Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKDOC2M)

• DOT Name: Engulfment and cell motility protein 2 (ELMO2)
• Synonyms: Protein ced-12 homolog A; hCed-12A
• Gene Name: ELMO2
• Related Disease:
  Primary intraosseous venous malformation
  Vascular malformation
  Ramon syndrome
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: ELMO2_HUMAN
• PDB ID: 6IDX; 6IE1
• Pfam ID: PF11841 ; PF04727 ; PF16457
• Sequence:
  MPPPSDIVKVAIEWPGANAQLLEIDQKRPLASIIKEVCDGWSLPNPEYYTLRYADGPQLY
  ITEQTRSDIKNGTILQLAISPSRAARQLMERTQSSNMETRLDAMKELAKLSADVTFATEF
  INMDGIIVLTRLVESGTKLLSHYSEMLAFTLTAFLELMDHGIVSWDMVSITFIKQIAGYV
  SQPMVDVSILQRSLAILESMVLNSQSLYQKIAEEITVGQLISHLQVSNQEIQTYAIALIN
  ALFLKAPEDKRQDMANAFAQKHLRSIILNHVIRGNRPIKTEMAHQLYVLQVLTFNLLEER
  MMTKMDPNDQAQRDIIFELRRIAFDAESDPSNAPGSGTEKRKAMYTKDYKMLGFTNHINP
  AMDFTQTPPGMLALDNMLYLAKVHQDTYIRIVLENSSREDKHECPFGRSAIELTKMLCEI
  LQVGELPNEGRNDYHPMFFTHDRAFEELFGICIQLLNKTWKEMRATAEDFNKVMQVVREQ
  ITRALPSKPNSLDQFKSKLRSLSYSEILRLRQSERMSQDDFQSPPIVELREKIQPEILEL
  IKQQRLNRLCEGSSFRKIGNRRRQERFWYCRLALNHKVLHYGDLDDNPQGEVTFESLQEK
  IPVADIKAIVTGKDCPHMKEKSALKQNKEVLELAFSILYDPDETLNFIAPNKYEYCIWID
  GLSALLGKDMSSELTKSDLDTLLSMEMKLRLLDLENIQIPEAPPPIPKEPSSYDFVYHYG
• 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 skeletal muscle, kidney and placenta.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  RHOG GTPase cycle (R-HSA-9013408)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary intraosseous venous malformation	DISSM0B0	Strong	Autosomal recessive	[1]
Vascular malformation	DIS2DB7A	Strong	Genetic Variation	[2]
Ramon syndrome	DISCTV2L	Supportive	Autosomal recessive	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Engulfment and cell motility protein 2 (ELMO2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Engulfment and cell motility protein 2 (ELMO2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Engulfment and cell motility protein 2 (ELMO2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Engulfment and cell motility protein 2 (ELMO2).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Engulfment and cell motility protein 2 (ELMO2).	[13]

References

• [1] Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling. Am J Hum Genet. 2016 Aug 4;99(2):299-317. doi: 10.1016/j.ajhg.2016.06.008. Epub 2016 Jul 28.
• [2] Clinical and Molecular Study of ELMO-2-Related Massive Intraosseous Vascular Malformations: Lessons Learned From 25 Years of Follow-up.Ann Plast Surg. 2019 Sep;83(3):293-299. doi: 10.1097/SAP.0000000000001786.
• [3] Homozygous mutation in ELMO2 may cause Ramon syndrome. Clin Genet. 2018 Mar;93(3):703-706. doi: 10.1111/cge.13166. Epub 2018 Jan 25.
• [4] HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion.J Biol Chem. 2018 Oct 5;293(40):15397-15418. doi: 10.1074/jbc.RA118.003063. Epub 2018 Aug 14.
• [5] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.