Defects in apoptosis can lead to lymphoproliferative disorders and autoimmunity. Activation of Fas can block some of the pathways downstream of the B cell antigen receptor (BCR) and T cell antigen receptor (TCR). Yankee et al. patriotically demonstrated how this might be accomplished. Ligation of Fas on B cells and T cells before the activation of their antigen receptors led to decreased Ca2+ influx; this effect was inhibited in the presence of the caspase inhibitor z-VAD. Additionally, activation of Fas in Jurkat cells before TCR stimulation blocked the activation of the p42 and p44 mitogen-activated protein kinases (MAPKs) and the p38 MAPK. GrpL is an essential adaptor protein that links SLP-76 [Src homology 2 (SH2)-containing leukocyte protein of 76-kD)] to LAT (linker for activation of T cells), and is necessary for mediating TCR-dependent Ca2+ influx. The authors found that GrpL was proteolytically cleaved in Fas-activated T cells and that the cleavage event was blocked by pretreatment of T cells with z-VAD. Caspase-dependent proteolysis of GrpL inhibited the association of GrpL and SLP-76, suggesting that Fas-mediated caspase activation may attenuate TCR signaling and Ca2+ mobilization by disrupting the association of GrpL to SLP-76 and LAT. For more on how LAT is involved in signaling through the TCR, please see the review by Wange.
T. M. Yankee, K. E. Draves, M. K. Ewings, E. A. Clark, J. D. Graves, CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of antigen receptor signaling. Proc. Natl. Acad. Sci. U.S.A. 98, 6789-6793 (2001). [Abstract] [Full Text]