3261-0. Epub 2018 Jan 27.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.