title: Cannabinoid 1 receptor-dependent transactivation of fibroblast growth factor receptor 1 emanates from lipid rafts and amplifies extracellular signal-regulated kinase 1/2 activation in embryonic cortical neurons.
abstract: G-protein coupled receptors may mediate their effects on neuronal growth and differentiation through activation of extracellular signal-regulated kinases 1/2 (ERK1/2), often elicited by transactivation of growth factor receptor tyrosine kinases. This elaborate signaling process includes inducible formation and trafficking of multiprotein signaling complexes and is facilitated by pre-ordained membrane microdomains, in particular lipid rafts. In this study, we have uncovered novel signaling interactions of cannabinoid receptors with fibroblast growth factor receptors, which depended on lipid rafts and led to ERK1/2 activation in primary neurons derived from chick embryo telencephalon. More specifically, the cannabinoid 1 receptor (CB1R) agonist methanandamide induced tyrosine phosphorylation and transactivation of fibroblast growth factor receptor (FGFR)1 via Src and Fyn, which drove an amplification wave in ERK1/2 activation. Transactivation of FGFR1 was accompanied by the formation of a protein kinase C ε-dependent multiprotein complex that included CB1R, Fyn, Src, and FGFR1. Recruitment of molecules increased with time of exposure to methanandamide, suggesting that in addition to signaling it also served trafficking of receptors. Upon agonist stimulation we also detected a rapid incorporation of CB1R, as well as activated Src and Fyn, and FGFR1 in lipid rafts. Most importantly, lipid raft integrity was a pre-requisite for CB1R-dependent complex formation. Our data provide evidence that lipid rafts may organize CB1 receptor proximal signaling events, namely activation of Src and Fyn, and transactivation of FGFR1 towards activation of ERK1/2 and induction of neuronal differentiation.
authors.affiliation: Center for Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Olga
authors.initials: O
authors.lastname: Asimaki
authors.forename: George
authors.initials: G
authors.lastname: Leondaritis
authors.forename: Giannis
authors.initials: G
authors.lastname: Lois
authors.forename: Nikos
authors.initials: N
authors.lastname: Sakellaridis
authors.forename: Dimitra
authors.initials: D
authors.lastname: Mangoura
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002642:Chick Embryo; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047468:Immunoprecipitation / Q000379:methods; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: C543264:Cnr1 protein, rat; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases