TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal gamma-secretase-mediated release of the p75 intracellular domain
Neurotrophins are trophic factors that regulate important neuronal functions. They bind two unrelated receptors, the Trk family of receptor-tyrosine kinases and the p75 neurotrophin receptor (p75). p75 was recently identified as a new substrate for Î³-secretase-mediated intramembrane proteolysis, generating a p75-derived intracellular domain (p75-ICD) with signaling capabilities. Using PC12 cells as a model, we studied how neurotrophins activate p75 processing and where these events occur in the cell. We demonstrate that activation of the TrkA receptor upon binding of nerve growth factor (NGF) regulates the metalloprotease-mediated shedding of p75 leaving a membrane-bound p75 C-terminal fragment (p75-CTF). Using subcellular fractionation to isolate a highly purified endosomal fraction, we demonstrate that p75-CTF ends up in endosomes where Î³-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for Î³-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75. Â© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
|Título según WOS:||TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal gamma-secretase-mediated release of the p75 intracellular domain|
|Título según SCOPUS:||TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal ?-secretase-mediated release of the p75 intracellular domain|
|Título de la Revista:||JOURNAL OF BIOLOGICAL CHEMISTRY|
|Editorial:||AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC|
|Fecha de publicación:||2007|
|Página de inicio:||7606|