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© 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*
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- * 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.
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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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.
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882
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