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PNAS 98 (12): 6789-6793

Copyright © 2001 by the National Academy of Sciences.


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}

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

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 »

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