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

Soledad Urra, Claudia A. Escudero, Patricio Ramos, Fernanda Lisbona, Edgardo Allende, Paulina Covarrubias, Jose I. Parraguez, Niccolo Zampieri, Moses V. Chao, Wim Annaert, Francisca C. Bronfman

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

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 γ-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 γ-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for γ-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75.

Original languageEnglish
Pages (from-to)7606-7615
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number10
DOIs
Publication statusPublished - 2 Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this