Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTZ5FW0)

• DOT Name: Reticulon-2 (RTN2)
• Synonyms: Neuroendocrine-specific protein-like 1; NSP-like protein 1; Neuroendocrine-specific protein-like I; NSP-like protein I; NSPLI
• Gene Name: RTN2
• Related Disease:
  Alphavirus infectious disease
  Gastroenteritis
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 12
  Severe acute respiratory syndrome (SARS)
• UniProt ID: RTN2_HUMAN
• Pfam ID: PF02453
• Sequence:
  MGQVLPVFAHCKEAPSTASSTPDSTEGGNDDSDFRELHTAREFSEEDEEETTSQDWGTPR
  ELTFSYIAFDGVVGSGGRRDSTARRPRPQGRSVSEPRDQHPQPSLGDSLESIPSLSQSPE
  PGRRGDPDTAPPSERPLEDLRLRLDHLGWVARGTGSGEDSSTSSSTPLEDEEPQEPNRLE
  TGEAGEELDLRLRLAQPSSPEVLTPQLSPGSGTPQAGTPSPSRSRDSNSGPEEPLLEEEE
  KQWGPLEREPVRGQCLDSTDQLEFTVEPRLLGTAMEWLKTSLLLAVYKTVPILELSPPLW
  TAIGWVQRGPTPPTPVLRVLLKWAKSPRSSGVPSLSLGADMGSKVADLLYWKDTRTSGVV
  FTGLMVSLLCLLHFSIVSVAAHLALLLLCGTISLRVYRKVLQAVHRGDGANPFQAYLDVD
  LTLTREQTERLSHQITSRVVSAATQLRHFFLVEDLVDSLKLALLFYILTFVGAIFNGLTL
  LILGVIGLFTIPLLYRQHQAQIDQYVGLVTNQLSHIKAKIRAKIPGTGALASAAAAVSGS
  KAKAE
• Function: Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity. Enhances trafficking of the glutamate transporter SLC1A1/EAAC1 from the endoplasmic reticulum to the cell surface. Plays a role in the translocation of SLC2A4/GLUT4 from intracellular membranes to the cell membrane which facilitates the uptake of glucose into the cell.
• Tissue Specificity: .Highly expressed in skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alphavirus infectious disease	DISZGSCJ	Strong	Genetic Variation	[1]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[2]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[3]
Hereditary spastic paraplegia 12	DISD8CPV	Strong	Autosomal dominant	[4]
Severe acute respiratory syndrome (SARS)	DISYW14W	Limited	Biomarker	[5]

16 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 Reticulon-2 (RTN2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Reticulon-2 (RTN2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Reticulon-2 (RTN2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Reticulon-2 (RTN2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Reticulon-2 (RTN2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Reticulon-2 (RTN2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Reticulon-2 (RTN2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Reticulon-2 (RTN2).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Reticulon-2 (RTN2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Reticulon-2 (RTN2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Reticulon-2 (RTN2).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Reticulon-2 (RTN2).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Reticulon-2 (RTN2).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Reticulon-2 (RTN2).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Reticulon-2 (RTN2).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Reticulon-2 (RTN2).	[20]

References

• [1] Novel Mutations in nsP2 Abolish Chikungunya Virus-Induced Transcriptional Shutoff and Make the Virus Less Cytopathic without Affecting Its Replication Rates.J Virol. 2019 Feb 5;93(4):e02062-18. doi: 10.1128/JVI.02062-18. Print 2019 Feb 15.
• [2] Porcine transmissible gastroenteritis virus nonstructural protein 2 contributes to inflammation via NF-B activation.Virulence. 2018;9(1):1685-1698. doi: 10.1080/21505594.2018.1536632.
• [3] Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest. 2012 Feb;122(2):538-44. doi: 10.1172/JCI60560. Epub 2012 Jan 9.
• [4] Clinical and genetic study of a large Italian family linked to SPG12 locus. Neurology. 2002 Nov 12;59(9):1395-401. doi: 10.1212/01.wnl.0000031423.43482.19.
• [5] Variation analysis of the severe acute respiratory syndrome coronavirus putative non-structural protein 2 gene and construction of three-dimensional model.Chin Med J (Engl). 2005 May 5;118(9):707-13.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [12] 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.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.