title: Brain-derived neurotrophic factor binding to the p75 neurotrophin receptor reduces TrkA signaling while increasing serine phosphorylation in the TrkA intracellular domain.
abstract: We have examined whether the low affinity neurotrophin receptor p75NTR modulates TrkA function by intracellular signaling. Using ligands that selectively bind p75NTR or TrkA, we found that a p75NTR-derived signal reduces TrkA activation. Short term treatment of PC12 cells with ceramide analogues also resulted in reduced NGF-stimulated TrkA activation, suggesting that p75-mediated increases in sphingomyelinase activity may contribute to this modulatory effect. Phosphoamino acid analysis was performed to determine if brain-derived neurotrophic factor- or ceramide-mediated phosphorylation of the TrkA intracellular domain correlated with a reduction in its ligand-induced activation. A specific increase in TrkA phosphoserine content was observed in response to both C2-ceramide and brain-derived neurotrophic factor. These results suggest that ligand binding of p75NTR can activate a signaling cascade that results in reduced TrkA activity through phosphorylation of its intracellular domain.
authors.affiliation: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Avenue, Montreal, Quebec H3A 2B4, Canada.
authors.forename: I J
authors.initials: IJ
authors.lastname: MacPhee
authors.forename: P A
authors.initials: PA
authors.lastname: Barker
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012694:Serine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA