Details of Drug Off-Target (DOT)

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

• DOT Name: Tenascin-R (TNR)
• Synonyms: TN-R; Janusin; Restrictin
• Gene Name: TNR
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Fuchs' endothelial dystrophy
  Glioblastoma multiforme
  Medulloblastoma
  Mucinous adenocarcinoma
  Neovascular age-related macular degeneration
  Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus
  Acute myelogenous leukaemia
  Chronic leukemia
  Intellectual disability
  leukaemia
  Leukemia
  Neoplasm
  Small lymphocytic lymphoma
• UniProt ID: TENR_HUMAN
• PDB ID: 8FN9; 8FNA
• Pfam ID: PF07974 ; PF18720 ; PF00147 ; PF00041
• Sequence:
  MGADGETVVLKNMLIGINLILLGSMIKPSECQLEVTTERVQRQSVEEEGGIANYNTSSKE
  QPVVFNHVYNINVPLDNLCSSGLEASAEQEVSAEDETLAEYMGQTSDHESQVTFTHRINF
  PKKACPCASSAQVLQELLSRIEMLEREVSVLRDQCNANCCQESAATGQLDYIPHCSGHGN
  FSFESCGCICNEGWFGKNCSEPYCPLGCSSRGVCVDGQCICDSEYSGDDCSELRCPTDCS
  SRGLCVDGECVCEEPYTGEDCRELRCPGDCSGKGRCANGTCLCEEGYVGEDCGQRQCLNA
  CSGRGQCEEGLCVCEEGYQGPDCSAVAPPEDLRVAGISDRSIELEWDGPMAVTEYVISYQ
  PTALGGLQLQQRVPGDWSGVTITELEPGLTYNISVYAVISNILSLPITAKVATHLSTPQG
  LQFKTITETTVEVQWEPFSFSFDGWEISFIPKNNEGGVIAQVPSDVTSFNQTGLKPGEEY
  IVNVVALKEQARSPPTSASVSTVIDGPTQILVRDVSDTVAFVEWIPPRAKVDFILLKYGL
  VGGEGGRTTFRLQPPLSQYSVQALRPGSRYEVSVSAVRGTNESDSATTQFTTEIDAPKNL
  RVGSRTATSLDLEWDNSEAEVQEYKVVYSTLAGEQYHEVLVPRGIGPTTRATLTDLVPGT
  EYGVGISAVMNSQQSVPATMNARTELDSPRDLMVTASSETSISLIWTKASGPIDHYRITF
  TPSSGIASEVTVPKDRTSYTLTDLEPGAEYIISVTAERGRQQSLESTVDAFTGFRPISHL
  HFSHVTSSSVNITWSDPSPPADRLILNYSPRDEEEEMMEVSLDATKRHAVLMGLQPATEY
  IVNLVAVHGTVTSEPIVGSITTGIDPPKDITISNVTKDSVMVSWSPPVASFDYYRVSYRP
  TQVGRLDSSVVPNTVTEFTITRLNPATEYEISLNSVRGREESERICTLVHTAMDNPVDLI
  ATNITPTEALLQWKAPVGEVENYVIVLTHFAVAGETILVDGVSEEFRLVDLLPSTHYTAT
  MYATNGPLTSGTISTNFSTLLDPPANLTASEVTRQSALISWQPPRAEIENYVLTYKSTDG
  SRKELIVDAEDTWIRLEGLLENTDYTVLLQAAQDTTWSSITSTAFTTGGRVFPHPQDCAQ
  HLMNGDTLSGVYPIFLNGELSQKLQVYCDMTTDGGGWIVFQRRQNGQTDFFRKWADYRVG
  FGNVEDEFWLGLDNIHRITSQGRYELRVDMRDGQEAAFASYDRFSVEDSRNLYKLRIGSY
  NGTAGDSLSYHQGRPFSTEDRDNDVAVTNCAMSYKGAWWYKNCHRTNLNGKYGESRHSQG
  INWYHWKGHEFSIPFVEMKMRPYNHRLMAGRKRQSLQF
• Function: Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components. These interactions can influence cellular behavior by either evoking a stable adhesion and differentiation, or repulsion and inhibition of neurite growth. Binding to cell surface gangliosides inhibits RGD-dependent integrin-mediated cell adhesion and results in an inhibition of PTK2/FAK1 (FAK) phosphorylation and cell detachment. Binding to membrane surface sulfatides results in a oligodendrocyte adhesion and differentiation. Interaction with CNTN1 induces a repulsion of neurons and an inhibition of neurite outgrowth. Interacts with SCN2B may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier. TNR-linked chondroitin sulfate glycosaminoglycans are involved in the interaction with FN1 and mediate inhibition of cell adhesion and neurite outgrowth. The highly regulated addition of sulfated carbohydrate structure may modulate the adhesive properties of TNR over the course of development and during synapse maintenance.
• Tissue Specificity: Brain specific.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Human papillomavirus infection (hsa05165)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway: ECM proteoglycans (R-HSA-3000178)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[5]
Mucinous adenocarcinoma	DISKNFE8	Strong	Biomarker	[6]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[7]
Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus	DISMQH8Y	Strong	Autosomal recessive	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Chronic leukemia	DIS0C4XI	Limited	Genetic Variation	[10]
Intellectual disability	DISMBNXP	Limited	Biomarker	[11]
leukaemia	DISS7D1V	Limited	Genetic Variation	[10]
Leukemia	DISNAKFL	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[10]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tenascin-R (TNR).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tenascin-R (TNR).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tenascin-R (TNR).	[14]

References

• [1] KIAA0510, the 3'-untranslated region of the tenascin-R gene, and tenascin-R are overexpressed in pilocytic astrocytomas.Neuropathol Appl Neurobiol. 2010 Aug;36(5):399-410. doi: 10.1111/j.1365-2990.2010.01074.x. Epub 2010 Feb 25.
• [2] Cerebrospinal Fluid Concentrations of Extracellular Matrix Proteins in Alzheimer's Disease.J Alzheimers Dis. 2019;69(4):1213-1220. doi: 10.3233/JAD-190187.
• [3] A case-control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene.Transl Psychiatry. 2018 Dec 18;8(1):284. doi: 10.1038/s41398-018-0329-x.
• [4] Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs' Endothelial Corneal Dystrophy.PLoS One. 2019 Jan 25;14(1):e0210996. doi: 10.1371/journal.pone.0210996. eCollection 2019.
• [5] Transcriptional profiling of medulloblastoma in children.J Neurosurg. 2003 Sep;99(3):534-41. doi: 10.3171/jns.2003.99.3.0534.
• [6] Assessment of pancreatic colloid carcinoma using (18)F-FDG PET/CT compared with MRI and enhanced CT.Oncol Lett. 2018 Aug;16(2):1557-1564. doi: 10.3892/ol.2018.8859. Epub 2018 May 31.
• [7] Genome-wide analysis of disease progression in age-related macular degeneration.Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
• [8] Severe cognitive and motor coordination deficits in tenascin-R-deficient mice. Genes Brain Behav. 2003 Feb;2(1):20-31. doi: 10.1034/j.1601-183x.2003.00003.x.
• [9] 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.
• [10] TNR/11q#1 trinucleotide (GCC)n repeat alleles and predisposition to acute and chronic leukemia.Ann Hum Genet. 2004 Jul;68(Pt 4):362-6. doi: 10.1046/j.1529-8817.2004.00101.x.
• [11] Homozygous deletion of Tenascin-R in a patient with intellectual disability.J Med Genet. 2012 Jul;49(7):451-4. doi: 10.1136/jmedgenet-2012-100831. Epub 2012 Jun 22.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.