Signaling by NTRK3 (TRKC) (Homo sapiens)

From WikiPathways

Jump to: navigation, search
1-3, 8-11, 13...9, 11, 21, 3750393339cytosolmitochondrial outer membraneplasma membranemitochondrial inner membranePIK3R1 NTF3 homodimerNTRK3(496-641):NELFBp-Y317-SHC1-2 NTRK3(496-641)SOS1 MyrG-p-Y419-SRC GTPNTF3 NTF3 p-4Y-PLCG1NTF3 NTF3 p-5Y-NTRK3 NTF3 NTF3 NTRK3(642-839)NTF3:NTRK3 homodimerADPNTF3 ADPNTF3 unidentified caspaseNRAS p-Y317-SHC1-2 p-5Y-NTRK3 NTF3:p-5Y-NTRK3homodimer:PI3KMyrG-p-Y419-SRC PTPRO NTF3:p-5Y-NTRK3homodimer:p-Y-SHC1:GRB2:SOS1p-5Y-NTRK3 BAXp-5Y-NTRK3 NRAS RAF/MAP kinasecascadeNTF3 NTF3 PIP3 activates AKTsignalingMyrG-p-Y419-SRC SOS1 ATPGTP IRS1 HRAS PLCG1 p-5Y-NTRK3 MyrG-SRCIntrinsic Pathwayfor ApoptosisNTF3:p-5Y-NTRK3homodimer:MyrG-p-Y419-SRCNTRK3 NTRK3(496-641):NELFBMyrG-SRC p-5Y-NTRK3 p-4Y-PLCG1 p-Y272-SHC1-3 p-5Y-NTRK3 SHC1-3 NTF3 ADPp-5Y-NTRK3 PIK3CA NTF3:p-5Y-NTKR3homodimer:MyrG-SRCGRB2-1:SOS1HRAS Protein-proteininteractions atsynapsesNTF3 KRAS PTPRS BAXATPKRAS PIK3CA NTRK3(496-641) DAG and IP3signalingGDPNTF3:p-5Y-NTRK3homodimer(NTF3:p-5Y-NTRK3homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC):IRS1IRS1 NTF3:p-5Y-NTRK3homodimer:p-4Y-PLCG1p21 RAS:GTP(NTF3:p-5Y-NTRK3homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)NTF3:p-5Y-NTRK3homodimer:p-Y-SHC1PI(3,4,5)P3SHC1-2 PiNTRK3(496-641) NELFB NTF3 NELFBp21 RAS:GDPPI(4,5)P2SHC1-2,SHC1-3NTRK3(32-495)SHC1-3 p-5Y-NTRK3 NTF3:p-5Y-NTRK3homodimer:SHC1PIK3R1 NTF3 p-5Y-NTRK3 (PTPRO,PTPRS)NTF3:p-5Y-NTRK3homodimer:PLCG1H2ONTRK3p-5Y-NTRK3 MyrG-p-Y419-SRC ATPSHC1-2 PLCG1NELFB NTF3:p-5Y-NTRK3homodimer:MyrG-p-Y419-SRC,(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)GRB2-1 IRS1PIK3CA:PIK3R1p-Y272-SHC1-3 GDP GRB2-1 p-5Y-NTRK3 394-6, 12, 14...29, 403530, 32, 4620, 36, 4531, 517


NTRK3 (TRKC) belongs to the family of neurotrophin receptor tyrosine kinases, which also includes NTRK1 (TRKA) and NTRK2 (TRKB). Neurotrophin-3 (NTF3, also known as NT-3) is the ligand for NTRK3. Similar to other NTRK receptors and receptor tyrosine kinases in general, ligand binding induces receptor dimerization followed by trans-autophosphorylation on conserved tyrosines in the intracellular (cytoplasmic) domain of the receptor (Lamballe et al. 1991, Philo et al. 1994, Tsoulfas et al. 1996, Yuen and Mobley 1999, Werner et al. 2014). These conserved tyrosines serve as docking sites for adaptor proteins that trigger downstream signaling cascades. Signaling through PLCG1 (Marsh and Palfrey 1996, Yuen and Mobley 1999, Huang and Reichardt 2001), PI3K (Yuen and Mobley 1999, Tognon et al. 2001, Huang and Reichardt 2001, Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008) and RAS (Marsh and Palfrey 1996, Gunn-Moore et al. 1997, Yuen and Mobley 1999, Gromnitza et al. 2018), downstream of activated NTRK3, regulates cell survival, proliferation and motility.

