Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3F32IU)

• DOT Name: Rho guanine nucleotide exchange factor 28 (ARHGEF28)
• Synonyms: 190 kDa guanine nucleotide exchange factor; p190-RhoGEF; p190RhoGEF; Rho guanine nucleotide exchange factor
• Gene Name: ARHGEF28
• Related Disease:
  Pancreatic ductal carcinoma
  Spinocerebellar ataxia
  Adult glioblastoma
  Allergic asthma
  Amyotrophic lateral sclerosis type 1
  Anal intraepithelial neoplasia
  Arteriosclerosis
  Asthma
  Astrocytoma
  Atherosclerosis
  Autoimmune disease
  Bacterial infection
  Colitis
  Colon carcinoma
  Crohn disease
  Epithelial ovarian cancer
  Familial amyotrophic lateral sclerosis
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Lung cancer
  Lung carcinoma
  Motor neurone disease
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Squamous cell carcinoma
  Systemic lupus erythematosus
  Ulcerative colitis
  Amyotrophic lateral sclerosis
  Hereditary breast carcinoma
  Venous thromboembolism
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Inflammation
  Meningitis
  Stomach cancer
• UniProt ID: ARG28_HUMAN
• PDB ID: 6BC0; 6BC1
• Pfam ID: PF00130 ; PF17838 ; PF00621
• Sequence:
  MELSCSEAPLYGQMMIYAKFDKNVYLPEDAEFYFTYDGSHQRHVMIAERIEDNVLQSSVP
  GHGLQETVTVSVCLCSEGYSPVTMGSGSVTYVDNMACRLARLLVTQANRLTACSHQTLLT
  PFALTAGALPALDEELVLALTHLELPLEWTVLGSSSLEVSSHRESLLHLAMRWGLAKLSQ
  FFLCLPGGVQALALPNEEGATPLDLALREGHSKLVEDVTNFQGRWSPSFSRVQLSEEASL
  HYIHSSETLTLTLNHTAEHLLEADIKLFRKYFWDRAFLVKAFEPEARPEERTAMPSSGAE
  TEEEIKNSVSSRSAAEKEDIKRVKSLVVQHNEHEDQHSLDLDRSFDILKKSKPPSTLLAA
  GRLSDMLNGGDEVYANCMVIDQVGDLDISYINIEGITATTSPESRGCTLWPQSSKHTLPT
  ETSPSVYPLSENVEGTAHTEAQQSFMSPSSSCASNLNLSFGWHGFEKEQSHLKKRSSSLD
  ALDADSEGEGHSEPSHICYTPGSQSSSRTGIPSGDELDSFETNTEPDFNISRAESLPLSS
  NLQSKESLLSGVRSRSYSCSSPKISLGKTRLVRELTVCSSSEEQRAYSLSEPPRENRIQE
  EEWDKYIIPAKSESEKYKVSRTFSFLMNRMTSPRNKSKTKSKDAKDKEKLNRHQFAPGTF
  SGVLQCLVCDKTLLGKESLQCSNCNANVHKGCKDAAPACTKKFQEKYNKNKPQTILGNSS
  FRDIPQPGLSLHPSSSVPVGLPTGRRETVGQVHPLSRSVPGTTLESFRRSATSLESESDH
  NSCRSRSHSDELLQSMGSSPSTESFIMEDVVDSSLWSDLSSDAQEFEAESWSLVVDPSFC
  NRQEKDVIKRQDVIFELMQTEMHHIQTLFIMSEIFRKGMKEELQLDHSTVDKIFPCLDEL
  LEIHRHFFYSMKERRQESCAGSDRNFVIDRIGDILVQQFSEENASKMKKIYGEFCCHHKE
  AVNLFKELQQNKKFQNFIKLRNSNLLARRRGIPECILLVTQRITKYPVLVERILQYTKER
  TEEHKDLRKALCLIKDMIATVDLKVNEYEKNQKWLEILNKIENKTYTKLKNGHVFRKQAL
  MSEERTLLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPSVISLQK
  LIAREVANEERGMFLISASSAGPEMYEIHTNSKEERNNWMRRIQQAVESCPEEKGGRTSE
  SDEDKRKAEARVAKIQQCQEILTNQDQQICAYLEEKLHIYAELGELSGFEDVHLEPHLLI
  KPDPGEPPQAASLLAAALKEAESLQVAVKASQMGAVSQSCEDSCGDSVLADTLSSHDVPG
