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The intracellular domain of the p75 neurotrophin receptor (p75ICD) can be released by gamma-secretase in response to the previous activation of alpha-secretase by phorbol esters. However, ligand-dependent release of p75ICD has yet to be described. We show here that nerve growth factor can induce the release of p75ICD and facilitate its translocation to the nucleus in a gamma-secretase-dependent manner. This effect was observed in RN22 schwannoma cells cultured under serum-free conditions, as well as in Schwann cells, and it was mimicked by other neurotrophins, such as brain-derived neurotrophic factor or neurotrophin-3. Unlike other known examples of regulated intramembrane proteolysis, ligand-dependent release of p75ICD did not need the previous activation of alpha-secretase. These results suggest that nuclear translocation of p75ICD may represent a novel neurotrophin-mediated signaling pathway.

Nuclear Translocation of the p75 Neurotrophin Receptor Cytoplasmic Domain in Response to Neurotrophin Binding