In the absence of its ligand, NTRK3 functions as a dependence receptor and triggers BAX and CASP9-dependent cell death (Tauszig-Delamasure et al. 2007, Ichim et al. 2013).<p>NTRK3 was reported to activate STAT3 through JAK2, but the exact mechanism has not been elucidated (Kim et al. 2016). NTRK3 was reported to interact with the adaptor protein SH2B2, but the biological role of this interaction has not been determined (Qian et al. 1998).<p>Receptor protein tyrosine phosphatases PTPRO and PTPRS (PTPsigma) negatively regulate NTRK3 signaling by dephosphorylating NTRK3 (Beltran et al. 2003, Faux et al. 2007, Hower et al. 2009, Tchetchelnitski et al. 2014). In addition to dephosphorylation of NTRK3 in-cis, the extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 9034015
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms



View all...
  1. Hower AE, Beltran PJ, Bixby JL.; ''Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC.''; PubMed Europe PMC
  2. Tsoulfas P, Stephens RM, Kaplan DR, Parada LF.; ''TrkC isoforms with inserts in the kinase domain show impaired signaling responses.''; PubMed Europe PMC
  3. Faux C, Hawadle M, Nixon J, Wallace A, Lee S, Murray S, Stoker A.; ''PTPsigma binds and dephosphorylates neurotrophin receptors and can suppress NGF-dependent neurite outgrowth from sensory neurons.''; PubMed Europe PMC
  4. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC
  5. 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
  6. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC
  7. 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
  8. Lamballe F, Klein R, Barbacid M.; ''trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.''; PubMed Europe PMC
  9. Yuen EC, Mobley WC.; ''Early BDNF, NT-3, and NT-4 signaling events.''; PubMed Europe PMC
  10. Gromnitza S, Lepa C, Weide T, Schwab A, Pavenstädt H, George B.; ''Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation.''; PubMed Europe PMC
  11. Huang EJ, Reichardt LF.; ''Neurotrophins: roles in neuronal development and function.''; PubMed Europe PMC
  12. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC
  13. Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH, Craig AM.; ''Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex.''; PubMed Europe PMC
  14. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC
  15. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC
  16. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC
  17. Tognon C, Garnett M, Kenward E, Kay R, Morrison K, Sorensen PH.; ''The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.''; PubMed Europe PMC
  18. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC
  19. Kim MS, Jeong J, Seo J, Kim HS, Kim SJ, Jin W.; ''Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.''; PubMed Europe PMC
  20. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC
  21. Urfer R, Tsoulfas P, O'Connell L, Shelton DL, Parada LF, Presta LG.; ''An immunoglobulin-like domain determines the specificity of neurotrophin receptors.''; PubMed Europe PMC
  22. Beltran PJ, Bixby JL, Masters BA.; ''Expression of PTPRO during mouse development suggests involvement in axonogenesis and differentiation of NT-3 and NGF-dependent neurons.''; PubMed Europe PMC
  23. Tchetchelnitski V, van den Eijnden M, Schmidt F, Stoker AW.; ''Developmental co-expression and functional redundancy of tyrosine phosphatases with neurotrophin receptors in developing sensory neurons.''; PubMed Europe PMC
  24. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC
  25. Morrison KB, Tognon CE, Garnett MJ, Deal C, Sorensen PH.; ''ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.''; PubMed Europe PMC
  26. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC
