Signaling by NTRK3 (TRKC)

Stable Identifier
Homo sapiens
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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).

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).

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).

Literature References
PubMed ID Title Journal Year
9856458 Identification and characterization of novel substrates of Trk receptors in developing neurons

Zhang, Y, Qian, X, Riccio, A, Ginty, DD

Neuron 1998
8752100 Neurotrophin-3 and brain-derived neurotrophic factor activate multiple signal transduction events but are not survival factors for hippocampal pyramidal neurons

Marsh, HN, Palfrey, HC

J. Neurochem. 1996
29162704 Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation

George, B, Weide, T, Gromnitza, S, Lepa, C, Pavenstädt, H, Schwab, A

FASEB J. 2018
27654855 Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer

Kim, HS, Jin, W, Kim, MS, Seo, J, Jeong, J, Kim, SJ

Sci Rep 2016
25385546 Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis

Zhang, P, Craig, AM, Elegheert, J, Nakagawa, T, Stoker, AW, Aricescu, AR, Jones, EY, Lu, W, Coles, CH, Mitakidis, N

Nat Commun 2014
12173038 ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation

Garnett, MJ, Tognon, CE, Deal, C, Morrison, KB, Sorensen, PH

Oncogene 2002
14668342 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

Tognon, CE, Martin, MJ, Jin, W, Sorensen, PH, Lannon, CL, Kim, SJ

J. Biol. Chem. 2004
10486198 Early BDNF, NT-3, and NT-4 signaling events

Yuen, EC, Mobley, WC

Exp. Neurol. 1999
11520916 Neurotrophins: roles in neuronal development and function

Reichardt, LF, Huang, EJ

Annu. Rev. Neurosci. 2001
8621434 TrkC isoforms with inserts in the kinase domain show impaired signaling responses

Parada, LF, Stephens, RM, Tsoulfas, P, Kaplan, DR

J. Biol. Chem. 1996
19573017 Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC

Bixby, JL, Beltran, PJ, Hower, AE

J. Neurochem. 2009
17686986 The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigm

Cabrera, JR, Bouzas-Rodriguez, J, Bordeaux, MC, Tauszig-Delamasure, S, Mehlen, P, Yu, LY, Guix, C, Arumäe, U, Mermet-Bouvier, C

Proc. Natl. Acad. Sci. U.S.A. 2007
17991742 c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway

Park, Y, Jin, W, Lee, HD, Yun, C, Jeong, J, Kim, SJ

J. Biol. Chem. 2008
24491805 Developmental co-expression and functional redundancy of tyrosine phosphatases with neurotrophin receptors in developing sensory neurons

Schmidt, F, Stoker, AW, Tchetchelnitski, V, van den Eijnden, M

Int. J. Dev. Neurosci. 2014
11751416 The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation

Kay, R, Kenward, E, Sorensen, PH, Tognon, C, Garnett, M, Morrison, K

Cancer Res. 2001
12532410 Expression of PTPRO during mouse development suggests involvement in axonogenesis and differentiation of NT-3 and NGF-dependent neurons

Masters, BA, Bixby, JL, Beltran, PJ

J. Comp. Neurol. 2003
24034695 The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment

Mehlen, P, Coelho-Aguiar, JM, Arumäe, U, Lefebvre, J, Tulasne, D, Le Douarin, N, Llambi, F, Ichim, G, Jarrosson-Wuilleme, L, Genevois, AL, Tauszig-Delamasure, S, Yu, LY, Ménard, M, Dupin, E

Mol. Cell 2013
9078261 Analysis of mitogen-activated protein kinase activation by naturally occurring splice variants of TrkC, the receptor for neurotrophin-3

Williams, AG, Gunn-Moore, FJ, Tavaré, JM

Biochem. J. 1997
1653651 trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3

Barbacid, M, Klein, R, Lamballe, F

Cell 1991
17967490 PTPsigma binds and dephosphorylates neurotrophin receptors and can suppress NGF-dependent neurite outgrowth from sensory neurons

Nixon, J, Murray, S, Wallace, A, Stoker, A, Lee, S, Faux, C, Hawadle, M

Biochim. Biophys. Acta 2007
21262467 Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex

Craig, AM, Murphy, TH, Takahashi, H, Arstikaitis, P, Wang, YT, Bartlett, TE, Prasad, T

Neuron 2011
7961713 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

Rosenfeld, R, Wen, J, Philo, J, Welcher, A, Arakawa, T, Talvenheimo, J

J. Biol. Chem. 1994
25196463 Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease

Iyer, R, Goldmuntz, E, Simpson, AM, Brodeur, GM, Latney, B, Werner, P, Paluru, P

Hum. Mutat. 2014
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