QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 25 August 2009
doi: 10.1242/jcs.055061

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.055061v1 122/18/3351    most recent Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Google Scholar Articles by Vilar, M. Articles by Ibáñez, C. F. PubMed PubMed Citation Articles by Vilar, M. Articles by Ibáñez, C. F. Social Bookmarking                         What's this?

Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor

Marçal Vilar^1,*, Ioannis Charalampopoulos^1,, Rajappa S. Kenchappa², Alessandra Reversi³, Joanna M. Klos-Applequist⁴, Esra Karaca¹, Anastasia Simi¹, Carlos Spuch^1,*, Soyoung Choi⁵, Wilma J. Friedman⁵, Johan Ericson⁴, Giampietro Schiavo³, Bruce D. Carter² and Carlos F. Ibáñez^1,

¹ Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden
² Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
³ Molecular NeuroPathobiology Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
⁴ Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden
⁵ Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA

Author for correspondence (carlos.ibanez{at}ki.se)

Accepted 15 July 2009

Dimerization is recognized as a crucial step in the activation of many plasma membrane receptors. However, a growing number of receptors pre-exist as dimers in the absence of ligand, indicating that, although necessary, dimerization is not always sufficient for signaling. The p75 neurotrophin receptor (p75^NTR) forms disulfide-linked dimers at the cell surface independently of ligand binding through Cys257 in its transmembrane domain. Here, we show that crosslinking of p75^NTR dimers by cysteine-scanning mutagenesis results in constitutive, ligand-independent activity in several pathways that are normally engaged upon neurotrophin stimulation of native receptors. The activity profiles of different disulfide-crosslinked p75^NTR mutants were similar but not identical, suggesting that different configurations of p75^NTR dimers might be endowed with different functions. Interestingly, crosslinked p75^NTR mutants did not mimic the effects of the myelin inhibitors Nogo or MAG, suggesting the existence of ligand-specific activation mechanisms. Together, these results support a conformational model of p75^NTR activation by neurotrophins, and reveal a genetic approach to generate gain-of-function receptor variants with distinct functional profiles.

Key words: Intracellular signaling, Nerve growth factor, Receptor activation, Receptor dimerization

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

This article has been cited by other articles:

				H. Yano, R. Torkin, L. A. Martin, M. V. Chao, and K. K. Teng Proneurotrophin-3 Is a Neuronal Apoptotic Ligand: Evidence for Retrograde-Directed Cell Killing J. Neurosci., November 25, 2009; 29(47): 14790 - 14802. [Abstract] [Full Text] [PDF]