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.
Subscribe

Logo for

PNAS 98 (12): 6789-6793

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of antigen receptor signaling

Thomas M. Yankee*,{dagger}, Kevin E. Draves*, Maria K. Ewings*, Edward A. Clark*,{ddagger},§, and Jonathan D. Graves{ddagger}

Departments of *Microbiology and {ddagger}Immunology, and §Regional Primate Research Center, University of Washington, Seattle, WA 98195

Accepted for publication April 2, 2001.

Received for publication February 5, 2001.

Abstract: The balance between cell survival and cell death is critical for normal lymphoid development. This balance is maintained by signals through lymphocyte antigen receptors and death receptors such as CD95/Fas. In some cells, ligating the B cell antigen receptor can protect the cell from apoptosis induced by CD95. Here we report that ligation of CD95 inhibits antigen receptor-mediated signaling. Pretreating CD40-stimulated tonsillar B cells with anti-CD95 abolished B cell antigen receptor-mediated calcium mobilization. Furthermore, CD95 ligation led to the caspase-dependent inhibition of antigen receptor-induced calcium mobilization and to the activation of mitogen-activated protein kinase pathways in B and T cell lines. A target of CD95-mediated caspase 3-like activity early in the apoptotic process is the adaptor protein GrpL/Gads. GrpL constitutively interacts with SLP-76 via its C-terminal SH3 domain to regulate transcription factors such as NF-AT. Cleavage of GrpL removes the C-terminal SH3 domain so that it is no longer capable of recruiting SLP-76 to the membrane. Transfection of a truncated form of GrpL into Jurkat T cells blocked T cell antigen receptor-induced activation of NF-AT. These results suggest that CD95 signaling can desensitize antigen receptors, in part via cleavage of the GrpL adaptor.

{dagger} To whom reprint requests should be addressed at: Department of Microbiology, HSB, I-321 Box 357330, University of Washington, Seattle, WA 98195. E-mail: tyankee{at}u.washington.edu.

Communicated by Edwin G. Krebs, University of Washington School of Medicine, Seattle, WA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Gads (GrpL) Adaptor Protein Regulates T Cell Homeostasis.
T. M. Yankee, T. J. Yun, K. E. Draves, K. Ganesh, M. J. Bevan, K. Murali-Krishna, and E. A. Clark (2004)
J. Immunol. 173, 1711-1720
   Abstract »    Full Text »    PDF »
Proteome Analysis Reveals Caspase Activation in Hyporesponsive CD4 T Lymphocytes Induced in Vivo by the Oral Administration of Antigen.
T. Kaji, S. Hachimura, W. Ise, and S. Kaminogawa (2003)
J. Biol. Chem. 278, 27836-27843
   Abstract »    Full Text »    PDF »
Expression of the Grb2-Related Protein of the Lymphoid System in B Cell Subsets Enhances B Cell Antigen Receptor Signaling Through Mitogen-Activated Protein Kinase Pathways.
T. M. Yankee, S. A. Solow, K. D. Draves, and E. A. Clark (2003)
J. Immunol. 170, 349-355
   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