Signaling by NTRK2 (TRKB) (Homo sapiens)

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3, 11, 12, 14, 17...3423357cytosolp-5Y-NTRK2 BDNF NTF3:NTRK2 homodimerGRB2-1 p-Y1474-GRIN2B BDNF:p-5Y-NTRK2homodimer:MyrG,p-Y420-FYN-1:GRIN2BNTF4 ADPBDNF GTP GRB2-1:SOS1NTF4 DAG and IP3signalingp-4Y-PLCG1 SOS1 MyrG-FYN-1GRB2-1 p-Y15-CDK5 NTF4:NTRK2BDNF:NTRK2 homodimerp-5Y-NTRK2 ATPNTRK2 MyrG-p-Y420-FYN-1 BDNF BDNF,NTF4:p-5Y-NTRK2:SHC1-2,SHC1-3p-Y-FRS2 BDNF:p-5Y,S479-NTRK2homodimerCDK5 p-Y-FRS3 NTF3 BDNF:p-5Y-NTRK2homodimer:MyrG,p-Y420-FYN-1:DOCK3MyrG-CDK5R1(2-307) SHC1-2,SHC1-3MyrG-p-Y420-FYN-1 BDNF:p-5Y,S479-NTRK2homodimer:TIAM1p-5Y-NTRK2 p-5Y,S479-NTRK2 ATPp-5Y-NTRK2 GRB2:GAB1BDNF GDPNTRK2 GAB1 NTF4 BDNF BDNF KRAS FRS2 BDNF,NTF4:p-5Y-NTRK2:FRS2BDNF p-5Y-NTRK2 NTF3 homodimerp-5Y-NTRK2 p-5Y-NTRK2 GRB2-1 MyrG-p-Y419-SRC NTRK2GDP p-5Y-NTRK2 BDNF p-Y15-CDK5:p35BDNF,NTF4:p-5Y-NTRK2:GRB2:GAB1:PIK3CA:PIK3R1p21 RAS:GDPNTF4 NTF4 BDNF RHO GTPases ActivateWASPs and WAVEsBDNF BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3)BDNF NTF4 NTF3:NTRK2BDNF:p-5Y-NTRK2homodimer:p-Y15-CDK5:p35PTPN11 p-Y317-SHC1-2 PTPN11ADPp-Y15-CDK5 p-5Y-NTRK2 NTF4:NTRK2 homodimerMyrG-p-Y420-FYN-1 FRS3p-5Y-NTRK2 BDNF p-5Y-NTRK2 BDNF:p-5Y-NTRK2homodimerBDNF:p-5Y-NTRK2homodimer:CDK5:p35CDK5 PIK3CA ADPMyrG-p-Y419-SRC,(MyrG-p-Y420-FYN-1)RAC1:GDPDOCK3 NTF3:p-5Y-NTRK2homodimerp-5Y-NTRK2 p-5Y-NTRK2 BDNF GTPNTF4 GRIN2B RAC1 BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS3NTF4 BDNF:p-5Y,S479-NTRK2:p-Y829-TIAM1BDNF:p-5Y-NTRK2homodimer:MyrG-FYN-1BDNF NTF3 ATPADPBDNF PLCG1 p-5Y,S479-NTRK2 PI(3,4,5)P3BDNF,NTF4:p-5Y-NTRK2:FRS3NTF4:p-5Y-NTRK2homodimerCDK5:p35GTPSHC1-2 NTF4 homodimerNTF4 p21 RAS:GTPNTF3 BDNF MyrG-CDK5R1(2-307) BDNF,NTF4:p-5Y-NTRK2MyrG-FYN-1 PIK3CA GDPp-4Y-PLCG1ADPMyrG-p-Y420-FYN-1 BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2GTP ADPGRB2-1 NTF4 ADPSOS1 NTF4 p-Y-FRS2 ATPMyrG-CDK5R1(2-307) BDNF p-5Y-NTRK2 RAF/MAP kinasecascadeSHC1-3 p-5Y-NTRK2 PIP3 activates AKTsignalingSOS1 RAC1 FRS2SHC1-2 p-5Y-NTRK2 BDNF homodimerNRAS p-Y272-SHC1-3 MyrG-p-Y420-FYN-1 NTF4 BDNF BDNF p-5Y-NTRK2 BDNF p-Y272-SHC1-3 BDNF BDNF BDNF,NTF4:p-5Y-NTRK2:p-4Y-PLCG1BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:PTPN11BDNF p-5Y-NTRK2 FRS3 SHC1-3 p-5Y,S479-NTRK2 ATPGRIN2Bp-Y706,Y707-NTRK2p-Y829-TIAM1 NTF4 NTF4 NTF4 GAB1 MyrG-CDK5R1(2-307) p-5Y-NTRK2 ATPPI(4,5)P2TIAM1 BDNF,NTF4:p-5Y-NTRK2:PLCG1p-5Y-NTRK2 NTRK2 p-5Y-NTRK2 NTRK2 p-Y317-SHC1-2 ADPNTF4 DOCK3BDNF PIK3R1 BDNF PIK3CA:PIK3R1BDNF KRAS ATPADPADPATPGRB2-1 NTF3 PLCG1ATPRAC1:GTPBDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3):GRB2-1:SOS1p-5Y-NTRK2 BDNF PIK3R1 GDP BDNF:p-5Y-NTRK2homodimer:MyrG,p-Y420-FYN-1:p-Y1474-GRIN2BNTRK2 TIAM1BDNF:NTRK2p-Y-FRS2 NRAS HRAS p-5Y-NTRK2 BDNF:p-5Y-NTRK2homodimer:MyrG,p-Y420-FYN-1HRAS BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:GRB2-1:SOS1ATPNTRK2 NTF4 1, 1099992, 5, 6, 13, 15...899494, 18313019


NTRK2 (TRKB) belongs to the family of neurotrophin tyrosine kinase receptors, also known as NTRKs or TRKs. Besides NTRK2, the family includes NTRK1 (TRKA) and NTRK3 (TRKC). Similar to other receptor tyrosine kinases (RTKs), NTRK2 is activated by ligand binding to its extracellular domain. Ligand binding induces receptor dimerization, followed by trans-autophosphorylation of dimerized receptors on conserved tyrosine residues in the cytoplasmic region. Phosphorylated tyrosines in the intracellular domain of the receptor serve as docking sites for adapter proteins, triggering downstream signaling cascaded. Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NTF4, also known as NT-4) are two high affinity ligands for NTRK2. Neurotrophin-3 (NTF3, also known as NT-3), a high affinity ligand for NTRK3, binds to NTRK2 with low affinity and it is not clear if it the low level of activation of NTRK2 by NTF3 plays a physiologically relevant role. Nerve growth factor (NGF), a high affinity ligand for NTRK1, does not interact with NTRK2. NTRK2 activation triggers downstream RAS, PI3K, and PLCgamma signaling cascades, thought to be involved in neuronal development in both the peripheral (PNS) and central nervous system (CNS). In addition, NTRK2 plays an important, but poorly elucidated, role in long-term potentiation (LTP) and learning (reviewed by Minichiello 2009). NTRK2 may modify neuronal excitability and synaptic transmission by directly phosphorylating voltage gated channels (Rogalski et al. 2000).

