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J. Biol. Chem. 277 (46): 44155-44163

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Control of Receptor-induced Signaling Complex Formation by the Kinetics of Ligand/Receptor Interaction*

Anja Krippner-Heidenreich, Fabian Tübing, Susanne Bryde, Sylvia Willi, Gudrun Zimmermann, and Peter ScheurichDagger

From the Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany

Tumor necrosis factor (TNF) exists both as a membrane-integrated type II precursor protein and a soluble cytokine that have different bioactivities on TNFR2 (CD120b) but not on TNFR1 (CD120a). To identify the molecular basis of this disparity, we have investigated receptor chimeras comprising the cytoplasmic part of Fas (CD95) and the extracellular domains of the two TNF receptors. The membrane form of TNF, but not its soluble form, was capable of inducing apoptosis as well as activation of c-Jun N-terminal kinase and NF-kappa B via the TNFR2-derived chimera. In contrast, the TNFR1-Fas chimera displayed strong responsiveness to both TNF forms. This pattern of responsiveness is identical to that of wild type TNF receptors, demonstrating that the underlying mechanisms are independent of the particular type of the intracellular signaling machinery and rather are controlled upstream of the intracellular domain. We further demonstrate that the signaling strength induced by a given ligand/receptor interaction is regulated at the level of adaptor protein recruitment, as shown for FADD, caspase-8, and TRAF2. Since both incidents, strong signaling and robust adapter protein recruitment, are paralleled by a high stability of individual ligand-receptor complexes, we propose that half-lives of individual ligand-receptor complexes control signaling at the level of adaptor protein recruitment.

* This work was supported by Deutsche Forschungsgemeinschaft Grant GR 1307/3-3 and Sonderforschungsbereich 495, project A4.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 49-711-685-6987; Fax: 49-711-685-7484.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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