Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSGHPD0)

• DOT Name: TBC1 domain family member 2A (TBC1D2)
• Synonyms: Armus; Prostate antigen recognized and identified by SEREX 1; PARIS-1
• Gene Name: TBC1D2
• Related Disease:
  Multiple sclerosis
  Hereditary hyperferritinemia with congenital cataracts
  Prostate cancer
  Prostate neoplasm
  Post-traumatic stress disorder
• UniProt ID: TBD2A_HUMAN
• PDB ID: 2DHK
• Pfam ID: PF00169 ; PF00566
• Sequence:
  MEGAGENAPESSSSAPGSEESARDPQVPPPEEESGDCARSLEAVPKKLCGYLSKFGGKGP
  IRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLSSAVFDCKADAEEGIFEIKTPSRVI
  TLKAATKQAMLYWLQQLQMKRWEFHNSPPAPPATPDAALAGNGPVLHLELGQEEAELEEF
  LCPVKTPPGLVGVAAALQPFPALQNISLKHLGTEIQNTMHNIRGNKQAQGTGHEPPGEDS
  PQSGEPQREEQPLASDASTPGREPEDSPKPAPKPSLTISFAQKAKRQNNTFPFFSEGITR
  NRTAQEKVAALEQQVLMLTKELKSQKELVKILHKALEAAQQEKRASSAYLAAAEDKDRLE
  LVRHKVRQIAELGRRVEALEQERESLAHTASLREQQVQELQQHVQLLMDKNHAKQQVICK
  LSEKVTQDFTHPPDQSPLRPDAANRDFLSQQGKIEHLKDDMEAYRTQNCFLNSEIHQVTK
  IWRKVAEKEKALLTKCAYLQARNCQVESKYLAGLRRLQEALGDEASECSELLRQLVQEAL
  QWEAGEASSDSIELSPISKYDEYGFLTVPDYEVEDLKLLAKIQALESRSHHLLGLEAVDR
  PLRERWAALGDLVPSAELKQLLRAGVPREHRPRVWRWLVHLRVQHLHTPGCYQELLSRGQ
  AREHPAARQIELDLNRTFPNNKHFTCPTSSFPDKLRRVLLAFSWQNPTIGYCQGLNRLAA
  IALLVLEEEESAFWCLVAIVETIMPADYYCNTLTASQVDQRVLQDLLSEKLPRLMAHLGQ
  HHVDLSLVTFNWFLVVFADSLISNILLRVWDAFLYEGTKVVFRYALAIFKYNEKEILRLQ
  NGLEIYQYLRFFTKTISNSRKLMNIAFNDMNPFRMKQLRQLRMVHRERLEAELRELEQLK
  AEYLERRASRRRAVSEGCASEDEVEGEA
• Function: Acts as a GTPase-activating protein for RAB7A. Signal effector acting as a linker between RAC1 and RAB7A, leading to RAB7A inactivation and subsequent inhibition of cadherin degradation and reduced cell-cell adhesion.
• Tissue Specificity: Expressed in a broad range of tissues, especially in kidney, liver, lung and placenta. Also expressed in keratinocytes and epithelia-containing organs. Isoform 2 is differentially expressed in prostate normal and cancer cells (at protein level).
• Reactome Pathway: TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Hereditary hyperferritinemia with congenital cataracts	DISGL689	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[4]

14 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 TBC1 domain family member 2A (TBC1D2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of TBC1 domain family member 2A (TBC1D2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TBC1 domain family member 2A (TBC1D2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TBC1 domain family member 2A (TBC1D2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of TBC1 domain family member 2A (TBC1D2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of TBC1 domain family member 2A (TBC1D2).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of TBC1 domain family member 2A (TBC1D2).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of TBC1 domain family member 2A (TBC1D2).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of TBC1 domain family member 2A (TBC1D2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of TBC1 domain family member 2A (TBC1D2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of TBC1 domain family member 2A (TBC1D2).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TBC1 domain family member 2A (TBC1D2).	[15]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of TBC1 domain family member 2A (TBC1D2).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of TBC1 domain family member 2A (TBC1D2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TBC1 domain family member 2A (TBC1D2).	[16]

References

• [1] Replication of top markers of a genome-wide association study in multiple sclerosis in Spain.Genes Immun. 2011 Mar;12(2):110-5. doi: 10.1038/gene.2010.52. Epub 2010 Oct 14.
• [2] Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome.Blood. 1998 Jun 1;91(11):4180-7.
• [3] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [4] Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans.J Affect Disord. 2015 Sep 15;184:225-34. doi: 10.1016/j.jad.2015.03.049. Epub 2015 Jun 12.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [12] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [14] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.