<p>It was recently demonstrated that the protein tyrosine phosphatase PTPN12 negatively regulates NTRK2 signaling and neurite outgrowth. In the presence of PTPN12, NTRK2 phosphorylation at tyrosine Y816 decreases. It has not yet been demonstrated that PTPN12 acts directly to dephosphorylate Y816 (and possibly other phosphotyrosines) of NTRK2 (Ambjorn et al. 2013).<p><p>Binding of SH2D1A (SAP) to NTRK2 attenuates NTRK2 trans autophosphorylation and downstream signaling through an unknown mechanism (Lo et al. 2005).<p><p>Little is known about downregulation of NTRK2 (TRKB) receptor via ubiquitin dependent pathways (Sanchez Sanchez and Arevalo 2017). CBL, a ubiquitin ligase involved in degradation of many receptor tyrosine kinases, was shown to ubiquitinate and, unexpectedly, increase stability of NTRK2 (Pandya et al. 2014). NTRK2 undergoes ubiquitination by the TRAF6 E3 ubiquitin ligase complex. While ubiquitination by the TRAF6 complex negatively regulates NTRK2 induced AKT activation, the effect of TRAF6 mediated ubiquitination on NTRK2 protein levels has not been examined (Jadhav et al. 2008).<p><p>Downregulation of the TRKB receptor may depend on the activating ligand, with BDNF inducing more rapid ubiquitination and degradation compared to NTF4 (NT 4). NTRK2 undergoes both lysosome dependent and proteasome dependent degradation upon stimulation by BDNF, while stimulation by NTF4 may protect NTRK2 from the lysosome degradation route (Proenca et al. 2016). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 9006115
Reactome version: 65
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC Scholia
  2. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  3. Lane J, Martin T, Weeks HP, Jiang WG.; ''Structure and role of WASP and WAVE in Rho GTPase signalling in cancer.''; PubMed Europe PMC Scholia
  4. Minichiello L.; ''TrkB signalling pathways in LTP and learning.''; PubMed Europe PMC Scholia
  5. Easton JB, Moody NM, Zhu X, Middlemas DS.; ''Brain-derived neurotrophic factor induces phosphorylation of fibroblast growth factor receptor substrate 2.''; PubMed Europe PMC Scholia
  6. Jadhav T, Geetha T, Jiang J, Wooten MW.; ''Identification of a consensus site for TRAF6/p62 polyubiquitination.''; PubMed Europe PMC Scholia
  7. Pandya C, Kutiyanawalla A, Turecki G, Pillai A.; ''Glucocorticoid regulates TrkB protein levels via c-Cbl dependent ubiquitination: a decrease in c-Cbl mRNA in the prefrontal cortex of suicide subjects.''; PubMed Europe PMC Scholia
  8. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  9. Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMed Europe PMC Scholia
  10. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  11. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  12. Zeng L, Kuti M, Mujtaba S, Zhou MM.; ''Structural insights into FRS2α PTB domain recognition by neurotrophin receptor TrkB.''; PubMed Europe PMC Scholia
  13. Lo KY, Chin WH, Ng YP, Cheng AW, Cheung ZH, Ip NY.; ''SLAM-associated protein as a potential negative regulator in Trk signaling.''; PubMed Europe PMC Scholia
  14. Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC Scholia
  15. Butte MJ, Hwang PK, Mobley WC, Fletterick RJ.; ''Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors.''; PubMed Europe PMC Scholia
  16. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  17. Ambjørn M, Dubreuil V, Miozzo F, Nigon F, Møller B, Issazadeh-Navikas S, Berg J, Lees M, Sap J.; ''A loss-of-function screen for phosphatases that regulate neurite outgrowth identifies PTPN12 as a negative regulator of TrkB tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  18. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  19. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  20. Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T.; ''Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex.''; PubMed Europe PMC Scholia
  21. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  22. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  23. Sánchez-Sánchez J, Arévalo JC.; ''A Review on Ubiquitination of Neurotrophin Receptors: Facts and Perspectives.''; PubMed Europe PMC Scholia
  24. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  25. Smit L, de Vries-Smits AM, Bos JL, Borst J.; ''B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins.''; PubMed Europe PMC Scholia
  26. Proenca CC, Song M, Lee FS.; ''Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors.''; PubMed Europe PMC Scholia
  27. Rosenfeld RD, Zeni L, Haniu M, Talvenheimo J, Radka SF, Bennett L, Miller JA, Welcher AA.; ''Purification and identification of brain-derived neurotrophic factor from human serum.''; PubMed Europe PMC Scholia
  28. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  29. Robinson RC, Radziejewski C, Spraggon G, Greenwald J, Kostura MR, Burtnick LD, Stuart DI, Choe S, Jones EY.; ''The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site.''; PubMed Europe PMC Scholia
  30. Rouer E.; ''[Neuronal isoforms of Src, Fyn and Lck tyrosine kinases: A specific role for p56lckN in neuron protection].''; PubMed Europe PMC Scholia
  31. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  32. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC Scholia
  33. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  34. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  35. Rogalski SL, Appleyard SM, Pattillo A, Terman GW, Chavkin C.; ''TrkB activation by brain-derived neurotrophic factor inhibits the G protein-gated inward rectifier Kir3 by tyrosine phosphorylation of the channel.''; PubMed Europe PMC Scholia


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102037view16:24, 26 November 2018Marvin M2Ontology Term : 'PW:0000003' removed !
