HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 10, 7606-7615, March 9, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/10/7606    most recent M610458200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Urra, S. Articles by Bronfman, F. C. Search for Related Content PubMed PubMed Citation Articles by Urra, S. Articles by Bronfman, F. C. Social Bookmarking                      What's this?

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^*

Soledad Urra¹, Claudia A. Escudero¹, Patricio Ramos, Fernanda Lisbona, Edgardo Allende, Paulina Covarrubias, Jose I. Parraguez, Niccolo Zampieri^¶, Moses V. Chao^¶, Wim Annaert², and Francisca C. Bronfman³

From the Department of Physiology, Center for Cellular Regulation and Pathology Joaquin V. Luco, Faculty of Biological Sciences, Pontificia Universidad Catolica, Alameda 340, Santiago 8320000, Chile, the ^¶Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, and the Laboratory for Membrane Trafficking, Center for Human Genetics, Gasthuisberg KULeuven & VIB, B-3000 Leuven, Belgium

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

Received for publication, November 9, 2006 , and in revised form, January 8, 2007.

^* This work was supported in part by grants from DIPUC, F. ANDES, FONDAP Center for Biomedicine, FONDECYT 1040799 (to F. C. B.), from VIB, FWO-Vlaanderen (G.0243.04), KULeuven (GOA/2004/12), the International Alzheimer Research Foundation (SAO-FRMA2006) (to W. A.), and the Bilateral Flemish-Chilean Cooperation Program (BIL) (to F. C. B. and W. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of financial support from DIPUC, FONDAP, and BIL Projects.

² To whom correspondence may be addressed: Laboratory for Membrane Trafficking, Center for Human Genetics, Gasthuisberg KULeuven and VIB 11, B-3000 Leuven, Belgium. Tel.: 32-16-330520; Fax: 32-16-330522; E-mail: Willem.Annaert{at}med.kuleuven.be.

³ To whom correspondence may be addressed: Dept. of Physiology, Faculty of Biological Sciences, Pontificia Universidad Catolica. Alameda 340, Santiago 8320000, Chile. Tel.: 56-2-6862879; Fax: 56-2-6862824; E-mail: fbronfman{at}bio.puc.cl.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. M. Elzinga, C. Twomey, J. C. Powell, F. Harte, and J. V. McCarthy Interleukin-1 Receptor Type 1 Is a Substrate for {gamma}-Secretase-dependent Regulated Intramembrane Proteolysis J. Biol. Chem., January 16, 2009; 284(3): 1394 - 1409. [Abstract] [Full Text] [PDF]

				A. Caporali and C. Emanueli Cardiovascular Actions of Neurotrophins Physiol Rev, January 1, 2009; 89(1): 279 - 308. [Abstract] [Full Text] [PDF]

				M. Volosin, C. Trotter, A. Cragnolini, R. S. Kenchappa, M. Light, B. L. Hempstead, B. D. Carter, and W. J. Friedman Induction of Proneurotrophins and Activation of p75NTR-Mediated Apoptosis via Neurotrophin Receptor-Interacting Factor in Hippocampal Neurons after Seizures J. Neurosci., September 24, 2008; 28(39): 9870 - 9879. [Abstract] [Full Text] [PDF]

				A. Sotthibundhu, A. M. Sykes, B. Fox, C. K. Underwood, W. Thangnipon, and E. J. Coulson {beta}-Amyloid1-42 Induces Neuronal Death through the p75 Neurotrophin Receptor J. Neurosci., April 9, 2008; 28(15): 3941 - 3946. [Abstract] [Full Text] [PDF]

				T. Vaccari, H. Lu, R. Kanwar, M. E. Fortini, and D. Bilder Endosomal entry regulates Notch receptor activation in Drosophila melanogaster J. Cell Biol., February 25, 2008; 180(4): 755 - 762. [Abstract] [Full Text] [PDF]