Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

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

T Cell Polarity at the Immunological Synapse Is Required for CD154-Dependent IL-12 Secretion by Dendritic Cells.
M. Tourret, S. Guegan, K. Chemin, S. Dogniaux, F. Miro, A. Bohineust, and C. Hivroz (2010)
J. Immunol. 185, 6809-6818
   Abstract »    Full Text »    PDF »
Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner.
Y. Koguchi, T. J. Thauland, M. K. Slifka, and D. C. Parker (2007)
Blood 110, 2520-2527
   Abstract »    Full Text »    PDF »
Requirement of Oxidation-dependent CD40 Homodimers for CD154/CD40 Bidirectional Signaling.
C. Reyes-Moreno, E. Sharif-Askari, J. Girouard, C. Leveille, M. Jundi, A. Akoum, R. Lapointe, A. Darveau, and W. Mourad (2007)
J. Biol. Chem. 282, 19473-19480
   Abstract »    Full Text »    PDF »
B cell proliferation following CD40 stimulation results in the expression and activation of Src protein tyrosine kinase.
S. Neron, G. Suck, X.-Z. Ma, D. Sakac, A. Roy, Y. Katsman, N. Dussault, C. Racine, and D. R. Branch (2006)
Int. Immunol. 18, 375-387
   Abstract »    Full Text »    PDF »
Caspase-dependent and -independent Activation of Acid Sphingomyelinase Signaling.
J. A. Rotolo, J. Zhang, M. Donepudi, H. Lee, Z. Fuks, and R. Kolesnick (2005)
J. Biol. Chem. 280, 26425-26434
   Abstract »    Full Text »    PDF »
UV-C Light Induces Raft-associated Acid Sphingomyelinase and JNK Activation and Translocation Independently on a Nuclear Signal.
A. Charruyer, S. Grazide, C. Bezombes, S. Muller, G. Laurent, and J.-P. Jaffrezou (2005)
J. Biol. Chem. 280, 19196-19204
   Abstract »    Full Text »    PDF »
The extracellular domains of FasL and Fas are sufficient for the formation of supramolecular FasL-Fas clusters of high stability.
F. Henkler, E. Behrle, K. M. Dennehy, A. Wicovsky, N. Peters, C. Warnke, K. Pfizenmaier, and H. Wajant (2005)
J. Cell Biol. 168, 1087-1098
   Abstract »    Full Text »    PDF »
CD40: A Growing Cytoplasmic Tale.
M. M. Harnett (2004)
Sci. STKE 2004, pe25
   Abstract »    Full Text »    PDF »
CD40 Stimulation of Human Peripheral B Lymphocytes: Distinct Response from Naive and Memory Cells.
J. F. Fecteau and S. Neron (2003)
J. Immunol. 171, 4621-4629
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

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