Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT551BVG)

• DOT Name: Erlin-2 (ERLIN2)
• Synonyms: Endoplasmic reticulum lipid raft-associated protein 2; Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2; SPFH domain-containing protein 2
• Gene Name: ERLIN2
• Related Disease:
  Neurodegenerative disease
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Estrogen-receptor positive breast cancer
  Hereditary spastic paraplegia 18
  Intellectual disability
  Neoplasm
  Papillon-Lefevre disease
  Pure hereditary spastic paraplegia
  Vascular purpura
  Peripheral sensory neuropathies
  Troyer syndrome
  Juvenile primary lateral sclerosis
  Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome
  Hereditary spastic paraplegia
• UniProt ID: ERLN2_HUMAN
• Pfam ID: PF01145
• Sequence:
  MAQLGAVVAVASSFFCASLFSAVHKIEEGHIGVYYRGGALLTSTSGPGFHLMLPFITSYK
  SVQTTLQTDEVKNVPCGTSGGVMIYFDRIEVVNFLVPNAVYDIVKNYTADYDKALIFNKI
  HHELNQFCSVHTLQEVYIELFDQIDENLKLALQQDLTSMAPGLVIQAVRVTKPNIPEAIR
  RNYELMESEKTKLLIAAQKQKVVEKEAETERKKALIEAEKVAQVAEITYGQKVMEKETEK
  KISEIEDAAFLAREKAKADAECYTAMKIAEANKLKLTPEYLQLMKYKAIASNSKIYFGKD
  IPNMFMDSAGSVSKQFEGLADKLSFGLEDEPLETATKEN
• Function: Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1. Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex. Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  Signaling by plasma membrane FGFR1 fusions (R-HSA-8853336)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegenerative disease	DISM20FF	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[3]
Hereditary spastic paraplegia 18	DISQRIBR	Strong	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Papillon-Lefevre disease	DIS3R7KX	Strong	Biomarker	[6]
Pure hereditary spastic paraplegia	DIS8X71E	Strong	Genetic Variation	[7]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[4]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[8]
Troyer syndrome	DISA9RYJ	moderate	Genetic Variation	[9]
Juvenile primary lateral sclerosis	DIS4OCLQ	Supportive	Autosomal recessive	[6]
Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome	DIS0YN4J	Supportive	Autosomal recessive	[5]
Hereditary spastic paraplegia	DISGZQV1	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Erlin-2 (ERLIN2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Erlin-2 (ERLIN2).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Erlin-2 (ERLIN2).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Erlin-2 (ERLIN2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Erlin-2 (ERLIN2).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Erlin-2 (ERLIN2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Erlin-2 (ERLIN2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Erlin-2 (ERLIN2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Erlin-2 (ERLIN2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Erlin-2 (ERLIN2).	[17]

References

• [1] Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias.Eur J Hum Genet. 2017 Nov;25(11):1217-1228. doi: 10.1038/ejhg.2017.124. Epub 2017 Aug 23.
• [2] Endoplasmic reticulum factor ERLIN2 regulates cytosolic lipid content in cancer cells.Biochem J. 2012 Sep 15;446(3):415-25. doi: 10.1042/BJ20112050.
• [3] MiR-410 Acts as a Tumor Suppressor in Estrogen Receptor-Positive Breast Cancer Cells by Directly Targeting ERLIN2 via the ERS Pathway.Cell Physiol Biochem. 2018;48(2):461-474. doi: 10.1159/000491777. Epub 2018 Jul 17.
• [4] Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.Nat Commun. 2019 Oct 21;10(1):4790. doi: 10.1038/s41467-019-12620-9.
• [5] A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures. Hum Mol Genet. 2011 May 15;20(10):1886-92. doi: 10.1093/hmg/ddr070. Epub 2011 Feb 17.
• [6] Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann Neurol. 2012 Oct;72(4):510-6. doi: 10.1002/ana.23641.
• [7] A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.Eur J Neurol. 2018 Jul;25(7):943-e71. doi: 10.1111/ene.13625. Epub 2018 Apr 15.
• [8] Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.Acta Neuropathol. 2013 Sep;126(3):307-28. doi: 10.1007/s00401-013-1115-8. Epub 2013 Jul 30.
• [9] Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.J Neurol Sci. 2012 Jul 15;318(1-2):1-18. doi: 10.1016/j.jns.2012.03.025. Epub 2012 May 1.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] 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.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [17] 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.
• [18] 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.
• [19] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.