102036view16:24, 26 November 2018Marvin M2Ontology Term : 'kinase mediated signaling pathway' added !
101699view14:37, 1 November 2018DeSlOntology Term : 'signaling pathway' added !
101480view11:34, 1 November 2018ReactomeTeamreactome version 66
101018view21:14, 31 October 2018ReactomeTeamreactome version 65
100724view20:11, 31 October 2018ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BDNF ProteinP23560 (Uniprot-TrEMBL)
BDNF homodimerComplexR-HSA-9024931 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS2ComplexR-HSA-9031934 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS3ComplexR-HSA-9032409 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:GRB2:GAB1:PIK3CA:PIK3R1ComplexR-HSA-9028508 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:PLCG1ComplexR-HSA-9026530 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:SHC1-2,SHC1-3ComplexR-HSA-9026491 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-4Y-PLCG1ComplexR-HSA-9026576 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:GRB2-1:SOS1ComplexR-HSA-9032071 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:PTPN11ComplexR-HSA-9031982 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2ComplexR-HSA-9031960 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS3ComplexR-HSA-9032422 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3):GRB2-1:SOS1ComplexR-HSA-9028334 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3)ComplexR-HSA-9028330 (Reactome)
BDNF,NTF4:p-5Y-NTRK2ComplexR-HSA-9026521 (Reactome)
BDNF:NTRK2 homodimerComplexR-HSA-9024966 (Reactome)
BDNF:NTRK2ComplexR-HSA-9024958 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimer:TIAM1ComplexR-HSA-9033279 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimerComplexR-HSA-9032862 (Reactome)
BDNF:p-5Y,S479-NTRK2:p-Y829-TIAM1ComplexR-HSA-9033288 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:CDK5:p35ComplexR-HSA-9032842 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:DOCK3ComplexR-HSA-9032760 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:GRIN2BComplexR-HSA-9032583 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:p-Y1474-GRIN2BComplexR-HSA-9032600 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1ComplexR-HSA-9032537 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG-FYN-1ComplexR-HSA-9032501 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:p-Y15-CDK5:p35ComplexR-HSA-9032852 (Reactome)
BDNF:p-5Y-NTRK2 homodimerComplexR-HSA-9026465 (Reactome)
CDK5 ProteinQ00535 (Uniprot-TrEMBL)
CDK5:p35ComplexR-HSA-421107 (Reactome)
DAG and IP3 signalingPathwayR-HSA-1489509 (Reactome) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
DOCK3 ProteinQ8IZD9 (Uniprot-TrEMBL)
DOCK3ProteinQ8IZD9 (Uniprot-TrEMBL)
FRS2 ProteinQ8WU20 (Uniprot-TrEMBL)
FRS2ProteinQ8WU20 (Uniprot-TrEMBL)
FRS3 ProteinO43559 (Uniprot-TrEMBL)
FRS3ProteinO43559 (Uniprot-TrEMBL)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2:GAB1ComplexR-HSA-179849 (Reactome)
GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
GRIN2BProteinQ13224 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
MyrG-CDK5R1(2-307) ProteinQ15078 (Uniprot-TrEMBL)
MyrG-FYN-1 ProteinP06241-1 (Uniprot-TrEMBL)
MyrG-FYN-1ProteinP06241-1 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC,(MyrG-p-Y420-FYN-1)ComplexR-HSA-9037043 (Reactome)
MyrG-p-Y420-FYN-1 ProteinP06241-1 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NTF3 ProteinP20783 (Uniprot-TrEMBL)
NTF3 homodimerComplexR-HSA-9025070 (Reactome)
NTF3:NTRK2 homodimerComplexR-HSA-9026367 (Reactome)
NTF3:NTRK2ComplexR-HSA-9025071 (Reactome)
NTF3:p-5Y-NTRK2 homodimerComplexR-HSA-9026501 (Reactome)
NTF4 ProteinP34130 (Uniprot-TrEMBL)
NTF4 homodimerComplexR-HSA-9025082 (Reactome)
NTF4:NTRK2 homodimerComplexR-HSA-9026375 (Reactome)
NTF4:NTRK2ComplexR-HSA-9026356 (Reactome)
NTF4:p-5Y-NTRK2 homodimerComplexR-HSA-9026514 (Reactome)
NTRK2 ProteinQ16620 (Uniprot-TrEMBL)
NTRK2ProteinQ16620 (Uniprot-TrEMBL)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CA:PIK3R1ComplexR-HSA-1806218 (Reactome)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-5674631 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RHO GTPases Activate WASPs and WAVEsPathwayR-HSA-5663213 (Reactome) WASP and WAVE proteins belong to the Wiskott-Aldrich Syndrome protein family, with recessive mutations in the founding member WASP being responsible for the X-linked recessive immunodeficieny known as the Wiskott-Aldrich Syndrome. WASP proteins include WASP and WASL (N-WASP). WAVE proteins include WASF1 (WAVE1), WASF2 (WAVE2) and WASF3 (WAVE3). WASPs and WAVEs contain a VCA domain (consisting of WH2 and CA subdomains) at the C-terminus, responsible for binding to G-actin (WH2 subdomain) and the actin-associated ARP2/3 complex (CA subdomain). WASPs contain a WH1 (WASP homology 1) domain at the N-terminus, responsible for binding to WIPs (WASP-interacting proteins). A RHO GTPase binding domain (GBD) is located in the N-terminal half of WASPs and C-terminally located in WAVEs. RHO GTPases activate WASPs by disrupting the autoinhibitory interaction between the GBD and VCA domains, which allows WASPs to bind actin and the ARP2/3 complex and act as nucleation promoting factors in actin polymerization. WAVEs have the WAVE/SCAR homology domain (WHD/SHD) at the N-terminus, which binds ABI, NCKAP1, CYFIP2 and BRK1 to form the WAVE regulatory complex (WRC). Binding of the RAC1:GTP to the GBD of WAVEs most likely induces a conformational change in the WRC that allows activating phosphorylation of WAVEs by ABL1, thus enabling them to function as nucleation promoting factors in actin polymerization through binding G-actin and the ARP2/3 complex (Reviewed by Lane et al. 2014).
SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
SHC1-2,SHC1-3ComplexR-HSA-1169480 (Reactome) SHC1 isoforms p46 and p52 are found in B cells (Smit et al. 1994).
SHC1-3 ProteinP29353-3 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
TIAM1 ProteinQ13009 (Uniprot-TrEMBL)
TIAM1ProteinQ13009 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-5Y,S479-NTRK2 ProteinQ16620 (Uniprot-TrEMBL)
p-5Y-NTRK2 ProteinQ16620 (Uniprot-TrEMBL)
p-Y-FRS2 ProteinQ8WU20 (Uniprot-TrEMBL)
p-Y-FRS3 ProteinO43559 (Uniprot-TrEMBL)
p-Y1474-GRIN2B ProteinQ13224 (Uniprot-TrEMBL)
p-Y15-CDK5 ProteinQ00535 (Uniprot-TrEMBL)
p-Y15-CDK5:p35ComplexR-HSA-421098 (Reactome)
p-Y272-SHC1-3 ProteinP29353-3 (Uniprot-TrEMBL)
p-Y317-SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
p-Y706,Y707-NTRK2ProteinQ16620 (Uniprot-TrEMBL)
p-Y829-TIAM1 ProteinQ13009 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9026464 (Reactome)
ADPArrowR-HSA-9026502 (Reactome)
ADPArrowR-HSA-9026510 (Reactome)
ADPArrowR-HSA-9026579 (Reactome)
ADPArrowR-HSA-9026890 (Reactome)
ADPArrowR-HSA-9028519 (Reactome)
ADPArrowR-HSA-9028728 (Reactome)
ADPArrowR-HSA-9032426 (Reactome)
ADPArrowR-HSA-9032532 (Reactome)
ADPArrowR-HSA-9032601 (Reactome)
ADPArrowR-HSA-9032854 (Reactome)
ADPArrowR-HSA-9032863 (Reactome)
ADPArrowR-HSA-9033284 (Reactome)
ADPArrowR-HSA-9037040 (Reactome)
ATPR-HSA-9026464 (Reactome)
ATPR-HSA-9026502 (Reactome)
ATPR-HSA-9026510 (Reactome)
ATPR-HSA-9026579 (Reactome)
ATPR-HSA-9026890 (Reactome)
ATPR-HSA-9028519 (Reactome)
ATPR-HSA-9028728 (Reactome)
ATPR-HSA-9032426 (Reactome)
ATPR-HSA-9032532 (Reactome)
ATPR-HSA-9032601 (Reactome)
ATPR-HSA-9032854 (Reactome)
ATPR-HSA-9032863 (Reactome)
ATPR-HSA-9033284 (Reactome)
ATPR-HSA-9037040 (Reactome)
BDNF homodimerR-HSA-9024906 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS2ArrowR-HSA-9028730 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS2R-HSA-9028728 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS2mim-catalysisR-HSA-9028728 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS3ArrowR-HSA-9032402 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS3R-HSA-9032426 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:FRS3mim-catalysisR-HSA-9032426 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:GRB2:GAB1:PIK3CA:PIK3R1ArrowR-HSA-9028505 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:GRB2:GAB1:PIK3CA:PIK3R1mim-catalysisR-HSA-9028519 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:PLCG1ArrowR-HSA-9026531 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:PLCG1R-HSA-9026579 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:PLCG1mim-catalysisR-HSA-9026579 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:SHC1-2,SHC1-3ArrowR-HSA-9026493 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:SHC1-2,SHC1-3R-HSA-9026890 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:SHC1-2,SHC1-3mim-catalysisR-HSA-9026890 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-4Y-PLCG1ArrowR-HSA-9026579 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-4Y-PLCG1R-HSA-9026894 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:GRB2-1:SOS1ArrowR-HSA-9032073 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:GRB2-1:SOS1mim-catalysisR-HSA-9032067 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:PTPN11ArrowR-HSA-9031981 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2:PTPN11ArrowR-HSA-9032067 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2ArrowR-HSA-9028728 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2R-HSA-9031981 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS2R-HSA-9032073 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y-FRS3ArrowR-HSA-9032426 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3):GRB2-1:SOS1ArrowR-HSA-9028328 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3):GRB2-1:SOS1mim-catalysisR-HSA-9026891 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3)ArrowR-HSA-9026890 (Reactome)
BDNF,NTF4:p-5Y-NTRK2:p-Y317-SHC1-2,(p-Y272-SHC1-3)R-HSA-9028328 (Reactome)
BDNF,NTF4:p-5Y-NTRK2ArrowR-HSA-9026894 (Reactome)
BDNF,NTF4:p-5Y-NTRK2R-HSA-9026493 (Reactome)
BDNF,NTF4:p-5Y-NTRK2R-HSA-9026531 (Reactome)
BDNF,NTF4:p-5Y-NTRK2R-HSA-9028505 (Reactome)
BDNF,NTF4:p-5Y-NTRK2R-HSA-9028730 (Reactome)