  27. Gunn-Moore FJ, Williams AG, Tavaré JM.; ''Analysis of mitogen-activated protein kinase activation by naturally occurring splice variants of TrkC, the receptor for neurotrophin-3.''; PubMed Europe PMC
  28. Tauszig-Delamasure S, Yu LY, Cabrera JR, Bouzas-Rodriguez J, Mermet-Bouvier C, Guix C, Bordeaux MC, Arumäe U, Mehlen P.; ''The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm.''; PubMed Europe PMC
  29. 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
  30. Dalva MB, McClelland AC, Kayser MS.; ''Cell adhesion molecules: signalling functions at the synapse.''; PubMed Europe PMC
  31. 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
  32. Südhof TC.; ''Neuroligins and neurexins link synaptic function to cognitive disease.''; PubMed Europe PMC
  33. Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMed Europe PMC
  34. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC
  35. Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMed Europe PMC
  36. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC
  37. Werner P, Paluru P, Simpson AM, Latney B, Iyer R, Brodeur GM, Goldmuntz E.; ''Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease.''; PubMed Europe PMC
  38. Qian X, Riccio A, Zhang Y, Ginty DD.; ''Identification and characterization of novel substrates of Trk receptors in developing neurons.''; PubMed Europe PMC
  39. Jin W, Yun C, Jeong J, Park Y, Lee HD, Kim SJ.; ''c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.''; PubMed Europe PMC
  40. 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
  41. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC
  42. Ichim G, Genevois AL, Ménard M, Yu LY, Coelho-Aguiar JM, Llambi F, Jarrosson-Wuilleme L, Lefebvre J, Tulasne D, Dupin E, Le Douarin N, Arumäe U, Tauszig-Delamasure S, Mehlen P.; ''The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment.''; PubMed Europe PMC
  43. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC
  44. Marsh HN, Palfrey HC.; ''Neurotrophin-3 and brain-derived neurotrophic factor activate multiple signal transduction events but are not survival factors for hippocampal pyramidal neurons.''; PubMed Europe PMC
  45. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC
  46. Dean C, Dresbach T.; ''Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function.''; PubMed Europe PMC
  47. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC
  48. Coles CH, Mitakidis N, Zhang P, Elegheert J, Lu W, Stoker AW, Nakagawa T, Craig AM, Jones EY, Aricescu AR.; ''Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis.''; PubMed Europe PMC
  49. Lannon CL, Martin MJ, Tognon CE, Jin W, Kim SJ, Sorensen PH.; ''A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.''; PubMed Europe PMC
  50. Philo J, Talvenheimo J, Wen J, Rosenfeld R, Welcher A, Arakawa T.; ''Interactions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and the NT-3.BDNF heterodimer with the extracellular domains of the TrkB and TrkC receptors.''; PubMed Europe PMC
  51. 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


View all...
102020view15:53, 26 November 2018Marvin M2Ontology Term : 'PW:0000003' removed !
102019view15:53, 26 November 2018Marvin M2Ontology Term : 'kinase mediated signaling pathway' added !
101675view13:55, 1 November 2018DeSlOntology Term : 'signaling pathway' added !
101612view11:48, 1 November 2018ReactomeTeamreactome version 66
101196view21:39, 31 October 2018ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC):IRS1ComplexR-HSA-9603435 (Reactome)
(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)ComplexR-HSA-9603433 (Reactome)
(PTPRO,PTPRS)ComplexR-HSA-9603724 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BAXProteinQ07812 (Uniprot-TrEMBL)
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.
