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The Journal of Neuroscience, February 9, 2005, 25(6):1407-1411; doi:10.1523/JNEUROSCI.3798-04.2005

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

José M. Frade

Instituto Cajal, Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain

The intracellular domain of the p75 neurotrophin receptor (p75^ICD) can be released by -secretase in response to the previous activation of -secretase by phorbol esters. However, ligand-dependent release of p75^ICD has yet to be described. We show here that nerve growth factor can induce the release of p75^ICD and facilitate its translocation to the nucleus in a -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 p75^ICD did not need the previous activation of -secretase. These results suggest that nuclear translocation of p75^ICD may represent a novel neurotrophin-mediated signaling pathway.

Key words: -secretase; -secretase; p75^NTR; neurotrophin; nuclear translocation; regulated intramembrane proteolysis

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Received June 9, 2004; revised December 24, 2004; accepted December 27, 2004.

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