BDNF,NTF4:p-5Y-NTRK2R-HSA-9032402 (Reactome)
BDNF:NTRK2 homodimerArrowR-HSA-9024967 (Reactome)
BDNF:NTRK2 homodimerR-HSA-9026464 (Reactome)
BDNF:NTRK2 homodimermim-catalysisR-HSA-9026464 (Reactome)
BDNF:NTRK2ArrowR-HSA-9024906 (Reactome)
BDNF:NTRK2R-HSA-9024967 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimer:TIAM1ArrowR-HSA-9033276 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimer:TIAM1R-HSA-9033284 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimer:TIAM1mim-catalysisR-HSA-9033284 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimerArrowR-HSA-9032863 (Reactome)
BDNF:p-5Y,S479-NTRK2 homodimerR-HSA-9033276 (Reactome)
BDNF:p-5Y,S479-NTRK2:p-Y829-TIAM1ArrowR-HSA-9033284 (Reactome)
BDNF:p-5Y,S479-NTRK2:p-Y829-TIAM1mim-catalysisR-HSA-9033292 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:CDK5:p35ArrowR-HSA-9032841 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:CDK5:p35R-HSA-9032854 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:CDK5:p35mim-catalysisR-HSA-9032854 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:DOCK3ArrowR-HSA-9032761 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:DOCK3mim-catalysisR-HSA-9032798 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:GRIN2BArrowR-HSA-9032582 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:GRIN2BR-HSA-9032601 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:GRIN2Bmim-catalysisR-HSA-9032601 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1:p-Y1474-GRIN2BArrowR-HSA-9032601 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1ArrowR-HSA-9032532 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1R-HSA-9032582 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG,p-Y420-FYN-1R-HSA-9032761 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG-FYN-1ArrowR-HSA-9032502 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG-FYN-1R-HSA-9032532 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:MyrG-FYN-1mim-catalysisR-HSA-9032532 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:p-Y15-CDK5:p35ArrowR-HSA-9032854 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:p-Y15-CDK5:p35R-HSA-9032863 (Reactome)
BDNF:p-5Y-NTRK2 homodimer:p-Y15-CDK5:p35mim-catalysisR-HSA-9032863 (Reactome)
BDNF:p-5Y-NTRK2 homodimerArrowR-HSA-9026464 (Reactome)
BDNF:p-5Y-NTRK2 homodimerR-HSA-9032502 (Reactome)
BDNF:p-5Y-NTRK2 homodimerR-HSA-9032841 (Reactome)
CDK5:p35R-HSA-9032841 (Reactome)
DOCK3R-HSA-9032761 (Reactome)
FRS2R-HSA-9028730 (Reactome)
FRS3R-HSA-9032402 (Reactome)
GDPArrowR-HSA-9026891 (Reactome)
GDPArrowR-HSA-9032067 (Reactome)
GDPArrowR-HSA-9032798 (Reactome)
GDPArrowR-HSA-9033292 (Reactome)
GRB2-1:SOS1R-HSA-9028328 (Reactome)
GRB2-1:SOS1R-HSA-9032073 (Reactome)
GRB2:GAB1R-HSA-9028505 (Reactome)
GRIN2BR-HSA-9032582 (Reactome)
GTPR-HSA-9026891 (Reactome)
GTPR-HSA-9032067 (Reactome)
GTPR-HSA-9032798 (Reactome)
GTPR-HSA-9033292 (Reactome)
MyrG-FYN-1R-HSA-9032502 (Reactome)
MyrG-p-Y419-SRC,(MyrG-p-Y420-FYN-1)mim-catalysisR-HSA-9037040 (Reactome)
NTF3 homodimerR-HSA-9025033 (Reactome)
NTF3:NTRK2 homodimerArrowR-HSA-9026366 (Reactome)
NTF3:NTRK2 homodimerR-HSA-9026502 (Reactome)
NTF3:NTRK2 homodimermim-catalysisR-HSA-9026502 (Reactome)
NTF3:NTRK2ArrowR-HSA-9025033 (Reactome)
NTF3:NTRK2R-HSA-9026366 (Reactome)
NTF3:p-5Y-NTRK2 homodimerArrowR-HSA-9026502 (Reactome)
NTF4 homodimerR-HSA-9026358 (Reactome)
NTF4:NTRK2 homodimerArrowR-HSA-9026377 (Reactome)
NTF4:NTRK2 homodimerR-HSA-9026510 (Reactome)
NTF4:NTRK2 homodimermim-catalysisR-HSA-9026510 (Reactome)
NTF4:NTRK2ArrowR-HSA-9026358 (Reactome)
NTF4:NTRK2R-HSA-9026377 (Reactome)
NTF4:p-5Y-NTRK2 homodimerArrowR-HSA-9026510 (Reactome)
NTRK2R-HSA-9024906 (Reactome)
NTRK2R-HSA-9024967 (Reactome)
NTRK2R-HSA-9025033 (Reactome)
NTRK2R-HSA-9026358 (Reactome)
NTRK2R-HSA-9026366 (Reactome)
NTRK2R-HSA-9026377 (Reactome)
NTRK2R-HSA-9037040 (Reactome)
PI(3,4,5)P3ArrowR-HSA-9028519 (Reactome)
PI(4,5)P2R-HSA-9028519 (Reactome)
PIK3CA:PIK3R1R-HSA-9028505 (Reactome)
PLCG1R-HSA-9026531 (Reactome)
PTPN11R-HSA-9031981 (Reactome)
R-HSA-9024906 (Reactome) The neurotrophic factor BDNF (brain-derived neurotrophic factor), which functions as a homodimer (Rosenfeld et al. 1995), is a ligand for the neurotrophin receptor tyrosine kinase NTRK2 (TRKB) (Soppet et al. 1991, Klein et al. 1991).
