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J. Biol. Chem. 277 (33): 30289-30299

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

Clustering of CD40 Ligand Is Required to Form a Functional Contact with CD40*

Heike GrassméDagger §, Jürgen BockDagger , Jutta Kun, and Erich GulbinsDagger §||

From the Dagger  Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the § Department of Molecular Biology, University of Essen, Hufelandstrasse 55, Essen 45147, Germany, and the  Department of Physiology, University of Tuebingen, Gmelinstrasse 5, Tuebingen 72076, Germany

Receptor clustering is a key event in the initiation of signaling by many types of receptor molecules. Here, we provide evidence for the novel concept that clustering of a ligand is a prerequisite for clustering of the cognate receptor. We show that clustering of the CD40 receptor depends on reciprocal clustering of the CD40 ligand (gp39, CD154). Clustering of the CD40 ligand is mediated by an association of the ligand with p53, a translocation of acid sphingomyelinase (ASM) to the cell membrane, an activation of the ASM, and a formation of ceramide. Ceramide appears to modify preexisting sphingolipid-rich membrane microdomains to fuse and form ceramide-enriched signaling platforms that serve to cluster CD40 ligand. Genetic deficiency of p53 or ASM or disruption of ceramide-enriched membrane domains prevents clustering of CD40 ligand. The functional significance of CD40 ligand clustering is indicated by the finding that clustering of CD40 on B lymphocytes upon co-incubation with CD40 ligand-expressing T cells depends on clustering of the CD40 ligand and is abrogated by inhibition of CD40 ligand clustering.


* The study was supported in part by Deutsche Forschungsgemeinschaft Grant Gu 335/9-4, the European Union, National Institutes of Health Grant CA 21765, and the American Lebanese Syrian Associated Charities (to E. G.).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: Dept. of Molecular Biology, University of Essen, Hufelandstrasse 55, Essen 45147, Germany. Tel.: 49-201-723-3118; Fax: 49-201-723-5974; E-mail: erich. gulbins{at}uni-essen.de.


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


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