  SPTASLVTGGREGRGCSDVDPGIQGVVTDLAVSDAGEKVECRNFPGSSQSEIIQAIQNLT
  RLLYSLQAALTIQDSHIEIHRLVLQQQEGLSLGHSILRGGPLQDQKSRDADRQHEELANV
  HQLQHQLQQEQRRWLRRCEQQQRAQATRESWLQERERECQSQEELLLRSRGELDLQLQEY
  QHSLERLREGQRLVEREQARMRAQQSLLGHWKHGRQRSLPAVLLPGGPEVMELNRSESLC
  HENSFFINEALVQMSFNTFNKLNPSVIHQDATYPTTQSHSDLVRTSEHQVDLKVDPSQPS
  NVSHKLWTAAGSGHQILPFHESSKDSCKNDLDTSHTESPTPHDSNSHRPQLQAFITEAKL
  NLPTRTMTRQDGETGDGAKENIVYL
• Function: Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors. Functions in axonal branching, synapse formation and dendritic morphogenesis. Functions also in focal adhesion formation, cell motility and B-lymphocytes activation. May regulate NEFL expression and aggregation and play a role in apoptosis.
• KEGG Pathway: Yersinia infection (hsa05135)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  EPHB-mediated forward signaling (R-HSA-3928662)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Spinocerebellar ataxia	DISYMHUK	Definitive	Genetic Variation	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[4]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Genetic Variation	[5]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Biomarker	[6]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[7]
Asthma	DISW9QNS	Strong	Altered Expression	[8]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[7]
Autoimmune disease	DISORMTM	Strong	Biomarker	[9]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[10]
Colitis	DISAF7DD	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[14]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
High blood pressure	DISY2OHH	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[18]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[18]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Altered Expression	[20]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[14]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[21]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[22]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[23]
Amyotrophic lateral sclerosis	DISF7HVM	Moderate	Autosomal dominant	[24]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[25]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[26]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[27]
Breast cancer	DIS7DPX1	Limited	Biomarker	[28]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[28]
Gastric cancer	DISXGOUK	Limited	Biomarker	[29]
Inflammation	DISJUQ5T	Limited	Biomarker	[8]
Meningitis	DISQABAA	Limited	Altered Expression	[30]
Stomach cancer	DISKIJSX	Limited	Biomarker	[29]

