Nuclear translocation of the p75 neurotrophin receptor cytoplasmic domain in response to neurotrophin binding.
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.
Frade
José M
JM
Instituto Cajal, Consejo Superior de Investigaciones Científicas, E-28002 Madrid, Spain. frade@cajal.csic.es
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D016895:Culture Media, Serum-Free; D010450:Endopeptidases; D006801:Humans; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000502:physiology*; D009442:Neurilemmoma / Q000473:pathology; D020933:Neurotrophin 3 / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D020932:Nerve Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human