R-HSA-9024967 (Reactome) Based on studies in macaque monkeys, BDNF binding induces dimerization of the NTRK2 (TRKB) receptor (Ohira et al. 2001). The existence of preformed, BDNF-independent, dimers of NTRK2 was demonstrated when NTRK2 was overexpressed from an exogenous vector (Shen and Maruyama).
R-HSA-9025033 (Reactome) The neurotrophic factor NTF3 (neurotrophin-3), which functions as a homodimer (Butte et al. 1998), is a ligand for the neurotrophin receptor tyrosine kinase NTRK2 (TRKB) (Soppet et al. 1991).
R-HSA-9026358 (Reactome) The neurotrophic factor NTF4 (neurotrophin-4), which functions as a homodimer (Robinson et al. 1999), is a ligand for the neurotrophin receptor tyrosine kinase NTRK2 (TRKB) (Klein et al. 1992, Ip et al. 1993, Ohira et al. 2001).
R-HSA-9026366 (Reactome) Based on studies in macaque monkeys, NTF3 (neurotrophin-3) binding induces dimerization of the NTRK2 (TRKB) receptor (Ohira et al. 2001).
R-HSA-9026377 (Reactome) Based on studies in macaque monkeys, NTF4 (neurotrophin-4) binding induces dimerization of the NTRK2 (TRKB) receptor (Ohira et al. 2001).
R-HSA-9026464 (Reactome) BDNF-induced dimerization of the receptor tyrosine kinase NTRK2 (TRKB) leads to trans-autophosphorylation of NTRK2 on five evolutionarily conserved tyrosine residues in the cytoplasmic tail of NTRK2: Y516, Y702, Y706, Y707 and Y817. Phosphorylation at Y516, Y702, Y706, Y707 and Y817 was demonstrated by using a recombinant human BDNF and a recombinant rat Ntrk2. Tyrosine residues Y516, Y702, Y706, Y707 and Y817 of full-length human NTRK2 correspond to Y484, Y670, Y674, Y675 and Y785 of mature rat Ntrk2 (Y515, Y701, Y705, Y706 and Y816 of full-length rat Ntrk2), respectively (Guiton et al. 1994, McCarty and Feinstein 1999). Human NTRK2 residue Y516 corresponds to mouse Ntrk2 residue Y515, which was also shown to be phosphorylated in response to BDNF stimulation (Minichiello et al. 1998).
R-HSA-9026493 (Reactome) Autophosphorylated tyrosine Y516 of NTRK2 (corresponds to Y515 of the full-length mouse Ntrk2 and Y484 of the mature rat Ntrk2) is a docking site for SHC1 isoforms p52 (SHC1-2) and p46 (SHC1-3), which function as activators of RAS signaling (Minichiello et al. 1998, McCarthy and Feinstein 1998, McCarthy and Feinstein 1999). SHC1 is recruited to Y516 of NTRK2 in response to BDNF stimulation (Minichiello et al. 1998, McCarthy and Feinstein 1999, Yuen and Mobley 1999) and NTF4 stimulation (Minichiello et al. 1998, Yuen and Mobley 1999). Recruitment of SHC1 to NTRK2 in response to stimulation by NTF3 has not been examined.
R-HSA-9026502 (Reactome) NTF3-induced dimerization of the receptor tyrosine kinase NTRK2 (TRKB) leads to trans-autophosphorylation of NTRK2 on evolutionarily conserved tyrosine residues in the cytoplasmic tail of NTRK2. Phosphorylation of NTRK2 at Y817 and in the region containing residues Y702, Y706 and Y707 in response to NTF3 stimulation was demonstrated with recombinant human NTF3 and recombinant rat Ntrk2. Residues Y702, Y706, Y707 and Y817 of the full-length human NTRK2 correspond to residues Y670, Y674, Y675 and Y785 of the mature rat Ntrk2 (Middlemas et al. 1994). Phosphorylation at Y516 of NTRK2 has not been examined but is assumed. NTRK2 is a low affinity receptor for NTF3, and NTF3 preferentially signals through NTRK3 (TRKC) (Marsh and Palfrey 1996).
R-HSA-9026510 (Reactome) NTF4-induced dimerization of the receptor tyrosine kinase NTRK2 (TRKB), similar to BDNF-induced dimerization, leads to trans-autophosphorylation of NTRK2. NTF4-induced phosphorylation of NTRK2 on tyrosine residue Y516 was demonstrated using mouse Ntrk2 (human Y516 corresponds to Y515 of mouse Ntrk2). As the electrophoretic migration pattern of Ntrk2 phosphorylated in response to NTF4 is indistinguishable from the electrophoretic migration pattern of Ntrk2 phosphorylated in response to BDNF, and identical downstream effectors are activated, it is assumed that NTF4 induces phosphorylation of NTRK2 on five evolutionarily conserved tyrosine residues in the cytoplasmic tail of NTRK2: Y516, Y702, Y706, Y707 and Y817 (Minichiello et al. 1998).
R-HSA-9026531 (Reactome) Autophosphorylated tyrosine Y817 of NTRK2 (corresponds to Y785 of the mature rat Ntrk2) is a docking site for PLCG1 (PLCgamma1), an activator of signaling via secondary messengers DAG and IP3 (Minichiello et al. 1998, McCarthy and Feinstein 1999, Minichiello et al. 2002). PLCG1 is recruited to Y817 of NTRK2 in response to BDNF stimulation (Minichiello et al. 1998, McCarthy and Feinstein 1999) and is also recruited to NTF4-activated NTRK2 (Minichiello et al. 1998). Recruitment on PLCG1 to NTRK2 in response to stimulation by NTF3 has not been examined.
