Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXU4HBW)

• DOT Name: Rho guanine nucleotide exchange factor 1 (ARHGEF1)
• Synonyms: 115 kDa guanine nucleotide exchange factor; p115-RhoGEF; p115RhoGEF; Sub1.5
• Gene Name: ARHGEF1
• Related Disease:
  Acute lymphocytic leukaemia
  Adenocarcinoma
  Arteriosclerosis
  Atherosclerosis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Breast cancer
  Breast carcinoma
  Bronchiectasis
  Cardiovascular disease
  Childhood acute lymphoblastic leukemia
  Endometrial cancer
  Endometrial carcinoma
  Liver cirrhosis
  Neoplasm
  Pheochromocytoma
  Prostate carcinoma
  Retinoblastoma
  Vulvar intraepithelial neoplasia
  Wilms tumor
  Acute myelogenous leukaemia
  Colon cancer
  Colon carcinoma
  leukaemia
  Leukemia
  Asthma
  Immunodeficiency 62
  Leukocyte adhesion deficiency
  Small lymphocytic lymphoma
  Type-1/2 diabetes
• UniProt ID: ARHG1_HUMAN
• PDB ID: 1IAP; 1SHZ; 3AB3; 3ODO; 3ODW; 3ODX; 3P6A
• Pfam ID: PF17838 ; PF09128 ; PF00621
• Sequence:
  MEDFARGAASPGPSRPGLVPVSIIGAEDEDFENELETNSEEQNSQFQSLEQVKRRPAHLM
  ALLQHVALQFEPGPLLCCLHADMLGSLGPKEAKKAFLDFYHSFLEKTAVLRVPVPPNVAF
  ELDRTRADLISEDVQRRFVQEVVQSQQVAVGRQLEDFRSKRLMGMTPWEQELAQLEAWVG
  RDRASYEARERHVAERLLMHLEEMQHTISTDEEKSAAVVNAIGLYMRHLGVRTKSGDKKS
  GRNFFRKKVMGNRRSDEPAKTKKGLSSILDAARWNRGEPQVPDFRHLKAEVDAEKPGATD
  RKGGVGMPSRDRNIGAPGQDTPGVSLHPLSLDSPDREPGADAPLELGDSSPQGPMSLESL
  APPESTDEGAETESPEPGDEGEPGRSGLELEPEEPPGWRELVPPDTLHSLPKSQVKRQEV
  ISELLVTEAAHVRMLRVLHDLFFQPMAECLFFPLEELQNIFPSLDELIEVHSLFLDRLMK
  RRQESGYLIEEIGDVLLARFDGAEGSWFQKISSRFCSRQSFALEQLKAKQRKDPRFCAFV
  QEAESRPRCRRLQLKDMIPTEMQRLTKYPLLLQSIGQNTEEPTEREKVELAAECCREILH
  HVNQAVRDMEDLLRLKDYQRRLDLSHLRQSSDPMLSEFKNLDITKKKLVHEGPLTWRVTK
  DKAVEVHVLLLDDLLLLLQRQDERLLLKSHSRTLTPTPDGKTMLRPVLRLTSAMTREVAT
  DHKAFYVLFTWDQEAQIYELVAQTVSERKNWCALITETAGSLKVPAPASRPKPRPSPSST
  REPLLSSSENGNGGRETSPADARTERILSDLLPFCRPGPEGQLAATALRKVLSLKQLLFP
  AEEDNGAGPPRDGDGVPGGGPLSPARTQEIQENLLSLEETMKQLEELEEEFCRLRPLLSQ
  LGGNSVPQPGCT
• Function: Seems to play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13) subunits. Acts as a GTPase-activating protein (GAP) for GNA12 and GNA13, and as guanine nucleotide exchange factor (GEF) for RhoA GTPase. Activated G alpha 13/GNA13 stimulates the RhoGEF activity through interaction with the RGS-like domain. This GEF activity is inhibited by binding to activated GNA12. Mediates angiotensin-2-induced RhoA activation.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Vascular smooth muscle contraction (hsa04270)
  Platelet activation (hsa04611)
  Regulation of actin cytoskeleton (hsa04810)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Pathogenic Escherichia coli infection (hsa05130)
  Yersinia infection (hsa05135)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Lipid and atherosclerosis (hsa05417)
• 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)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Bronchiectasis	DIS5MYEE	Strong	Altered Expression	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[2]
Vulvar intraepithelial neoplasia	DISA474V	Strong	Biomarker	[12]
Wilms tumor	DISB6T16	Strong	Altered Expression	[13]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[14]
Colon cancer	DISVC52G	moderate	Biomarker	[15]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[15]
leukaemia	DISS7D1V	moderate	Biomarker	[16]
Leukemia	DISNAKFL	moderate	Biomarker	[16]
Asthma	DISW9QNS	Disputed	Altered Expression	[17]
Immunodeficiency 62	DISD7AC9	Limited	Autosomal recessive	[18]
Leukocyte adhesion deficiency	DISEJ9VG	Limited	Biomarker	[19]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[20]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[21]

4 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 1 (ARHGEF1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[25]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 1 (ARHGEF1).	[28]

References

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• [10] Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression.Endocr Relat Cancer. 2016 Apr;23(4):281-93. doi: 10.1530/ERC-15-0502. Epub 2016 Feb 24.
• [11] Phospholipase C gamma 1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion.Oncogene. 2008 May 1;27(20):2823-32. doi: 10.1038/sj.onc.1210954. Epub 2007 Nov 26.
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• [13] Proteomics analysis of siRNA-mediated silencing of Wilms' tumor 1 in the MDA-MB-468 breast cancer cell line.Oncol Rep. 2014 Apr;31(4):1754-60. doi: 10.3892/or.2014.3013. Epub 2014 Feb 5.
• [14] CD9 in acute myeloid leukemia: Prognostic role and usefulness to target leukemic stem cells.Cancer Med. 2019 Mar;8(3):1279-1288. doi: 10.1002/cam4.2007. Epub 2019 Feb 10.
• [15] Disruption of Core 1-mediated O-glycosylation oppositely regulates CD44 expression in human colon cancer cells and tumor-derived exosomes.Biochem Biophys Res Commun. 2020 Jan 8;521(2):514-520. doi: 10.1016/j.bbrc.2019.10.149. Epub 2019 Oct 31.
• [16] METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.Cell Stem Cell. 2018 Feb 1;22(2):191-205.e9. doi: 10.1016/j.stem.2017.11.016. Epub 2017 Dec 28.
• [17] Transforming growth factor- enhances Rho-kinase activity and contraction in airway smooth muscle via the nucleotide exchange factor ARHGEF1.J Physiol. 2018 Jan 1;596(1):47-66. doi: 10.1113/JP275033. Epub 2017 Nov 23.
• [18] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [19] The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1.J Clin Immunol. 2009 Jan;29(1):117-22. doi: 10.1007/s10875-008-9226-z. Epub 2008 Aug 16.
• [20] Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells.Leukemia. 2017 Dec;31(12):2615-2622. doi: 10.1038/leu.2017.133. Epub 2017 May 3.
• [21] Comparative gene expression profile and DNA methylation status in diabetic patients of Kazak and Han people.Medicine (Baltimore). 2018 Sep;97(36):e11982. doi: 10.1097/MD.0000000000011982.
• [22] 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.
• [23] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [24] 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.
• [25] 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.
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• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.