Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2ORXK)

• DOT Name: Engulfment and cell motility protein 1 (ELMO1)
• Synonyms: Protein ced-12 homolog
• Gene Name: ELMO1
• Related Disease:
  Cardiomyopathy
  Chronic kidney disease
  Crohn disease
  Dilated cardiomyopathy
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Ulcerative colitis
  Alzheimer disease
  Arteriosclerosis
  Arthritis
  Atherosclerosis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Cardiovascular disease
  Coeliac disease
  Colitis
  Epilepsy
  Familial multiple trichoepithelioma
  Glioma
  Hypothyroidism
  Multiple sclerosis
  Narcolepsy
  Nephropathy
  Polycystic kidney disease
  Polycystic ovarian syndrome
  Primary biliary cholangitis
  Rheumatoid arthritis
  STAT3-related early-onset multisystem autoimmune disease
  Stevens-Johnson syndrome
  Toxic epidermal necrolysis
  Triple negative breast cancer
  Acute myelogenous leukaemia
  Chronic renal failure
  End-stage renal disease
  Esophageal adenocarcinoma
  Gastritis
  Hepatocellular carcinoma
  Immune system disorder
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Advanced cancer
  Coronary atherosclerosis
  Coronary heart disease
  Non-insulin dependent diabetes
  Psoriasis
  Squamous cell carcinoma
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: ELMO1_HUMAN
• PDB ID: 2RQR; 2VSZ; 3A98; 6JPP; 6TGB; 6TGC; 7DPA; 7Y4A
• Pfam ID: PF11841 ; PF04727 ; PF16457
• Sequence:
  MPPPADIVKVAIEWPGAYPKLMEIDQKKPLSAIIKEVCDGWSLANHEYFALQHADSSNFY
  ITEKNRNEIKNGTILRLTTSPAQNAQQLHERIQSSSMDAKLEALKDLASLSRDVTFAQEF
  INLDGISLLTQMVESGTERYQKLQKIMKPCFGDMLSFTLTAFVELMDHGIVSWDTFSVAF
  IKKIASFVNKSAIDISILQRSLAILESMVLNSHDLYQKVAQEITIGQLIPHLQGSDQEIQ
  TYTIAVINALFLKAPDERRQEMANILAQKQLRSIILTHVIRAQRAINNEMAHQLYVLQVL
  TFNLLEDRMMTKMDPQDQAQRDIIFELRRIAFDAESEPNNSSGSMEKRKSMYTRDYKKLG
  FINHVNPAMDFTQTPPGMLALDNMLYFAKHHQDAYIRIVLENSSREDKHECPFGRSSIEL
  TKMLCEILKVGELPSETCNDFHPMFFTHDRSFEEFFCICIQLLNKTWKEMRATSEDFNKV
  MQVVKEQVMRALTTKPSSLDQFKSKLQNLSYTEILKIRQSERMNQEDFQSRPILELKEKI
  QPEILELIKQQRLNRLVEGTCFRKLNARRRQDKFWYCRLSPNHKVLHYGDLEESPQGEVP
  HDSLQDKLPVADIKAVVTGKDCPHMKEKGALKQNKEVLELAFSILYDSNCQLNFIAPDKH
  EYCIWTDGLNALLGKDMMSDLTRNDLDTLLSMEIKLRLLDLENIQIPDAPPPIPKEPSNY
  DFVYDCN
• Function: Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1.
• Tissue Specificity: Widely expressed, with a higher expression in the spleen and placenta.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Efferocytosis (hsa04148)
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Nef and signal transduction (R-HSA-164944)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Definitive	Posttranslational Modification	[2]
Crohn disease	DIS2C5Q8	Definitive	Genetic Variation	[3]
Dilated cardiomyopathy	DISX608J	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[4]
Neoplasm	DISZKGEW	Definitive	Biomarker	[5]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[4]
Ulcerative colitis	DIS8K27O	Definitive	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[7]
Arthritis	DIST1YEL	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[7]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[9]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[9]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[10]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[11]
Colitis	DISAF7DD	Strong	Biomarker	[12]
Epilepsy	DISBB28L	Strong	Altered Expression	[13]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Genetic Variation	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[9]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[16]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[17]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[18]
Polycystic kidney disease	DISWS3UY	Strong	Biomarker	[19]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[20]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[11]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[9]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[22]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[24]
Chronic renal failure	DISGG7K6	moderate	Biomarker	[25]
End-stage renal disease	DISXA7GG	moderate	Biomarker	[25]
Esophageal adenocarcinoma	DISODWFP	moderate	Biomarker	[14]
Gastritis	DIS8G07K	moderate	Biomarker	[26]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[5]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[27]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[28]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[29]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[30]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[30]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[31]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[32]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[33]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[34]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Engulfment and cell motility protein 1 (ELMO1) affects the response to substance of Temozolomide.	[45]
DTI-015	DMXZRW0	Approved	Engulfment and cell motility protein 1 (ELMO1) affects the response to substance of DTI-015.	[45]

9 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 Engulfment and cell motility protein 1 (ELMO1).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Engulfment and cell motility protein 1 (ELMO1).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Engulfment and cell motility protein 1 (ELMO1).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Engulfment and cell motility protein 1 (ELMO1).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Engulfment and cell motility protein 1 (ELMO1).	[42]