R-HSA-9026579 (Reactome) Ligand-activated NTRK2 (TRKB) phosphorylates PLCG1 (PLCgamma1). Direct phosphorylation of PLCG1 by NTF3-stimulated NTRK2 on PLCG1 tyrosine residues Y783 and Y1253 was demonstrated using rat Ntrk2 and Plcg1. Phosphorylation of Y771 of PLCG1 was indirectly inferred (Middlemas et al. 1994). While phosphorylation of tyrosine residue Y472 of PLCG1 by NTRK2 has not been examined, it is assumed based on similarity with other receptor tyrosine kinases and requirements for the catalytic activity of PLCG1.

PLCG1 signaling is activated in response to BDNF-mediated activation of the NTRK2 receptor (Eide et al. 1996, Yamada et al. 2002) and involves NTRK2-mediated phosphorylation of PLCG1 (McCarthy and Feinstein 1999, Yuen and Mobley 1999).

Activation of NTRK2 signaling by NTF4 (NT-4) also results in tyrosine phosphorylation of PLCG1 (Yuen and Mobley 1999).

R-HSA-9026890 (Reactome) Activated NTRK2 (TRKB) phosphorylates SHC1-2 (SHC1 p52) isoform at tyrosine residue Y317. This tyrosine residue corresponds to Y272 of SHC1-3 (SHC1 p46) isoform (Chan et al. 2011).
R-HSA-9026891 (Reactome) SHC1-mediated recruitment of GRB2:SOS1 to the activated NTRK2 (TRKB) receptor leads to activation of RAS signaling and downstream phosphorylation of ERK1 (MAPK3) and ERK2 (MAPK1) (Chan et al. 2001). SOS1 functions as a guanine-nucleotide exchange factor for RAS proteins, catalyzing exchange of GDP for GTP, resulting in formation of the active RAS:GTP complex (Chardin et al. 1993).
R-HSA-9026894 (Reactome) Based on the accepted model of PLCgamma1 (PLCG1) signaling, although this has not been tested in the context of the NTRK2 (TRKB) receptor-mediated activation of PLCG1, phosphorylated, active, PLCG1 dissociates from the receptor tyrosine kinase and catalyzes formation of DAG and IP3 second messengers (Carpener and Ji 1999).
R-HSA-9028328 (Reactome) NTRK2 (TRKB)-mediated activation of RAS signaling downstream of SHC1 recruitment is dependent on binding of the GRB2:SOS1 complex to tyrosine phosphorylated SHC1 (Chan et al. 2011).
R-HSA-9028505 (Reactome) Activated NTRK2 (TRKB) receptor co-immunoprecipitates with the PI3K complex (Yuen and Mobley 1999), as well as the adapter protein GAB1 which, in complex with GRB2, is involved in recruitment of the PI3K complex to some receptor tyrosine kinases (Cao et al. 2013). None of the five autophosphorylated tyrosine residues in the C-terminal tail of NTRK2 conform to the GRB2 or PIK3R1 consensus binding site. It is possible that other phosphorylated tyrosine residues of NTRK2 or additional adapter proteins are involved in PI3K recruitment.
R-HSA-9028519 (Reactome) Based on studies in mice, activated NTRK2 induces activation of PI3K/AKT signaling (Cao et al. 2013).
R-HSA-9028728 (Reactome) Activated NTRK2 (TRKB) phosphorylates FRS2 (also known as FRS2alpha or SNT) on unknown tyrosine residues (Yuen and Mobley 1999, Easton et al. 1999).
R-HSA-9028730 (Reactome) Activation of NTRK2 (TrkB) by binding to BDNF or NTF4 (NT-4) leads to phosphorylation of FRS2 (also known as SNT or FRS2alpha) (Yuen and Mobley 1999). FRS2 binds to phosphorylated tyrosine Y516 of activated NTRK2 (Zeng et al. 2014 - Y516 is mislabeled as Y512 in the paper). Human FRS2 was also shown to bind to intracellular domain of rat Ntrk2 (Dixon et al. 2006).
R-HSA-9031981 (Reactome) Protein tyrosine phosphatase PTPN11 (SHP2) binds to FRS2 (also known as FRS2alpha or STN1) upon phosphorylation of FRS2 by activated NTRK2 (TRKB) (Easton et al. 2006).
R-HSA-9032067 (Reactome) FRS2 is involved in TRKB-mediated activation of RAS signaling. The exact mechanism has not been elucidated. It is likely that SOS1, in complex with GRB2, recruited to activated NTRK2 (TRKB) receptor through phosphorylated FRS2, catalyzes guanine nucleotide exchange on RAS (HRAS, KRAS or NRAS), resulting in formation of the active RAS:GTP complex and initiation of RAS/RAF/MAPK signaling. PTPN11 (SHP2) facilitates FRS2-mediated activation of RAS downstream of NTRK2, possibly by contributing to GRB2 recruitment (Easton et al. 1999, Easton et al. 2006).
R-HSA-9032073 (Reactome) BDNF treatment induces formation of a complex between FRS2 and GRB2 and leads to activation of RAS signaling. It is assumed that SOS1 is in complex with GRB2, although this has not been experimentally verified (Easton et al. 1999).
R-HSA-9032402 (Reactome) Activated NTRK2 (TRKB) binds FRS3 (also known as FRS2beta or STN2) (Yamada et al. 2001, Dixon et al. 2006).
