Trk Receptors: Roles in Neuronal Signal Transduction

Abstract

Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Binding of mature BDNF (mBDNF) to TrkB triggers tyrosine phosphorylation in its cytoplasmic domain, leading to activation of at least three signaling pathways: MEK-MAPK, phosphatidylinositol-3-kinase (PI-3-K) and phospholipase C-g (PLC-g) (Kaplan and Miller, 2000;Chao, 2003;Huang and Reichardt, 2003). The majority of BDNF-induced functions have been attributed to signaling through TrkB.…”

Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

“…BDNF activates not only the PI3-K/Akt, but also other major signaling pathways [28]. To establish whether IL-1β affects BDNF signaling in general, we examined the influence of the cytokine on the activation of the Ras/MAPK and the PLCγ/PKC pathways.…”

“…BDNF, a major trophic factor in the CNS, is critical for the development and survival of certain neuronal populations. In addition to protecting neurons from damage caused by insults of various kinds, BDNF also modulates synaptic transmission and plays a role in synaptic plasticity, including LTP and certain forms of learning and memory processes in animal models [7,21,28,44,52,80]. Accordingly, conditions that may interfere with BDNF signaling may affect a variety of downstream neuronal functions and may contribute to neurodegenerative diseases, including Alzheimer's disease (AD) [13].…”

Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death

“…BDNF binds to the tyrosine kinase receptor TrkB and initiates multiple signaling cascades, including mitogen-activated protein kinase (MAPK) pathway, phosphatidyl-inositide 3-kinase (PI3K) pathway, and phospholipase C-gamma (PLC-g) pathways. 4,5 BDNF promotes survival of NB cells and protects them from chemotherapy. 6,7 Our previous studies show that TrkB activation by BDNF protects NB cells from chemotherapy via activation of the PI3K pathway.…”