12 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 28 (ARHGEF28).	[31]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[34]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[36]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[37]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[38]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[44]

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 28 (ARHGEF28).	[40]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho guanine nucleotide exchange factor 28 (ARHGEF28).	[43]

References

• [1] Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma.Oncogene. 2020 Jan;39(2):308-321. doi: 10.1038/s41388-019-0985-1. Epub 2019 Sep 2.
• [2] An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.Am J Hum Genet. 2005 Aug;77(2):280-96. doi: 10.1086/432518. Epub 2005 Jul 6.
• [3] RIP2 promotes glioma cell growth by regulating TRAF3 and activating the NFB and p38 signaling pathways.Oncol Rep. 2018 Jun;39(6):2915-2923. doi: 10.3892/or.2018.6397. Epub 2018 Apr 23.
• [4] Association of the RIP2 gene with childhood atopic asthma.Allergol Int. 2006 Mar;55(1):77-83. doi: 10.2332/allergolint.55.77.
• [5] Detection of a novel frameshift mutation and regions with homozygosis within ARHGEF28 gene in familial amyotrophic lateral sclerosis.Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5-6):444-51. doi: 10.3109/21678421.2012.758288. Epub 2013 Jan 4.
• [6] NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer.J Clin Invest. 2013 Feb;123(2):700-11. doi: 10.1172/JCI62236. Epub 2013 Jan 2.
• [7] Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation.Circ Res. 2011 Nov 11;109(11):1210-8. doi: 10.1161/CIRCRESAHA.111.246702. Epub 2011 Sep 29.
• [8] RIP2 activity in inflammatory disease and implications for novel therapeutics.J Leukoc Biol. 2013 Nov;94(5):927-32. doi: 10.1189/jlb.0213109. Epub 2013 Jun 21.
• [9] Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.ACS Med Chem Lett. 2018 Sep 26;9(10):1039-1044. doi: 10.1021/acsmedchemlett.8b00344. eCollection 2018 Oct 11.
• [10] Histone H2A cooperates with RIP2 to induce the expression of antibacterial genes and MHC related genes.Dev Comp Immunol. 2019 Dec;101:103455. doi: 10.1016/j.dci.2019.103455. Epub 2019 Jul 20.
• [11] Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis.Nat Immunol. 2013 Sep;14(9):927-36. doi: 10.1038/ni.2669. Epub 2013 Jul 28.
• [12] p190RhoGEF (Rgnef) promotes colon carcinoma tumor progression via interaction with focal adhesion kinase.Cancer Res. 2011 Jan 15;71(2):360-70. doi: 10.1158/0008-5472.CAN-10-2894. Epub 2011 Jan 11.
• [13] Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1.Inflamm Bowel Dis. 2012 Apr;18(4):603-12. doi: 10.1002/ibd.21851. Epub 2011 Sep 1.
• [14] Rgnef promotes ovarian tumor progression and confers protection from oxidative stress.Oncogene. 2019 Sep;38(36):6323-6337. doi: 10.1038/s41388-019-0881-8. Epub 2019 Jul 15.
• [15] -Catulin marks the invasion front of squamous cell carcinoma and is important for tumor cell metastasis.Mol Cancer Res. 2012 Jul;10(7):892-903. doi: 10.1158/1541-7786.MCR-12-0169. Epub 2012 May 30.
• [16] GEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling.J Pathol. 2012 Dec;228(4):575-85. doi: 10.1002/path.4084. Epub 2012 Sep 28.
• [17] Reduced mRNA and protein content of rho guanine nucleotide exchange factor (RhoGEF) in Bartter's and Gitelman's syndromes: relevance for the pathophysiology of hypertension.Am J Hypertens. 2005 Sep;18(9 Pt 1):1200-5. doi: 10.1016/j.amjhyper.2005.03.747.
• [18] A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans.Cancer. 2006 Jun 15;106(12):2716-24. doi: 10.1002/cncr.21944.
• [19] Rho guanine nucleotide exchange factor is an NFL mRNA destabilizing factor that forms cytoplasmic inclusions in amyotrophic lateral sclerosis.Neurobiol Aging. 2013 Jan;34(1):248-62. doi: 10.1016/j.neurobiolaging.2012.06.021. Epub 2012 Jul 24.
• [20] GEFT protein expression in digestive tract malignant tumors and its clinical significance.Oncol Lett. 2019 Nov;18(5):5577-5590. doi: 10.3892/ol.2019.10915. Epub 2019 Sep 24.
• [21] NOD1, RIP2 and Caspase12 are potentially novel biomarkers for oral squamous cell carcinoma development and progression.Int J Clin Exp Pathol. 2014 Mar 15;7(4):1677-86. eCollection 2014.
• [22] Association of RIP2 gene polymorphisms and systemic lupus erythematosus in a Chinese population.Mutagenesis. 2012 May;27(3):319-22. doi: 10.1093/mutage/ger081. Epub 2011 Nov 9.
• [23] Altered expression of innate immunity genes in different intestinal sites of children with ulcerative colitis.Dig Liver Dis. 2010 Dec;42(12):848-53. doi: 10.1016/j.dld.2010.04.003. Epub 2010 May 7.
• [24] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [25] Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer.Carcinogenesis. 2006 Mar;27(3):593-8. doi: 10.1093/carcin/bgi245. Epub 2005 Oct 18.
• [26] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [27] A novel overlapping NLS/NES region within the PH domain of Rho Guanine Nucleotide Exchange Factor (RGNEF) regulates its nuclear-cytoplasmic localization.Eur J Cell Biol. 2019 Jan;98(1):27-35. doi: 10.1016/j.ejcb.2018.11.001. Epub 2018 Nov 19.
• [28] Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways.Breast Cancer Res. 2014 Mar 19;16(2):R28. doi: 10.1186/bcr3629.
• [29] miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis.J Exp Clin Cancer Res. 2018 Mar 27;37(1):71. doi: 10.1186/s13046-018-0729-z.
• [30] NOD2-RIP2 contributes to the inflammatory responses of mice in vivo to Streptococcus pneumoniae.Neurosci Lett. 2018 Apr 3;671:43-49. doi: 10.1016/j.neulet.2018.01.057. Epub 2018 Feb 3.
• [31] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [32] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [33] 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.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] 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.
• [36] 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.
• [37] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [38] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [39] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [40] 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.
• [41] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [42] 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.
• [43] 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.
• [44] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.