Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPYIPT6)

• DOT Name: Rho guanine nucleotide exchange factor TIAM2 (TIAM2)
• Synonyms: SIF and TIAM1-like exchange factor; T-lymphoma invasion and metastasis-inducing protein 2; TIAM-2
• Gene Name: TIAM2
• Related Disease:
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Drug dependence
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Substance abuse
  Substance dependence
• UniProt ID: TIAM2_HUMAN
• Pfam ID: PF00595 ; PF00169 ; PF00621 ; PF18385
• Sequence:
  MGNSDSQYTLQGSKNHSNTITGAKQIPCSLKIRGIHAKEEKSLHGWGHGSNGAGYKSRSL
  ARSCLSHFKSNQPYASRLGGPTCKVSRGVAYSTHRTNAPGKDFQGISAAFSTENGFHSVG
  HELADNHITSRDCNGHLLNCYGRNESIASTPPGEDRKSPRVLIKTLGKLDGCLRVEFHNG
  GNPSKVPAEDCSEPVQLLRYSPTLASETSPVPEARRGSSADSLPSHRPSPTDSRLRSSKG
  SSLSSESSWYDSPWGNAGELSEAEGSFLAPGMPDPSLHASFPPGDAKKPFNQSSSLSSLR
  ELYKDANLGSLSPSGIRLSDEYMGTHASLSNRVSFASDIDVPSRVAHGDPIQYSSFTLPC
  RKPKAFVEDTAKKDSLKARMRRISDWTGSLSRKKRKLQEPRSKEGSDYFDSRSDGLNTDV
  QGSSQASAFLWSGGSTQILSQRSESTHAIGSDPLRQNIYENFMRELEMSRTNTENIETST
  ETAESSSESLSSLEQLDLLFEKEQGVVRKAGWLFFKPLVTVQKERKLELVARRKWKQYWV
  TLKGCTLLFYETYGKNSMDQSSAPRCALFAEDSIVQSVPEHPKKENVFCLSNSFGDVYLF
  QATSQTDLENWVTAVHSACASLFAKKHGKEDTLRLLKNQTKNLLQKIDMDSKMKKMAELQ
  LSVVSDPKNRKAIENQIQQWEQNLEKFHMDLFRMRCYLASLQGGELPNPKSLLAAASRPS
  KLALGRLGILSVSSFHALVCSRDDSALRKRTLSLTQRGRNKKGIFSSLKGLDTLARKGKE
  KRPSITQVDELLHIYGSTVDGVPRDNAWEIQTYVHFQDNHGVTVGIKPEHRVEDILTLAC
  KMRQLEPSHYGLQLRKLVDDNVEYCIPAPYEYMQQQVYDEIEVFPLNVYDVQLTKTGSVC
  DFGFAVTAQVDERQHLSRIFISDVLPDGLAYGEGLRKGNEIMTLNGEAVSDLDLKQMEAL
  FSEKSVGLTLIARPPDTKATLCTSWSDSDLFSRDQKSLLPPPNQSQLLEEFLDNFKKNTA
  NDFSNVPDITTGLKRSQTDGTLDQVSHREKMEQTFRSAEQITALCRSFNDSQANGMEGPR
  ENQDPPPRSLARHLSDADRLRKVIQELVDTEKSYVKDLSCLFELYLEPLQNETFLTQDEM
  ESLFGSLPEMLEFQKVFLETLEDGISASSDFNTLETPSQFRKLLFSLGGSFLYYADHFKL
  YSGFCANHIKVQKVLERAKTDKAFKAFLDARNPTKQHSSTLESYLIKPVQRVLKYPLLLK
  ELVSLTDQESEEHYHLTEALKAMEKVASHINEMQKIYEDYGTVFDQLVAEQSGTEKEVTE
  LSMGELLMHSTVSWLNPFLSLGKARKDLELTVFVFKRAVILVYKENCKLKKKLPSNSRPA
  HNSTDLDPFKFRWLIPISALQVRLGNPAGTENNSIWELIHTKSEIEGRPETIFQLCCSDS
  ESKTNIVKVIRSILRENFRRHIKCELPLEKTCKDRLVPLKNRVPVSAKLASSRSLKVLKN
  SSSNEWTGETGKGTLLDSDEGSLSSGTQSSGCPTAEGRQDSKSTSPGKYPHPGLADFADN
  LIKESDILSDEDDDHRQTVKQGSPTKDIEIQFQRLRISEDPDVHPEAEQQPGPESGEGQK
  GGEQPKLVRGHFCPIKRKANSTKRDRGTLLKAQIRHQSLDSQSENATIDLNSVLEREFSV
  QSLTSVVSEECFYETESHGKS
• Function: Modulates the activity of RHO-like proteins and connects extracellular signals to cytoskeletal activities. Acts as a GDP-dissociation stimulator protein that stimulates the GDP-GTP exchange activity of RHO-like GTPases and activates them. Mediates extracellular laminin signals to activate Rac1, contributing to neurite growth. Involved in lamellipodial formation and advancement of the growth cone of embryonic hippocampal neurons. Promotes migration of neurons in the cerebral cortex. When overexpressed, induces membrane ruffling accompanied by the accumulation of actin filaments along the altered plasma membrane. Activates specifically RAC1, but not CDC42 and RHOA.
• Tissue Specificity: Expressed in the occipital, frontal and temporal lobes, cerebellum, putamen and testis.
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  G alpha (12/13) signalling events (R-HSA-416482)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Substance abuse	DIS327VW	Strong	Biomarker	[3]
Substance dependence	DISDRAAR	Strong	Biomarker	[3]

3 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 Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[13]

8 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 Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho guanine nucleotide exchange factor TIAM2 (TIAM2).	[15]

References

• [1] The Fibroblast TIAM2 Promotes Lung Cancer Cell Invasion and Metastasis.J Cancer. 2019 Apr 21;10(8):1879-1889. doi: 10.7150/jca.30477. eCollection 2019.
• [2] Sp1-mediated ectopic expression of T-cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma.Cancer Med. 2016 Mar;5(3):465-77. doi: 10.1002/cam4.611. Epub 2016 Jan 14.
• [3] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [4] TIAM2 enhances non-small cell lung cancer cell invasion and motility.Asian Pac J Cancer Prev. 2013;14(11):6305-9. doi: 10.7314/apjcp.2013.14.11.6305.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens. Arch Toxicol. 2019 Nov;93(11):3335-3344. doi: 10.1007/s00204-019-02569-5. Epub 2019 Sep 25.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.