References

• [1] Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production.JCI Insight. 2019 Jun 20;4(12):e127660. doi: 10.1172/jci.insight.127660. eCollection 2019 Jun 20.
• [2] DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease.Epigenetics. 2014 Mar;9(3):366-76. doi: 10.4161/epi.27161. Epub 2013 Nov 19.
• [3] Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients.Genes Immun. 2012 Sep;13(6):474-80. doi: 10.1038/gene.2012.21. Epub 2012 May 17.
• [4] Elmo1 helps dock180 to regulate Rac1 activity and cell migration of ovarian cancer.Int J Gynecol Cancer. 2014 Jun;24(5):844-50. doi: 10.1097/IGC.0000000000000137.
• [5] Intergrated analysis of ELMO1, serves as a link between tumour mutation burden and epithelial-mesenchymal transition in hepatocellular carcinoma.EBioMedicine. 2019 Aug;46:105-118. doi: 10.1016/j.ebiom.2019.07.002. Epub 2019 Jul 16.
• [6] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [7] circRNA/lncRNA-miRNA-mRNA Network in Oxidized, Low-Density, Lipoprotein-Induced Foam Cells.DNA Cell Biol. 2019 Dec;38(12):1499-1511. doi: 10.1089/dna.2019.4865.
• [8] A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.Nat Immunol. 2019 Feb;20(2):141-151. doi: 10.1038/s41590-018-0293-x. Epub 2019 Jan 14.
• [9] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [10] Genetics of diabetes complications.Mamm Genome. 2014 Oct;25(9-10):384-400. doi: 10.1007/s00335-014-9543-x. Epub 2014 Aug 29.
• [11] Functional implications of disease-specific variants in loci jointly associated with coeliac disease and rheumatoid arthritis.Hum Mol Genet. 2016 Jan 1;25(1):180-90. doi: 10.1093/hmg/ddv455. Epub 2015 Nov 5.
• [12] Engulfment and Cell Motility Protein 1 Protects Against DSS-induced Colonic Injury in Mice via Rac1 Activation.J Crohns Colitis. 2019 Jan 1;13(1):100-114. doi: 10.1093/ecco-jcc/jjy133.
• [13] Kainic Acid Induces mTORC1-Dependent Expression of Elmo1 in Hippocampal Neurons.Mol Neurobiol. 2017 May;54(4):2562-2578. doi: 10.1007/s12035-016-9821-6. Epub 2016 Mar 19.
• [14] Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.Nat Genet. 2013 May;45(5):478-86. doi: 10.1038/ng.2591. Epub 2013 Mar 24.
• [15] Autocrine IL-8 promotes F-actin polymerization and mediate mesenchymal transition via ELMO1-NF-B-Snail signaling in glioma.Cancer Biol Ther. 2015;16(6):898-911. doi: 10.1080/15384047.2015.1028702. Epub 2015 Apr 14.
• [16] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [17] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [18] Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population.Ann Hum Genet. 2016 Nov;80(6):336-341. doi: 10.1111/ahg.12174. Epub 2016 Oct 4.
• [19] ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions.Sci Rep. 2016 Nov 16;6:37172. doi: 10.1038/srep37172.
• [20] RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model.Reprod Sci. 2017 May;24(5):738-752. doi: 10.1177/1933719116669057. Epub 2016 Sep 22.
• [21] Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2012 Oct;44(10):1137-41. doi: 10.1038/ng.2395. Epub 2012 Sep 9.
• [22] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [23] Downregulation of Dock1 and Elmo1 suppresses the migration and invasion of triple-negative breast cancer epithelial cells through the RhoA/Rac1 pathway.Oncol Lett. 2018 Sep;16(3):3481-3488. doi: 10.3892/ol.2018.9077. Epub 2018 Jul 4.
• [24] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [25] High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy.Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2218-22. doi: 10.1073/pnas.1600511113. Epub 2016 Feb 8.
• [26] Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies.Oncotarget. 2017 Jun 13;8(24):38501-38516. doi: 10.18632/oncotarget.16258.
• [27] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [28] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [29] Intermolecular steric inhibition of Ephexin4 is relieved by Elmo1.Sci Rep. 2017 Jun 30;7(1):4404. doi: 10.1038/s41598-017-04810-6.
• [30] Genetics of diabetes complications.Curr Diab Rep. 2010 Dec;10(6):467-75. doi: 10.1007/s11892-010-0147-x.
• [31] Identification and characterization of differentially expressed genes in Type 2 Diabetes using in silico approach.Comput Biol Chem. 2019 Apr;79:24-35. doi: 10.1016/j.compbiolchem.2019.01.010. Epub 2019 Jan 24.
• [32] Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.
• [33] De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGF-deficient squamous cell carcinoma from transition zones.Elife. 2017 Feb 21;6:e22914. doi: 10.7554/eLife.22914.
• [34] Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy.Diabetes. 2009 Nov;58(11):2698-702. doi: 10.2337/db09-0641. Epub 2009 Aug 3.
• [35] 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.
• [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] 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.
• [38] 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.
• [39] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [40] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [41] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [42] 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.
• [43] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [44] 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.
• [45] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.