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1ProteinP35568 (Uniprot-TrEMBL)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

KRAS ProteinP01116 (Uniprot-TrEMBL)
MyrG-SRC ProteinP12931 (Uniprot-TrEMBL)
MyrG-SRCProteinP12931 (Uniprot-TrEMBL)
MyrG-p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL)
NELFB ProteinQ8WX92 (Uniprot-TrEMBL)
NELFBProteinQ8WX92 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NTF3 ProteinP20783 (Uniprot-TrEMBL)
NTF3 homodimerComplexR-HSA-9025070 (Reactome)
NTF3:NTRK3 homodimerComplexR-HSA-9034025 (Reactome)
NTF3:p-5Y-NTKR3 homodimer:MyrG-SRCComplexR-HSA-9603421 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC,(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)ComplexR-HSA-9603446 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRCComplexR-HSA-9603427 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PI3KComplexR-HSA-9603404 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PLCG1ComplexR-HSA-9034798 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:SHC1ComplexR-HSA-9034865 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-4Y-PLCG1ComplexR-HSA-9034820 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1:GRB2:SOS1ComplexR-HSA-9036947 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1ComplexR-HSA-9034877 (Reactome)
NTF3:p-5Y-NTRK3 homodimerComplexR-HSA-9034727 (Reactome)
NTRK3 ProteinQ16288 (Uniprot-TrEMBL)
NTRK3(32-495)ProteinQ16288 (Uniprot-TrEMBL)
NTRK3(496-641) ProteinQ16288 (Uniprot-TrEMBL)
NTRK3(496-641):NELFBComplexR-HSA-9603547 (Reactome)
NTRK3(496-641):NELFBComplexR-HSA-9603556 (Reactome)
NTRK3(496-641)ProteinQ16288 (Uniprot-TrEMBL)
NTRK3(642-839)ProteinQ16288 (Uniprot-TrEMBL)
NTRK3ProteinQ16288 (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)
PTPRO ProteinQ16827 (Uniprot-TrEMBL)
PTPRS ProteinQ13332 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)

interactions at

PathwayR-HSA-6794362 (Reactome) Synapses constitute highly specialized sites of asymmetric cell-cell adhesion and intercellular communication. Its formation involves the recruitment of presynaptic and postsynaptic molecules at newly formed contacts. Synapse assembly and maintenance invokes heterophilic presynaptic and postsynaptic transmembrane proteins that bind each other in the extracellular space and recruit additional proteins via their intracellular domains. Members of the cadherin and immunoglobulin (Ig) superfamilies are thought to mediate this function. Several molecules, including synaptic cell-adhesion molecule (SynCAM), N-cadherin, neural cell-adhesion molecule (NCAM), Eph receptor tyrosine kinases, and neuroligins and neurexins, have been implicated in synapse formation and maintenance (Dean & Dresbach 2006, Craig et al. 2006, Craig & Kang 2007, Sudhof 2008).
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).
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)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-5Y-NTRK3 ProteinQ16288 (Uniprot-TrEMBL)
p-Y272-SHC1-3 ProteinP29353-3 (Uniprot-TrEMBL)
p-Y317-SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
unidentified caspaseR-HSA-351835 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC):IRS1ArrowR-HSA-9603437 (Reactome)
(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)R-HSA-9603437 (Reactome)
(PTPRO,PTPRS)mim-catalysisR-HSA-9603719 (Reactome)
ADPArrowR-HSA-9034714 (Reactome)
ADPArrowR-HSA-9034814 (Reactome)
ADPArrowR-HSA-9034875 (Reactome)
ADPArrowR-HSA-9603420 (Reactome)
ADPArrowR-HSA-9603445 (Reactome)
ATPR-HSA-9034714 (Reactome)
ATPR-HSA-9034814 (Reactome)
ATPR-HSA-9034875 (Reactome)
ATPR-HSA-9603420 (Reactome)
