TrkA Receptor Activation by Nerve Growth Factor Induces Shedding of the p75 Neurotrophin Receptor Followed by Endosomal γ-Secretase-mediated Release of the p75 Intracellular Domain
| Autor: | Claudia A. Escudero, Niccolò Zampieri, Paulina Covarrubias, Francisca C. Bronfman, Soledad Urra, Jose I. Parraguez, Fernanda Lisbona, Edgardo Allende, W. Annaert, Moses V. Chao, Patricio Ramos |
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| Rok vydání: | 2007 |
| Předmět: |
musculoskeletal diseases
Endosomes Tropomyosin receptor kinase A PC12 Cells Receptor Nerve Growth Factor Biochemistry Growth factor receptor Nerve Growth Factor Animals Low-affinity nerve growth factor receptor Receptor trkA skin and connective tissue diseases Molecular Biology Brain-derived neurotrophic factor biology Brain-Derived Neurotrophic Factor Cell Biology Endocytosis biological factors Protein Structure Tertiary Rats Cell biology nervous system Trk receptor biology.protein Tetradecanoylphorbol Acetate sense organs Amyloid Precursor Protein Secretases Signal transduction Amyloid precursor protein secretase Signal Transduction Neurotrophin |
| Zdroj: | Journal of Biological Chemistry. 282:7606-7615 |
| ISSN: | 0021-9258 |
| Popis: | 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 gamma-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 gamma-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for gamma-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75. ispartof: Journal of Biological Chemistry vol:282 issue:10 pages:7606-15 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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