Journal of Biological Chemistry
Volume 283, Issue 39, 26 September 2008, Pages 26401-26408
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Mechanisms of Signal Transduction
CD95 Stimulation Results in the Formation of a Novel Death Effector Domain Protein-containing Complex*

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Stimulation of CD95 (APO-1/Fas) by its natural ligand CD95L (APO-1L/FasL) leads to the formation of the death-inducing signaling complex. Here we report that upon CD95 stimulation in several T and B cell lines, a novel signaling complex is formed, which we term complex II. Complex II is composed of the death effector domain proteins as follows: procaspase-8a/b, three isoforms of c-FLIP (c-FLIPL, c-FLIPS, c-FLIPR), and FADD. Notably, complex II does not contain CD95. Based on our findings we suggest that CD95 signaling includes two steps. The first step involves formation of the death-inducing signaling complex at the cell membrane. The second step involves formation of the cytosolic death effector domain protein-containing complex that may play an important role in amplification of caspase activation.

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*

This work was supported by Grant SB 405 from Wilhelm Sander Stiftung, SB Cancer and Tumorzentrum, Heidelberg/Mannheim, Germany. 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.

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Present address: Novartis Pharma AG, CH-4002 Basel, Switzerland.