ATPR-HSA-9603445 (Reactome)
BAXArrowR-HSA-9603598 (Reactome)
BAXR-HSA-9603598 (Reactome)
GDPArrowR-HSA-9036970 (Reactome)
GRB2-1:SOS1R-HSA-9036949 (Reactome)
GTPR-HSA-9036970 (Reactome)
H2OR-HSA-9603719 (Reactome)
IRS1R-HSA-9603437 (Reactome)
MyrG-SRCR-HSA-9603419 (Reactome)
NELFBR-HSA-9603548 (Reactome)
NTF3 homodimerR-HSA-9034016 (Reactome)
NTF3:NTRK3 homodimerArrowR-HSA-9034016 (Reactome)
NTF3:NTRK3 homodimerArrowR-HSA-9603719 (Reactome)
NTF3:NTRK3 homodimerR-HSA-9034714 (Reactome)
NTF3:NTRK3 homodimermim-catalysisR-HSA-9034714 (Reactome)
NTF3:p-5Y-NTKR3 homodimer:MyrG-SRCArrowR-HSA-9603419 (Reactome)
NTF3:p-5Y-NTKR3 homodimer:MyrG-SRCR-HSA-9603420 (Reactome)
NTF3:p-5Y-NTKR3 homodimer:MyrG-SRCmim-catalysisR-HSA-9603420 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC,(NTF3:p-5Y-NTRK3 homodimer,NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRC)ArrowR-HSA-9603445 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:MyrG-p-Y419-SRCArrowR-HSA-9603420 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PI3KArrowR-HSA-9603407 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PI3Kmim-catalysisR-HSA-9603445 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PLCG1ArrowR-HSA-9034796 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PLCG1R-HSA-9034814 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:PLCG1mim-catalysisR-HSA-9034814 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:SHC1ArrowR-HSA-9034862 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:SHC1R-HSA-9034875 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:SHC1mim-catalysisR-HSA-9034875 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-4Y-PLCG1ArrowR-HSA-9034814 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-4Y-PLCG1R-HSA-9034855 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1:GRB2:SOS1ArrowR-HSA-9036949 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1:GRB2:SOS1ArrowR-HSA-9036970 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1ArrowR-HSA-9034875 (Reactome)
NTF3:p-5Y-NTRK3 homodimer:p-Y-SHC1R-HSA-9036949 (Reactome)
NTF3:p-5Y-NTRK3 homodimerArrowR-HSA-9034714 (Reactome)
NTF3:p-5Y-NTRK3 homodimerArrowR-HSA-9034855 (Reactome)
NTF3:p-5Y-NTRK3 homodimerR-HSA-9034796 (Reactome)
NTF3:p-5Y-NTRK3 homodimerR-HSA-9034862 (Reactome)
NTF3:p-5Y-NTRK3 homodimerR-HSA-9603407 (Reactome)
NTF3:p-5Y-NTRK3 homodimerR-HSA-9603419 (Reactome)
NTF3:p-5Y-NTRK3 homodimerR-HSA-9603719 (Reactome)
NTRK3(32-495)ArrowR-HSA-9603534 (Reactome)
NTRK3(496-641):NELFBArrowR-HSA-9603548 (Reactome)
NTRK3(496-641):NELFBArrowR-HSA-9603554 (Reactome)
NTRK3(496-641):NELFBArrowR-HSA-9603598 (Reactome)
NTRK3(496-641):NELFBR-HSA-9603554 (Reactome)
NTRK3(496-641)ArrowR-HSA-9603534 (Reactome)
NTRK3(496-641)R-HSA-9603548 (Reactome)
NTRK3(642-839)ArrowR-HSA-9603534 (Reactome)
NTRK3R-HSA-9034016 (Reactome)
NTRK3R-HSA-9603534 (Reactome)
PI(3,4,5)P3ArrowR-HSA-9603445 (Reactome)
PI(4,5)P2R-HSA-9603445 (Reactome)
PIK3CA:PIK3R1R-HSA-9603407 (Reactome)
PLCG1R-HSA-9034796 (Reactome)
PiArrowR-HSA-9603719 (Reactome)
R-HSA-9034016 (Reactome) Neurtrophin-3 (NTF3, also known as NT-3) is the main ligand for the neuronal receptor tyrosine kinase NTRK3 (TRKC) (Lamballe et al. 1991). NTRK3 is not activated by other member of the neurotrophin family (NGF, BDNF and NTF4) (Lamballe et al. 1991, Ip et al. 1993). Binding to the NTF3 homodimer induces dimerization of the NTRK3 (TRKC) receptor, so that the stoichiometry of the ligand:receptor complex is 2:2 (Philo et al. 1994). In the study by Philo et al., a recombinant human NTF3 was used with a recombinant extracellular region of NTRK3, but the origin of NTRK3 was not specified.
