Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUVGFT9)

• DOT Name: Rho guanine nucleotide exchange factor 5 (ARHGEF5)
• Synonyms: Ephexin-3; Guanine nucleotide regulatory protein TIM; Oncogene TIM; Transforming immortalized mammary oncogene; p60 TIM
• Gene Name: ARHGEF5
• Related Disease:
  Allergic rhinitis
  Ebola virus infection
  Allergic asthma
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Atopic dermatitis
  Atrial fibrillation
  Autism spectrum disorder
  Autoimmune disease
  B-cell lymphoma
  Bipolar disorder
  Brain neoplasm
  Breast neoplasm
  Cardiac failure
  Cardiovascular disease
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Head and neck cancer
  Head and neck carcinoma
  Hepatitis A virus infection
  Hepatitis C virus infection
  Immune system disorder
  Lung adenocarcinoma
  Lung carcinoma
  Major depressive disorder
  Non-small-cell lung cancer
  Ovarian cancer
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Rheumatoid arthritis
  Systemic sclerosis
  Tuberculosis
  Vascular purpura
  Lung cancer
  Adenocarcinoma
  Arthritis
  Dengue
  Melanoma
  Squamous cell carcinoma
• UniProt ID: ARHG5_HUMAN
• Pfam ID: PF15441 ; PF00169 ; PF00621 ; PF00018
• Sequence:
  MEAEEAQRGASPPISAIEEFSIIPEAPMRSSQVSALGLEAQEDEDPSYKWREEHRLSATQ
  QSELRDVCDYAIETMPSFPKEGSADVEPNQESLVAEACDTPEHWEAVPQSLAGRQARTLA
  PPELWACPIQSEHLDMAPFSSDLGSEEEEVEFWPGLTSLTLGSGQAEEEEETSSDNSGQT
  RYYSPCEEHPAETNQNEGSESGTIRQGEELPPEELQESQGLLHPQEVQVLEEQGQQEAGF
  RGEGTLREDVCADGLLGEEQMIEQVNDEKGEQKQKQEQVQDVMLGRQGERMGLTGEPEGL
  NDGEWEQEDMERKAQGQGGPEQGEERKRELQVPEENRADSQDEKSQTFLGKSEEVTGKQE
  DHGIKEKGVPVSGQEAKEPESWDGGRLGAVGRARSREEENEHHGPSMPALIAPEDSPHCD
  LFPGASYLMTQIPGTQTESRAEELSPAALSPSLEPIRCSHQPISLLGSFLTEESPDKEID
  QNSQQEESRLRKGTVSSQGTEVVFASASVTPPRTPDSAPPSPAEAYPITPASVSARPPVA
  FPRRETSCAARAPETASAPLSMDDPSPCGTSEMCPAALYGFPSTGTSPPRPPANSTGTVQ
  HLRSDSFPGSHRTEQTPDLVGMLLSYSHSELPQRPPKPAIYSSVTPRRDRRSGRDYSTVS
  ASPTALSTLKQDSQESISNLERPSSPPSIQPWVSPHNPAFATESPAYGSSPSFVSMEDVR
  IHEPLPPPPPQRRDTHPSVVETDGHARVVVPTLKQHSHPPPLALGSGLHAPHKGPLPQAS
  DPAVARQHRPLPSTPDSSHHAQATPRWRYNKPLPPTPDLPQPHLPPISAPGSSRIYRPLP
  PLPIIDPPTEPPPLPPKSRGRSRSTRGGHMNSGGHAKTRPACQDWTVPLPASAGRTSWPP
  ATARSTESFTSTSRSKSEVSPGMAFSNMTNFLCPSSPTTPWTPELQGPTSKDEAGVSEHP
  EAPAREPLRRTTPQQGASGPGRSPVGQARQPEKPSHLHLEKASSWPHRRDSGRPPGDSSG
  QAVAPSEGANKHKGWSRQGLRRPSILPEGSSDSRGPAVEKHPGPSDTVVFREKKPKEVMG
  GFSRRCSKLINSSQLLYQEYSDVVLNKEIQSQQRLESLSETPGPSSPRQPRKALVSSESY
  LQRLSMASSGSLWQEIPVVRNSTVLLSMTHEDQKLQEVKFELIVSEASYLRSLNIAVDHF
  QLSTSLRATLSNQEHQWLFSRLQDVRDVSATFLSDLEENFENNIFSFQVCDVVLNHAPDF
  RRVYLPYVTNQTYQERTFQSLMNSNSNFREVLEKLESDPVCQRLSLKSFLILPFQRITRL
  KLLLQNILKRTQPGSSEEAEATKAHHALEQLIRDCNNNVQSMRRTEELIYLSQKIEFECK
  IFPLISQSRWLVKSGELTALEFSASPGLRRKLNTRPVHLHLFNDCLLLSRPREGSRFLVF
  DHAPFSSIRGEKCEMKLHGPHKNLFRLFLRQNTQGAQAEFLFRTETQSEKLRWISALAMP
  REELDLLECYNSPQVQCLRAYKPRENDELALEKADVVMVTQQSSDGWLEGVRLSDGERGW
  FPVQQVEFISNPEVRAQNLKEAHRVKTAKLQLVEQQA
• Function: Guanine nucleotide exchange factor which activates Rho GTPases. Strongly activates RHOA. Also strongly activates RHOB, weakly activates RHOC and RHOG and shows no effect on RHOD, RHOV, RHOQ or RAC1. Involved in regulation of cell shape and actin cytoskeletal organization. Plays a role in actin organization by generating a loss of actin stress fibers and the formation of membrane ruffles and filopodia. Required for SRC-induced podosome formation. Involved in positive regulation of immature dendritic cell migration.
