Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD557PU)

• DOT Name: BDNF/NT-3 growth factors receptor (NTRK2)
• Synonyms: EC 2.7.10.1; GP145-TrkB; Trk-B; Neurotrophic tyrosine kinase receptor type 2; TrkB tyrosine kinase; Tropomyosin-related kinase B
• Gene Name: NTRK2
• Related Disease:
  Developmental and epileptic encephalopathy, 58
  Obesity, hyperphagia, and developmental delay
  Undetermined early-onset epileptic encephalopathy
  West syndrome
• UniProt ID: NTRK2_HUMAN
• PDB ID: 1HCF; 1WWB; 2MFQ; 4ASZ; 4AT3; 4AT4; 4AT5; 5MO9
• EC Number: 2.7.10.1
• Pfam ID: PF07679 ; PF13855 ; PF16920 ; PF01462 ; PF07714
• Sequence:
  MSSWIRWHGPAMARLWGFCWLVVGFWRAAFACPTSCKCSASRIWCSDPSPGIVAFPRLEP
  NSVDPENITEIFIANQKRLEIINEDDVEAYVGLRNLTIVDSGLKFVAHKAFLKNSNLQHI
  NFTRNKLTSLSRKHFRHLDLSELILVGNPFTCSCDIMWIKTLQEAKSSPDTQDLYCLNES
  SKNIPLANLQIPNCGLPSANLAAPNLTVEEGKSITLSCSVAGDPVPNMYWDVGNLVSKHM
  NETSHTQGSLRITNISSDDSGKQISCVAENLVGEDQDSVNLTVHFAPTITFLESPTSDHH
  WCIPFTVKGNPKPALQWFYNGAILNESKYICTKIHVTNHTEYHGCLQLDNPTHMNNGDYT
  LIAKNEYGKDEKQISAHFMGWPGIDDGANPNYPDVIYEDYGTAANDIGDTTNRSNEIPST
  DVTDKTGREHLSVYAVVVIASVVGFCLLVMLFLLKLARHSKFGMKGPASVISNDDDSASP
  LHHISNGSNTPSSSEGGPDAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVL
  KRELGEGAFGKVFLAECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHI
  VKFYGVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQI
  AAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWM
  PPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQ
  EVYELMLGCWQREPHMRKNIKGIHTLLQNLAKASPVYLDILG
• Function: Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells and mediate communication between neurons and glia.
• Tissue Specificity: Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Neurotrophin sig.ling pathway (hsa04722)
  Alcoholism (hsa05034)
• Reactome Pathway:
  BDNF activates NTRK2 (TRKB) signaling (R-HSA-9024909)
  NTF3 activates NTRK2 (TRKB) signaling (R-HSA-9025046)
  NTF4 activates NTRK2 (TRKB) signaling (R-HSA-9026357)
  Activated NTRK2 signals through RAS (R-HSA-9026519)
  Activated NTRK2 signals through PLCG1 (R-HSA-9026527)
  Activated NTRK2 signals through PI3K (R-HSA-9028335)
  Activated NTRK2 signals through FRS2 and FRS3 (R-HSA-9028731)
  Activated NTRK2 signals through FYN (R-HSA-9032500)
  NTRK2 activates RAC1 (R-HSA-9032759)
  Activated NTRK2 signals through CDK5 (R-HSA-9032845)
  NGF-independant TRKA activation (R-HSA-187024)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 58	DISYIZ2S	Strong	Autosomal dominant	[1]
Obesity, hyperphagia, and developmental delay	DIS1DTBJ	Strong	Autosomal dominant	[2]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sodium lauryl sulfate	DMLJ634	Approved	BDNF/NT-3 growth factors receptor (NTRK2) affects the response to substance of Sodium lauryl sulfate.	[26]

22 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 BDNF/NT-3 growth factors receptor (NTRK2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[15]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[16]
Malathion	DMXZ84M	Approved	Malathion increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[18]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[19]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[22]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of BDNF/NT-3 growth factors receptor (NTRK2).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[25]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal decreases the expression of BDNF/NT-3 growth factors receptor (NTRK2).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of BDNF/NT-3 growth factors receptor (NTRK2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of BDNF/NT-3 growth factors receptor (NTRK2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of BDNF/NT-3 growth factors receptor (NTRK2).	[24]

References

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• [11] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
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• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
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• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Nicotine regulates SH-SY5Y neuroblastoma cell proliferation through the release of brain-derived neurotrophic factor. Brain Res. 2006 Jul 26;1101(1):36-42. doi: 10.1016/j.brainres.2006.05.023. Epub 2006 Jun 21.
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• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [20] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [21] 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.
• [22] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [23] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [24] 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.
• [25] Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol. 2015 Jun 15;28(6):1234-45. doi: 10.1021/acs.chemrestox.5b00067. Epub 2015 May 11.
• [26] Genetic Basis of Irritant Susceptibility in Health Care Workers. J Occup Environ Med. 2016 Aug;58(8):753-9. doi: 10.1097/JOM.0000000000000784.