Mechanisms of neurotrophin trafficking via Trk receptors

Abstract

In neurons, long-distance communication between axon terminals and cell bodies is a critical determinant in establishing and maintaining neural circuits. Neurotrophins are soluble factors secreted by post-synaptic target tissues that retrogradely control axon and dendrite growth, survival, and synaptogenesis of innervating neurons. Neurotrophins bind Trk receptor tyrosine kinases in axon terminals to promote endocytosis of ligand-bound phosphorylated receptors into signaling endosomes. Trk-harboring endosomes function locally in axons to acutely promote growth events, and can also be retrogradely transported long-distances to remote cell bodies and dendrites to stimulate cytoplasmic and transcriptional signaling necessary for neuron survival, morphogenesis, and maturation. Neuronal responsiveness to target-derived neurotrophins also requires the precise axonal targeting of newly synthesized Trk receptors. Recent studies suggest that anterograde delivery of Trk receptors is regulated by retrograde neurotrophin signaling. In this review, we summarize current knowledge on the functions and mechanisms of retrograde trafficking of Trk signaling endosomes, and highlight recent discoveries on the forward trafficking of nascent receptors.

PAG1 directs SRC-family kinase intracellular localization to mediate receptor tyrosine kinase-induced differentiation

“…Receptor signaling from endosomal membranes after endocytosis influences temporal and spatial regulation of signaling effector pathways downstream from receptor activation (Bergeron et al, 2016;Irannejad et al, 2015). The presence of activated FYN in the lumen of MVBs, together with its role in neuronal differentiation noted above, suggests that FYN is potentially another important component of signaling endosomes in neurons, which play an important role in nervous system development and neurodegenerative disease (Bergeron et al, 2016;Chen and Mobley, 2019;Cosker and Segal, 2014;Harrington and Ginty, 2013;Marlin and Li, 2015;Scott-Solomon and Kuruvilla, 2018). Signaling endosomes containing NGF and TRKA have been identified in neurons to be Rab7 positive MVBs (Von Bartheld and Altick, 2011;Harrington and Ginty, 2013).…”

Prenylation of axonally translated proteins controls NGF-dependent axon growth

“…NGF mediates growth of sympathetic axons by binding to TrkA receptors in axons and promoting the formation of NGF-TrkA signaling endosomes that signal locally or are retrogradely trafficked to cell bodies (Scott-Solomon and Kuruvilla, 2018). Several protein effectors involved in NGF-mediated signaling, trafficking, and cytoskeletal remodeling are predicted to be prenylated (Delcroix et al, 2003;Wang and Casey, 2016;Wu et al, 2007;Zweifel et al, 2005), although the functional requirement for the lipid modifications is unknown.…”

“…NGF signaling is initiated by binding TrkA receptors in sympathetic axons, receptor dimerization and autophosphorylation, and internalization of ligand/receptor complexes in endosomes where internalized TrkA receptors continue to signal (Scott-Solomon and Kuruvilla, 2018). TrkA endosomes acutely regulate signaling pathways in axons, and are also retrogradely transported to cell bodies to activate transcriptional programs needed for long-term axonal growth and neuron survival (Scott-Solomon and Kuruvilla, 2018). TrkA trafficking is known to rely on several effector proteins, especially small GTPases, that are predicted to be prenylated (Harrington et al, 2011;Kawata et al, 1990;Wu et al, 2001).…”

Novel design of (PEG-ylated)PAMAM-based nanoparticles for sustained delivery of BDNF to neurotoxin-injured differentiated neuroblastoma cells

“…4,5 BDNF binds with high a nity to tyrosine kinase B (TrkB) receptor to promote trophic signaling and apoptotic events. [6][7][8] Indeed, low BDNF levels are observed in brains of patients suffering from multiple pathologies of CNS and changes in BDNF concentration or its distribution have been linked with several neurodegenerative and psychiatric disorders, like depression and schizophrenia. 9,10 Neurotrophins are challenging candidates for drug development, because of their low bioavailability for therapeutic targets and insubstantial pharmacokinetic behavior.…”