• Tissue Specificity: Ubiquitously expressed with highest levels in placenta. High levels are also found in colon, kidney, trachea, prostate, liver, pancreas, pituitary gland, thyroid gland and mammary gland. In fetal tissues, expressed at high levels in kidney, lung and liver . Expressed at low levels in lung and heart .
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOG GTPase cycle (R-HSA-9013408)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Definitive	Biomarker	[1]
Ebola virus infection	DISJAVM1	Definitive	Biomarker	[2]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[6]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[8]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[9]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[10]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[11]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[12]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[13]
Cardiac failure	DISDC067	Strong	Biomarker	[14]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[15]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[16]
Colon cancer	DISVC52G	Strong	Biomarker	[17]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[17]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[14]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[18]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[19]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[19]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[20]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[21]
Immune system disorder	DISAEGPH	Strong	Genetic Variation	[18]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[22]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[23]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[24]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[23]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[16]
Pneumonia	DIS8EF3M	Strong	Biomarker	[25]
Pneumonitis	DIS88E0K	Strong	Biomarker	[25]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[27]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[16]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[28]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[29]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[30]
Vascular purpura	DIS6ZZMF	Strong	Altered Expression	[31]
Lung cancer	DISCM4YA	moderate	Altered Expression	[23]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[32]
Arthritis	DIST1YEL	Limited	Biomarker	[33]
Dengue	DISKH221	Limited	Biomarker	[34]
Melanoma	DIS1RRCY	Limited	Biomarker	[35]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[36]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 5 (ARHGEF5).	[37]

References

• [1] The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity.Allergy Asthma Proc. 2013 Jan-Feb;34(1):e21-6. doi: 10.2500/aap.2013.34.3646.
• [2] Biomechanical characterization of TIM protein-mediated Ebola virus-host cell adhesion.Sci Rep. 2019 Jan 22;9(1):267. doi: 10.1038/s41598-018-36449-2.
• [3] Association analysis of -416G>C polymorphism of T-cell immunoglobulin and mucin domain-1 gene with asthma in Iran.Int J Immunogenet. 2015 Aug;42(4):265-9. doi: 10.1111/iji.12209. Epub 2015 Jun 3.
• [4] G proteins, p60TRP, and neurodegenerative diseases.Mol Neurobiol. 2013 Jun;47(3):1103-11. doi: 10.1007/s12035-013-8410-1. Epub 2013 Jan 24.
• [5] Anti-TIM-1 Monoclonal Antibody (RMT1-10) Attenuates Atherosclerosis By Expanding IgM-producing B1a Cells.J Am Heart Assoc. 2018 Jun 23;7(13):e008447. doi: 10.1161/JAHA.117.008447.
• [6] Genetic association studies between the T cell immunoglobulin mucin (TIM) gene locus and childhood atopic dermatitis.Int Arch Allergy Immunol. 2006;141(4):331-6. doi: 10.1159/000095459. Epub 2006 Aug 29.
• [7] Discovery of new biomarkers for atrial fibrillation using a custom-made proteomics chip.Heart. 2017 Mar;103(5):377-382. doi: 10.1136/heartjnl-2016-309764. Epub 2016 Sep 8.
• [8] Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children.Mol Immunol. 2019 Feb;106:77-86. doi: 10.1016/j.molimm.2018.12.020. Epub 2018 Dec 24.
• [9] Association between T-Cell Immunoglobulin and Mucin Domain 3 (TIM-3) Genetic Polymorphisms and Susceptibility to Autoimmune Diseases.Immunol Invest. 2019 Aug;48(6):563-576. doi: 10.1080/08820139.2019.1599009. Epub 2019 May 2.
• [10] Expression of Tim-1 in primary CNS lymphoma.Cancer Med. 2016 Nov;5(11):3235-3245. doi: 10.1002/cam4.930. Epub 2016 Oct 5.
• [11] Polymorphism of circadian clock genes and prophylactic lithium response.Bipolar Disord. 2014 Mar;16(2):151-8. doi: 10.1111/bdi.12136.
• [12] GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.J Cell Physiol. 2015 Jul;230(7):1661-76. doi: 10.1002/jcp.24919.
