Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1ABGL)

• DOT Name: Rho guanine nucleotide exchange factor 6 (ARHGEF6)
• Synonyms: Alpha-Pix; COOL-2; PAK-interacting exchange factor alpha; Rac/Cdc42 guanine nucleotide exchange factor 6
• Gene Name: ARHGEF6
• Related Disease:
  Borjeson-Forssman-Lehmann syndrome
  Crohn disease
  Intellectual disability, X-linked 1
  Pulmonary hypertension
  Schizophrenia
  Ulcerative colitis
  X-linked intellectual disability
  Non-syndromic X-linked intellectual disability
  Glioma
  Complex neurodevelopmental disorder
  Inflammatory bowel disease
  Intellectual disability
  Intellectual disability, X-linked 46
• UniProt ID: ARHG6_HUMAN
• PDB ID: 1UJY; 1WYR
• Pfam ID: PF16523 ; PF00307 ; PF00169 ; PF00621 ; PF16615 ; PF16614 ; PF07653
• Sequence:
  MNPEEQIVTWLISLGVLESPKKTICDPEEFLKSSLKNGVVLCKLINRLMPGSVEKFCLDP
  QTEADCINNINDFLKGCATLQVEIFDPDDLYSGVNFSKVLSTLLAVNKATEDQLSERPCG
  RSSSLSAANTSQTNPQGAVSSTVSGLQRQSKTVEMTENGSHQLIVKARFNFKQTNEDELS
  VCKGDIIYVTRVEEGGWWEGTLNGRTGWFPSNYVREIKSSERPLSPKAVKGFETAPLTKN
  YYTVVLQNILDTEKEYAKELQSLLVTYLRPLQSNNNLSTVEVTSLLGNFEEVCTFQQTLC
  QALEECSKFPENQHKVGGCLLSLMPHFKSMYLAYCANHPSAVNVLTQHSDELEQFMENQG
  ASSPGILILTTNLSKPFMRLEKYVTLLQELERHMEDTHPDHQDILKAIVAFKTLMGQCQD
  LRKRKQLELQILSEPIQAWEGEDIKNLGNVIFMSQVMVQYGACEEKEERYLMLFSNVLIM
  LSASPRMSGFIYQGKIPIAGTVVTRLDEIEGNDCTFEITGNTVERIVVHCNNNQDFQEWL
  EQLNRLIRGPASCSSLSKTSSSSCSAHSSFSSTGQPRGPLEPPQIIKPWSLSCLRPAPPL
  RPSAALGYKERMSYILKESSKSPKTMKKFLHKRKTERKPSEEEYVIRKSTAALEEDAQIL
  KVIEAYCTSANFQQGHGSSTRKDSIPQVLLPEEEKLIIEETRSNGQTIMEEKSLVDTVYA
  LKDEVRELKQENKRMKQCLEEELKSRRDLEKLVRRLLKQTDECIRGESSSKTSILP
• Function: Acts as a RAC1 guanine nucleotide exchange factor (GEF).
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Regulation of actin cytoskeleton (hsa04810)
  Pancreatic cancer (hsa05212)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  Regulation of cytoskeletal remodeling and cell spreading by IPP complex components (R-HSA-446388)
  G beta (R-HSA-8964616)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOU GTPase cycle (R-HSA-9013420)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Borjeson-Forssman-Lehmann syndrome	DISJ5QNF	Strong	Biomarker	[1]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[2]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[3]
Pulmonary hypertension	DIS1RSP5	Strong	Altered Expression	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[2]
X-linked intellectual disability	DISYJBY3	moderate	Biomarker	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[3]
Glioma	DIS5RPEH	Disputed	Biomarker	[6]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[7]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Limited	Biomarker	[1]
Intellectual disability, X-linked 46	DISO2WQ2	Limited	X-linked recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 6 (ARHGEF6).	[22]

References

• [1] Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Brjeson-Forssman-Lehmann syndrome and MRX27.Am J Med Genet. 2001 Apr 15;100(1):43-8. doi: 10.1002/ajmg.1189.
• [2] Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.PLoS One. 2014 Dec 5;9(12):e113684. doi: 10.1371/journal.pone.0113684. eCollection 2014.
• [3] Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet. 2000 Oct;26(2):247-50. doi: 10.1038/80002.
• [4] Rac regulates thrombin-induced tissue factor expression in pulmonary artery smooth muscle cells involving the nuclear factor-kappaB pathway.Antioxid Redox Signal. 2004 Aug;6(4):713-20. doi: 10.1089/1523086041361703.
• [5] Dysbindin-1 contributes to prefrontal cortical dendritic arbor pathology in schizophrenia.Schizophr Res. 2018 Nov;201:270-277. doi: 10.1016/j.schres.2018.04.042. Epub 2018 May 11.
• [6] Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin.Acta Neuropathol. 2006 Jan;111(1):29-38. doi: 10.1007/s00401-005-1085-6. Epub 2005 Nov 30.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] X Chromosome-wide Association Study Identifies a Susceptibility Locus for Inflammatory Bowel Disease in Koreans.J Crohns Colitis. 2017 Jul 1;11(7):820-830. doi: 10.1093/ecco-jcc/jjx023.
• [9] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [12] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [19] 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.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] 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.
• [22] 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.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.