Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDKKOE7)

• DOT Name: Reticulon-4 receptor-like 1 (RTN4RL1)
• Synonyms: Nogo receptor-like 2; Nogo-66 receptor homolog 2; Nogo-66 receptor-related protein 3; NgR3
• Gene Name: RTN4RL1
• Related Disease:
  Non-insulin dependent diabetes
  Acute myelogenous leukaemia
  Congenital heart disease
  Nasopharyngeal carcinoma
• UniProt ID: R4RL1_HUMAN
• Pfam ID: PF13855
• Sequence:
  MLRKGCCVELLLLLVAAELPLGGGCPRDCVCYPAPMTVSCQAHNFAAIPEGIPVDSERVF
  LQNNRIGLLQPGHFSPAMVTLWIYSNNITYIHPSTFEGFVHLEELDLGDNRQLRTLAPET
  FQGLVKLHALYLYKCGLSALPAGVFGGLHSLQYLYLQDNHIEYLQDDIFVDLVNLSHLFL
  HGNKLWSLGPGTFRGLVNLDRLLLHENQLQWVHHKAFHDLRRLTTLFLFNNSLSELQGEC
  LAPLGALEFLRLNGNPWDCGCRARSLWEWLQRFRGSSSAVPCVSPGLRHGQDLKLLRAED
  FRNCTGPASPHQIKSHTLTTTDRAARKEHHSPHGPTRSKGHPHGPRPGHRKPGKNCTNPR
  NRNQISKAGAGKQAPELPDYAPDYQHKFSFDIMPTARPKRKGKCARRTPIRAPSGVQQAS
  SASSLGASLLAWTLGLAVTLR
• Function: Cell surface receptor. Plays a functionally redundant role in postnatal brain development and in regulating axon regeneration in the adult central nervous system. Contributes to normal axon migration across the brain midline and normal formation of the corpus callosum. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated by MAG. Plays a role in inhibiting neurite outgrowth and axon regeneration via its binding to neuronal chondroitin sulfate proteoglycans. Binds heparin. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development. Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton.
• Tissue Specificity: Predominantly expressed in brain. Expressed at lower levels in kidney, lung, mammary gland, placenta, salivary gland, skeletal muscle and spleen.
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[2]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[3]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Reticulon-4 receptor-like 1 (RTN4RL1).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Reticulon-4 receptor-like 1 (RTN4RL1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Reticulon-4 receptor-like 1 (RTN4RL1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[16]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Reticulon-4 receptor-like 1 (RTN4RL1).	[17]

References

• [1] Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey.PLoS Genet. 2018 Apr 5;14(4):e1007275. doi: 10.1371/journal.pgen.1007275. eCollection 2018 Apr.
• [2] 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.
• [3] Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability.Am J Med Genet A. 2015 Dec;167A(12):3174-9. doi: 10.1002/ajmg.a.37347. Epub 2015 Sep 3.
• [4] Overexpression of Nogo receptor 3 (NgR3) correlates with poor prognosis and contributes to the migration of epithelial cells of nasopharyngeal carcinoma patients.J Mol Med (Berl). 2018 Apr;96(3-4):265-279. doi: 10.1007/s00109-017-1618-1. Epub 2018 Jan 11.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] 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.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [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] 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.
• [17] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.