Abstract:

Activation of the cell surface CD95 receptor triggers a cascade of signaling events, including assembly of the death-inducing signaling complex (DISC), that culminate in cellular apoptosis. In this study, we demonstrate a general requirement of receptor internalization for CD95 ligand-mediated DISC amplification, caspase activation and apoptosis in type I cells. Recruitment of DISC components to the activated receptor predominantly occurs after the receptor has moved into an endosomal compartment and blockade of CD95 internalization impairs DISC formation and apoptosis. In contrast, CD95 ligand stimulation of cells unable to internalize CD95 results in activation of proliferative Erk and NF-kappaB signaling pathways. Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates.

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The role of receptor internalization in CD95 signaling

^{Department of Immunology, Genentech Inc., South San Francisco, CA, USA}

^{The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, USA}

^{Institute of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany}

^{These authors shared senior authorship}

^{Department of Immunology, Genentech Inc., MS-34, Bldg. 12-281, 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 8104; Fax: +1 650 225 8136; E-mail:}moc.eneg@cca or ude.ogacihcu@retePM

^{These authors contributed equally to this work}

Received 2005 Sep 6; Accepted 2006 Jan 30.

Abstract

Activation of the cell surface CD95 receptor triggers a cascade of signaling events, including assembly of the death-inducing signaling complex (DISC), that culminate in cellular apoptosis. In this study, we demonstrate a general requirement of receptor internalization for CD95 ligand-mediated DISC amplification, caspase activation and apoptosis in type I cells. Recruitment of DISC components to the activated receptor predominantly occurs after the receptor has moved into an endosomal compartment and blockade of CD95 internalization impairs DISC formation and apoptosis. In contrast, CD95 ligand stimulation of cells unable to internalize CD95 results in activation of proliferative Erk and NF-κB signaling pathways. Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates.

Keywords: endosomes, signal transduction

Abstract

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Acknowledgments

We thank Drs Ashkenazi, Dixit, Newton and Scheller for critical discussion. We thank Drs Krammer, Walczak and Jaatella for providing us with reagents and Drs Murmann and Jakob for help with confocal microscopy. KHL and ACC are employees of Genentech, Inc. RS is supported by DAMDI17-03-1-0200 and CH by the DFG-SFB 415, A11. MEP was supported through NIH grant RO1 CA93519.

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