• [13] Expression and molecular characterization of alternative transcripts of the ARHGEF5/TIM oncogene specific for human breast cancer.Hum Mol Genet. 2004 Feb 1;13(3):323-34. doi: 10.1093/hmg/ddh024. Epub 2003 Dec 8.
• [14] Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: results from the TIM-HF2 trial.Eur J Heart Fail. 2019 Nov;21(11):1445-1458. doi: 10.1002/ejhf.1530. Epub 2019 Jun 17.
• [15] Proteomic Profiling for Cardiovascular Biomarker Discovery in Orthostatic Hypotension.Hypertension. 2018 Mar;71(3):465-472. doi: 10.1161/HYPERTENSIONAHA.117.10365. Epub 2018 Jan 2.
• [16] Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1.Mol Cancer Ther. 2016 Dec;15(12):2946-2954. doi: 10.1158/1535-7163.MCT-16-0393. Epub 2016 Sep 26.
• [17] Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression.Biochem Biophys Res Commun. 2016 Apr 29;473(2):377-81. doi: 10.1016/j.bbrc.2016.02.085. Epub 2016 Feb 26.
• [18] Associations Between TIM1 Polymorphisms and Dilated Cardiomyopathy in a Han Chinese Population.Int Heart J. 2016 Dec 2;57(6):742-746. doi: 10.1536/ihj.16-119. Epub 2016 Nov 4.
• [19] Increased PD-1(+) and TIM-3(+) TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.Cancer Immunol Res. 2017 May;5(5):408-416. doi: 10.1158/2326-6066.CIR-16-0333. Epub 2017 Apr 13.
• [20] Exosomes Exploit the Virus Entry Machinery and Pathway To Transmit Alpha Interferon-Induced Antiviral Activity.J Virol. 2018 Nov 27;92(24):e01578-18. doi: 10.1128/JVI.01578-18. Print 2018 Dec 15.
• [21] TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.J Virol. 2017 Jan 3;91(2):e01583-16. doi: 10.1128/JVI.01583-16. Print 2017 Jan 15.
• [22] Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation.Mol Cancer Ther. 2015 Jul;14(7):1671-9. doi: 10.1158/1535-7163.MCT-14-0724. Epub 2015 Mar 16.
• [23] Prognostic value of TIM-1 expression in human non-small-cell lung cancer.J Transl Med. 2019 May 28;17(1):178. doi: 10.1186/s12967-019-1931-2.
• [24] Altered Transcranial Magnetic Stimulation-Electroencephalographic Markers of Inhibition and Excitation in the Dorsolateral Prefrontal Cortex in Major Depressive Disorder.Biol Psychiatry. 2019 Mar 15;85(6):477-486. doi: 10.1016/j.biopsych.2018.09.032. Epub 2018 Oct 18.
• [25] Tim1 and Tim3 are not essential for experimental allergic asthma.Clin Exp Allergy. 2011 Jul;41(7):1012-21. doi: 10.1111/j.1365-2222.2011.03728.x. Epub 2011 Apr 7.
• [26] The role of katanin p60 in breast cancer bone metastasis.Oncol Lett. 2018 Apr;15(4):4963-4969. doi: 10.3892/ol.2018.7942. Epub 2018 Feb 2.
• [27] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [28] TIM family gene polymorphism and susceptibility to rheumatoid arthritis: Systematic review and meta-analysis.PLoS One. 2019 Feb 7;14(2):e0211146. doi: 10.1371/journal.pone.0211146. eCollection 2019.
• [29] TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients.Arthritis Res Ther. 2017 Jan 19;19(1):8. doi: 10.1186/s13075-016-1213-9.
• [30] Crystal structure of the apurinic/apyrimidinic endonuclease IV from Mycobacterium tuberculosis.Biochem Biophys Res Commun. 2018 Mar 25;498(1):111-118. doi: 10.1016/j.bbrc.2018.02.181. Epub 2018 Feb 27.
• [31] Decreased TIM-3 mRNA expression in peripheral blood mononuclear cells from nephropathy patients.Genet Mol Res. 2015 Jun 12;14(2):6543-8. doi: 10.4238/2015.June.12.7.
• [32] Co-expression of Rho guanine nucleotide exchange factor 5 and Src associates with poor prognosis of patients with resected non-small cell lung cancer.Oncol Rep. 2013 Dec;30(6):2864-70. doi: 10.3892/or.2013.2797. Epub 2013 Oct 14.
• [33] Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins.Int Immunol. 2006 Mar;18(3):473-84. doi: 10.1093/intimm/dxh388. Epub 2006 Feb 15.
• [34] TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy.Int J Mol Sci. 2019 Oct 2;20(19):4893. doi: 10.3390/ijms20194893.
• [35] TIM-4 Identifies IFN--Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.J Immunol. 2017 Oct 1;199(7):2585-2595. doi: 10.4049/jimmunol.1602107. Epub 2017 Aug 28.
• [36] 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.
• [37] 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.
• [38] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [39] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [40] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.