Target General Infomation
Target ID
T84703
Former ID
TTDNR00649
Target Name
BDNF/NT-3 growth factors receptor
Gene Name
NTRK2
Synonyms
GP145-TrkB; Neurotrophic tyrosine kinase receptor type 2; Trk-B; TrkB tyrosine kinase; Tropomyosin-related kinase B; NTRK2
Target Type
Clinical Trial
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Neurodegenerative disease [ICD9: 330-337; ICD10: G30-G32]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Receptor tyrosine kinase involved inthe 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.
BioChemical Class
Kinase
UniProt ID
EC Number
EC 2.7.10.1
Sequence
MSSWIRWHGPAMARLWGFCWLVVGFWRAAFACPTSCKCSASRIWCSDPSPGIVAFPRLEP
NSVDPENITEIFIANQKRLEIINEDDVEAYVGLRNLTIVDSGLKFVAHKAFLKNSNLQHI
NFTRNKLTSLSRKHFRHLDLSELILVGNPFTCSCDIMWIKTLQEAKSSPDTQDLYCLNES
SKNIPLANLQIPNCGLPSANLAAPNLTVEEGKSITLSCSVAGDPVPNMYWDVGNLVSKHM
NETSHTQGSLRITNISSDDSGKQISCVAENLVGEDQDSVNLTVHFAPTITFLESPTSDHH
WCIPFTVKGNPKPALQWFYNGAILNESKYICTKIHVTNHTEYHGCLQLDNPTHMNNGDYT
LIAKNEYGKDEKQISAHFMGWPGIDDGANPNYPDVIYEDYGTAANDIGDTTNRSNEIPST
DVTDKTGREHLSVYAVVVIASVVGFCLLVMLFLLKLARHSKFGMKGPASVISNDDDSASP
LHHISNGSNTPSSSEGGPDAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVL
KRELGEGAFGKVFLAECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHI
VKFYGVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQI
AAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWM
PPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQ
EVYELMLGCWQREPHMRKNIKGIHTLLQNLAKASPVYLDILG
Drugs and Mode of Action
Drug(s) MK-2461 Drug Info Phase 1/2 Alzheimer disease [530708]
RXDX 101 Drug Info Phase 1/2 Solid tumours [532994]
LOXO-101 Drug Info Phase 1 Solid tumours [524734]
Inhibitor AZD1332 Drug Info [543504]
compound 8e Drug Info [532627]
GNF-5837 Drug Info [532813]
LOXO-101 Drug Info [543504]
MK-2461 Drug Info [530708]
RXDX 101 Drug Info [543504]
Modulator TrkB NAM Drug Info [543504]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway MAPK signaling pathway
Neurotrophin signaling pathway
Alcoholism
Pathway Interaction Database SHP2 signaling
Posttranslational regulation of adherens junction stability and dissassembly
Neurotrophic factor-mediated Trk receptor signaling
Reactome NGF-independant TRKA activation
WikiPathways SIDS Susceptibility Pathways
BDNF signaling pathway
References
Ref 524734ClinicalTrials.gov (NCT02122913) Oral TRK Inhibitor LOXO-101 for Treatment of Advanced Adult Solid Tumors. U.S. National Institutes of Health.
Ref 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 532994ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.
Ref 530708MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
Ref 532627Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87.
Ref 532813Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. ACS Med Chem Lett. 2012 Jan 1;3(2):140-5.
Ref 543504(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1818).

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