R-HSA-9032426 (Reactome) Activated NTRK2 (TRKB) receptor phosphorylates FRS3 (also known as FRS2beta or STN2). Downstream of NTRK1 (TRKA)-mediated recruitment and phosphorylation, phosphorylated FRS3 binds to GRB2, SHP2 (PTPN11) and CKS proteins (CKS1, also known as CKS1B, and CKS2). FRS3 binding to GRB2, PTPN11 and CKSs has not been examined in the context of NTRK2 signaling (Dixon et al. 2006).
R-HSA-9032502 (Reactome) Upon BDNF-mediated activation, FYN, a SRC family kinase, binds to the phosphorylated C-tail of NTRK2 (TRKB) (Iwasaki et al. 1998).
R-HSA-9032532 (Reactome) Upon binding to BDNF-activated NTRK2 (TRKB) receptor, autophosphorylation of FYN at tyrosine residue Y420 increases (Mizuno et al. 2003). The exact stoichiometry and involvement of other proteins is not known.
R-HSA-9032582 (Reactome) The complex of activated NTRK2 (TRKB) and activated FYN binds to the NMDA receptor complex subunit GRIN2B (also known as NR2B or GluN2B). The GRIN2A subunit of the NMDA receptor does not co-immunoprecipitate with activated FYN (Mizuno et al. 2003, Li et al. 2017). It is not clear whether FYN interacts with GRIN2B in the context of the NMDA receptor complex.
R-HSA-9032601 (Reactome) Kinase activity of FYN is needed for tyrosine phosphorylation of the GRIN2B (also known as NR2B or GluN2B) subunit of the NMDA receptor complex in response to BDNF-mediated activation of the NTRK2 (TRKB) receptor (Mizuno et al. 2003, Li et al. 2017). The exact stoichiometry of this reaction and involvement of other proteins is not known.

Based on studies in rats, phosphorylation of GRIN2B by FYN downstream of NTRK2 signaling plays an important role in long term potentiation (LTP) and spatial memory formation (Mizuno et al. 2003) as well as in spinal LTP and pain hypersensitivity after peripheral nerve injury (Li et al. 2017).

R-HSA-9032761 (Reactome) DOCK3 binds to FYN activated downstream of BDNF-triggered NTRK2 (TRKB) signaling (Namekata et al. 2010).
R-HSA-9032798 (Reactome) DOCK3 activates RAC1 and contributes to recruitment of the RAC1 effector WASF1 (WAVE1). DOCK3-mediated activation of RAC1 is involved in BDNF-induced axonal sprouting (Namekata et al. 2010).

WASF1 has recently been implicated in endocytosis of the BDNF:NTRK2 (BDNF:TRKB) complex (Xu et al. 2016).

R-HSA-9032841 (Reactome) BDNF-activated NTRK2 binds CDK5 indirectly, by interacting with p35, a non-cyclin activator of CDK5 which forms a complex with CDK5 (Cheung et al. 2007).
R-HSA-9032854 (Reactome) BDNF-activated NTRK2 (TRKB) phosphorylates CDK5 on tyrosine residue Y15, thus increasing CDK5 catalytic activity (Cheung et al. 2007).
R-HSA-9032863 (Reactome) CDK5 phosphorylates NTRK2 (TRKB) on serine residue S479 (corresponds to S478 in mouse and rat Ntrk2). CDK5-mediated phosphorylation does not affect NTRK2-mediated activation of RAS, PLCgamma or PI3K signaling (Cheung et al. 2007, Lai et al. 2012). It was originally suggested that S479 phosphorylation was needed for NTRK2-mediated activation of CDC42, which plays a role in dendritic growth (Cheung et al. 2007), but the involvement of CDC42 was later disputed (Lai et al. 2012).

CDK5 activated by chemical long-term potentiation, independently of BDNF and NTRK2, can phosphorylate intracellular NTRK2 at S479 and promote its insertion into plasma membrane (Zhao et al. 2009), but S479 phosphorylation does not significantly affect NTRK2 localization in vivo (Lai et al. 2012).

R-HSA-9033276 (Reactome) TIAM1, a guanine nucleotide exchange factor (GEF) for the RHO GTPase RAC1, binds to NTRK2 (TRKB) phosphorylated at serine residue S479 (corresponds to S478 in mice) by CDK5 (Lai et al. 2012).
R-HSA-9033284 (Reactome) Upon binding to NTRK2 (TRKB), TIAM1 is phosphorylated at tyrosine residue Y829, presumably by NTRK2, but this has not been shown directly (Lai et al. 2012).
R-HSA-9033292 (Reactome) TIAM1, activated by binding to CDK5-phosphorylated and BDNF-activated NTRK2 (TRKB), promotes guanine nucleotide exchange on RAC1, which results in formation of the active RAC1:GTP complex (Lai et al. 2012).
R-HSA-9037040 (Reactome) Activated SRC and, probably FYN, can phosphorylate NTRK2 (TRKB) on tyrosine residues Y706 and Y707 in the absence of ligand binding, thus increasing the catalytic activity of NTRK2 (Huang and McNamara 2010).
RAC1:GDPR-HSA-9032798 (Reactome)
RAC1:GDPR-HSA-9033292 (Reactome)
RAC1:GTPArrowR-HSA-9032798 (Reactome)
RAC1:GTPArrowR-HSA-9033292 (Reactome)
SHC1-2,SHC1-3R-HSA-9026493 (Reactome)
TIAM1R-HSA-9033276 (Reactome)
p-4Y-PLCG1ArrowR-HSA-9026894 (Reactome)
p-Y15-CDK5:p35ArrowR-HSA-9032863 (Reactome)
p-Y706,Y707-NTRK2ArrowR-HSA-9037040 (Reactome)
p21 RAS:GDPR-HSA-9026891 (Reactome)
p21 RAS:GDPR-HSA-9032067 (Reactome)
p21 RAS:GTPArrowR-HSA-9026891 (Reactome)
p21 RAS:GTPArrowR-HSA-9032067 (Reactome)

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