¹Equipe Labelisée La Ligue, Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Nice, France

Correspondence: A-O Hueber, Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A Lacassagne, 33, Avenue de Valombrose, Nice 06189, France. Tel: +33 49203 1241; Fax: +33 49203 1245; E-mail: hueber@unice.fr

²Current address: Immunology Research Group of the Hungarian Academy of Sciences, University Eötvös Lorand, Pazmany s 1/C, Budapest, Hungary.

Received 7 March 2007; Revised 17 October 2007; Accepted 24 October 2007; Published online 7 December 2007.

Abstract

The actin cytoskeleton association is required for caspase 8-independent Fas/CD95 receptor internalization, a critical step for an optimal death-inducing signaling complex formation along the endocytic pathway, leading to efficient activation of the caspase cascade and, ultimately, cell death. However, the way in which this initiation phase of Fas receptor signaling is regulated is still unknown. We report herein that, in B cells, upon Fas engagement, the tyrosine phosphatase SHP-1-regulated Vav dephosphorylation, by downmodulating the Fas–ezrin–actin linkage is a fine-tune switch-off mechanism that the cell uses as a way to terminate the receptor internalization, controlling therefore the time and extent of the DISC formation and cell death.