Transactivation of Trk neurotrophin receptors by G protein-coupled receptors

Neurotrophins are growth factors that support neuronal survival and differentiation and also influence neuronal functions such as synaptic transmission. The Trk family of tyrosine kinases serves as receptors for neurotrophins that can mediate their positive regulatory effects on neuronal survival and growth. Survival signaling through these receptors also occurs in the absence of neurotrophins via signals from other receptor systems such as G protein-coupled receptors (GPCRs), a process termed transactivation. Adenosine and pituitary adenylate cyclase-activating peptide (PACAP), two ligands for GPCRs, both possess neurotrophic properties and are capable of promoting Trk activity through transactivation. GPCR-mediated Trk activation differs from neurotrophin-induced Trk activation in a number of regards, including slower kinetics and different downstream signaling patterns. It is a mechanism that depends on novel protein synthesis, calcium, and Src kinases, but does not involve novel production of neurotrophins or neurotrophin receptors.; Some of the unique features of signaling through transactivated Trk are explained by the cellular location of these events. Surface biotinylation experiments and indirect immunofluorescence analysis indicated that in response to GPCR signaling intracellular Trk receptors are exclusively activated and that this event appears to occur on Golgi membranes. Disruption of the Golgi apparatus with brefeldin A confirmed a role for the Golgi in transactivation. Further analysis into transactivation mechanisms revealed a unique role for the Src family kinase, Fyn, in mediating signaling between GPCRs and Trk. Fyn co-localizes with Trk in a juxtanuclear membrane compartment and binds to Trk in response to GPCR signals. GPCR stimulation enhances Fyn tyrosine kinase activity towards Trk, and GPCR-stimulated Fyn directly phosphorylates Trk in vitro. Taken together, these findings support a novel model for Trk transactivation in which Fyn responds to GPCRs by associating with and directly phosphorylating Trk on intracellular membranes.; GPCR-mediated Trk activation occurs by a unique signaling system that may represent a neurotrophin-independent survival mechanism. Given the previous failure of neurotrophin-based therapy, further elucidation into the mechanism of Trk transactivation will be of great clinical value as indirect activation of neurotrophic pathways by small molecule ligands for GPCRs may be useful in the treatment of neurodegenerative disease.