Brain-derived neurotrophic factor binding to the p75 neurotrophin receptor reduces TrkA signaling while increasing serine phosphorylation in the TrkA intracellular domain

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 C-2-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.