Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM2D3LT)

• DOT Name: Rho guanine nucleotide exchange factor 12 (ARHGEF12)
• Synonyms: Leukemia-associated RhoGEF
• Gene Name: ARHGEF12
• Related Disease:
  Glaucoma/ocular hypertension
  OPTN-related open angle glaucoma
  Acute lymphocytic leukaemia
  Anemia
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Hyperinsulinemia
  leukaemia
  Leukemia
  Neoplasm
  Open-angle glaucoma
  Shwachman-Diamond syndrome
  Squamous cell carcinoma
  Coronary heart disease
  Acute myelogenous leukaemia
  Advanced cancer
  Asthma
  Cardiac disease
• UniProt ID: ARHGC_HUMAN
• PDB ID: 1TXD; 1X86; 2OMJ; 2OS6
• Pfam ID: PF00595 ; PF17838 ; PF09128 ; PF00621
• Sequence:
  MSGTQSTITDRFPLKKPIRHGSILNRESPTDKKQKVERIASHDFDPTDSSSKKTKSSSEE
  SRSEIYGLVQRCVIIQKDDNGFGLTVSGDNPVFVQSVKEDGAAMRAGVQTGDRIIKVNGT
  LVTHSNHLEVVKLIKSGSYVALTVQGRPPGSPQIPLADSEVEPSVIGHMSPIMTSPHSPG
  ASGNMERITSPVLMGEENNVVHNQKVEILRKMLQKEQERLQLLQEDYNRTPAQRLLKEIQ
  EAKKHIPQLQEQLSKATGSAQDGAVVTPSRPLGDTLTVSEAETDPGDVLGRTDCSSGDAS
  RPSSDNADSPKSGPKERIYLEENPEKSETIQDTDTQSLVGSPSTRIAPHIIGAEDDDFGT
  EHEQINGQCSCFQSIELLKSRPAHLAVFLHHVVSQFDPATLLCYLYSDLYKHTNSKETRR
  IFLEFHQFFLDRSAHLKVSVPDEMSADLEKRRPELIPEDLHRHYIQTMQERVHPEVQRHL
  EDFRQKRSMGLTLAESELTKLDAERDKDRLTLEKERTCAEQIVAKIEEVLMTAQAVEEDK
  SSTMQYVILMYMKHLGVKVKEPRNLEHKRGRIGFLPKIKQSMKKDKEGEEKGKRRGFPSI
  LGPPRRPSRHDNSAIGRAMELQKARHPKHLSTPSSVSPEPQDSAKLRQSGLANEGTDAGY
  LPANSMSSVASGASFSQEGGKENDTGSKQVGETSAPGDTLDGTPRTLNTVFDFPPPPLDQ
  VQEEECEVERVTEHGTPKPFRKFDSVAFGESQSEDEQFENDLETDPPNWQQLVSREVLLG
  LKPCEIKRQEVINELFYTERAHVRTLKVLDQVFYQRVSREGILSPSELRKIFSNLEDILQ
  LHIGLNEQMKAVRKRNETSVIDQIGEDLLTWFSGPGEEKLKHAAATFCSNQPFALEMIKS
  RQKKDSRFQTFVQDAESNPLCRRLQLKDIIPTQMQRLTKYPLLLDNIAKYTEWPTEREKV
  KKAADHCRQILNYVNQAVKEAENKQRLEDYQRRLDTSSLKLSEYPNVEELRNLDLTKRKM
  IHEGPLVWKVNRDKTIDLYTLLLEDILVLLQKQDDRLVLRCHSKILASTADSKHTFSPVI
  KLSTVLVRQVATDNKALFVISMSDNGAQIYELVAQTVSEKTVWQDLICRMAASVKEQSTK
  PIPLPQSTPGEGDNDEEDPSKLKEEQHGISVTGLQSPDRDLGLESTLISSKPQSHSLSTS
  GKSEVRDLFVAERQFAKEQHTDGTLKEVGEDYQIAIPDSHLPVSEERWALDALRNLGLLK
  QLLVQQLGLTEKSVQEDWQHFPRYRTASQGPQTDSVIQNSENIKAYHSGEGHMPFRTGTG
  DIATCYSPRTSTESFAPRDSVGLAPQDSQASNILVMDHMIMTPEMPTMEPEGGLDDSGEH
  FFDAREAHSDENPSEGDGAVNKEEKDVNLRISGNYLILDGYDPVQESSTDEEVASSLTLQ
  PMTGIPAVESTHQQQHSPQNTHSDGAISPFTPEFLVQQRWGAMEYSCFEIQSPSSCADSQ
  SQIMEYIHKIEADLEHLKKVEESYTILCQRLAGSALTDKHSDKS
• Function: May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.
• Tissue Specificity: Ubiquitously expressed. Isoform 2 is found in jejunum and testis.
• KEGG Pathway:
  Vascular smooth muscle contraction (hsa04270)
  Axon guidance (hsa04360)
  Platelet activation (hsa04611)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Yersinia infection (hsa05135)
  Tuberculosis (hsa05152)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[7]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[8]
Shwachman-Diamond syndrome	DISW57NW	Strong	Altered Expression	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[10]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Asthma	DISW9QNS	Limited	Biomarker	[14]
Cardiac disease	DISVO1I5	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Rho guanine nucleotide exchange factor 12 (ARHGEF12) increases the response to substance of Arsenic.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the phosphorylation of Rho guanine nucleotide exchange factor 12 (ARHGEF12).	[23]

References

• [1] Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.Nat Genet. 2018 Aug;50(8):1067-1071. doi: 10.1038/s41588-018-0176-y. Epub 2018 Jul 27.
• [2] Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.PLoS One. 2017 Aug 23;12(8):e0183709. doi: 10.1371/journal.pone.0183709. eCollection 2017.
• [3] ARHGEF12 regulates erythropoiesis and is involved in erythroid regeneration after chemotherapy in acute lymphoblastic leukemia patients.Haematologica. 2020 Apr;105(4):925-936. doi: 10.3324/haematol.2018.210286. Epub 2019 Aug 29.
• [4] LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer.Oncogene. 2009 Nov 26;28(47):4189-200. doi: 10.1038/onc.2009.266. Epub 2009 Sep 7.
• [5] Formin-like2 regulates Rho/ROCK pathway to promote actin assembly and cell invasion of colorectal cancer.Cancer Sci. 2015 Oct;106(10):1385-93. doi: 10.1111/cas.12768.
• [6] A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo.Diabetes. 2006 May;55(5):1497-503. doi: 10.2337/db05-1331.
• [7] Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells.J Biol Chem. 2004 Jul 9;279(28):28831-4. doi: 10.1074/jbc.C400105200. Epub 2004 May 13.
• [8] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [9] Leukaemia-related gene expression in bone marrow cells from patients with the preleukaemic disorder Shwachman-Diamond syndrome.Br J Haematol. 2007 Jun;137(6):537-44. doi: 10.1111/j.1365-2141.2007.06608.x.
• [10] Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells.J Biol Chem. 2006 May 19;281(20):14026-40. doi: 10.1074/jbc.M507734200. Epub 2006 Mar 24.
• [11] Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.Nat Genet. 2018 Sep;50(9):1335-1341. doi: 10.1038/s41588-018-0184-y. Epub 2018 Aug 13.
• [12] Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2145-50. doi: 10.1073/pnas.040569197.
• [13] Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1.Cell Signal. 2016 Jan;28(1):43-52. doi: 10.1016/j.cellsig.2015.10.004. Epub 2015 Oct 19.
• [14] Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice.JCI Insight. 2018 Nov 2;3(21):e123578. doi: 10.1172/jci.insight.123578.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [20] 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.
• [21] 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.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [24] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.