R-HSA-9034714 (Reactome) NTRK3 (TRKC), activated by NTF3 binding, trans-autophosphorylates on tyrosine residues in the intracellular domain (Urfer et al. 1995, Yuen and Mobley 1999, Huang and Reichardt 2001). Tyrosine residue Y516 of NTRK3 was directly shown to be autophosphorylated (Werner et al. 2014), while tyrosine residues Y705, Y709, Y710 and Y834 are predicted to be phosphorylated based on sequence similarity with NTRK2 (TRKB).
R-HSA-9034796 (Reactome) Upon activation by NTF3 (NT-3), autophosphorylated NTRK3 (TRKC) binds Phospholipase C gamma1 (PLCG1) (Yuen and Mobley 1999, Huang and Reichardt 2001).
R-HSA-9034814 (Reactome) Kinase activity of NTRK3 (TRKC) is needed for tyrosine phosphorylation and activation of PLCG1 in response to NTF3 (NT-3) (Guiton et al. 1995, Marsh and Palfrey 1996). NTRK3-mediated phosphorylation sites on PLCG1 have not been determined but are predicted to involve four tyrosine residues whose phosphorylation is known to be required for the phospholipase activity of PLCG1: Y472, Y771, Y783 and Y1253.
R-HSA-9034855 (Reactome) Based on the accepted model of PLCgamma1 (PLCG1) signaling, although this has not been tested in the context of the NTRK3 (TRKC) receptor-mediated activation of PLCG1, phosphorylated, active, PLCG1 dissociates from the receptor tyrosine kinase and catalyzes formation of DAG and IP3 second messengers (Carpenter and Ji 1999). Activation of rat Ntrk3 by human NTF3 (NT-3) is known to result in tyrosine phosphorylation of rat Plcg1 and activation of DAG and IP3 signaling (Marsh and Palfrey 1996).
R-HSA-9034862 (Reactome) NTRK3, activated by NTF3 (NT-3), binds SHC1 isoforms p52 (SHC1-2) and p46 (SHC1-3), which function as activators of RAS signaling (Yuen and Mobley 1999).
R-HSA-9034875 (Reactome) NTRK3 (TRKC), activated by NTF3 (NT-3), phosphorylates the adaptor protein SHC1 on unknown tyrosine residue(s) (Gunn-Moore et al. 1997, Yuen and Mobley 1999).
R-HSA-9036949 (Reactome) SHC1, phosphorylated by NTRK3 (TRKC), binds GRB2. Based on studies of NTRK1 (TRKA) and NTRK2 (TRKB2) and evidence that RAS signaling is activated downstream of NTRK3 (Gunn-Moore et al. 1997, Yuen and Mobley 1999), GRB2 is shown in complex with RAS guanine nucleotide exchange factor SOS1.
R-HSA-9036970 (Reactome) Stimulation of NTRK3 (TRKC) by recombinant human NTF3 (NT-3) increases the amount of GTP-bound RAS (Marsh and Palfrey 1996). Activation of RAS targets MAPK3 (ERK1) and MAPK1 (ERK2) was shown to depend on SHC1-mediated recruitment of GRB2 to activated NTRK3 (Gunn-Moore et al. 1997, Yuen and Mobley 1999).
R-HSA-9603407 (Reactome) The PI3K complex, composed of the catalytic subunit PIK3CA and the regulatory subunit PIK3R1, co-immunoprecipitates with activated NTRK3. It is uncertain whether the interaction between NTRK3 and PI3K is direct or if adaptor protein(s) are involved (Yuen and Mobley 1999).
R-HSA-9603419 (Reactome) Endogenous SRC binds to endogenous, activated, NTRK3 (TRKC) in both human and mouse cells (Jin et al. 2008)
R-HSA-9603420 (Reactome) Binding of SRC to activated NTRK3 (TRKC) promotes activating SRC autophosphorylation (Jin et al. 2008).
R-HSA-9603437 (Reactome) Activated wild-type NTRK3 (TRKC), as well as constitutively active ETV6-NTRK3 oncogene, a product of translocation between ETV6 and NTRK3 gene loci in congenital fibrosarcoma and cellular mesoblastic nephroma, are able to bind to adaptor protein IRS1 (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008). Binding of IRS1 to NTRK3 is enhanced in the presence of SRC (Jin et al. 2008).
R-HSA-9603445 (Reactome) Activation of PI3K signaling downstream of NTRK3 (TRKC) is evident from PI3K-dependent activating phosphorylation of AKT in response to NTRK3 activity. SRC and IRS1 contribute to NTRK3-mediated induction of PI3K activity, but the exact mechanism is not known (Tognon et al. 2001, Jin et al. 2008).
R-HSA-9603534 (Reactome) In the absence of ligand, NTRK3 (TRKC) is cleaved by an unknown caspase. CASP3 (caspase-3) cleaves NTRK3 in vitro, but CASP3 inhibitors do not prevent NTRK3 cleavage in live cells. CASP8 (caspase-8) is unable to cleave NTRK3 in vitro. A general caspase inhibitor prevents NTRK3 cleavage in live cells (Tauszig-Delamasure et al. 2007).
R-HSA-9603548 (Reactome) NTRK3(496-641), the NTRK3 (TRKC) killer fragment (KF) binds to NELFB in the cytosol. NELFB (COBRA1) is known as a negative regulator of transcriptional elongation and a BRCA1 co-factor. NELFB is predominantly nuclear but is also found outside of the nucleus (Ichim et al. 2013).
R-HSA-9603554 (Reactome) The complex of the NTRK3 (TRKC) killer fragment (KF) and NELFB (COBRA1) translocates to the mitochondrial outer membrane (Ichim et al. 2013).
R-HSA-9603598 (Reactome) The complex of NTRK3 (TRKC) killer fragment (KF) and NELFB (COBRA1) stimulates BAX activation through an unknown mechanism. This is followed by BAX-dependent cytochrome C release and apoptosome-dependent cell death (Ichim et al. 2013).
R-HSA-9603719 (Reactome) Receptor protein tyrosine phosphatases PTPRO and PTPRS (PTPsigma) are co-expressed with NTRK3 (TRKC) in a large portion of NTRK3 positive neurons. Recombinant PTPRO (Beltran et al. 2003, Hower et al. 2009, Tchetchelnitski et al. 2014) and PTPRS (Faux et al. 2007, Tchetchelnitski et al. 2014) are both able to bind NTRK3 and promote NTRK3 dephosphorylation, thus attenuating NTRK3 signaling. The precise mechanism has not been elucidated.

In addition to interaction between PTPRS and NTRK3 in-cis, extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014).

SHC1-2,SHC1-3R-HSA-9034862 (Reactome)
p-4Y-PLCG1ArrowR-HSA-9034855 (Reactome)
p21 RAS:GDPR-HSA-9036970 (Reactome)
p21 RAS:GTPArrowR-HSA-9036970 (Reactome)
unidentified caspasemim-catalysisR-HSA-9603534 (Reactome)

Personal tools