title: CD95/Fas induces cleavage of the GrpL/Gads adaptor and desensitization of antigen receptor signaling.
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.
authors.affiliation: Department of Microbiology, Regional Primate Research Center, University of Washington, Seattle, WA 98195, USA. tyankee@u.washington.edu
authors.forename: T M
authors.initials: TM
authors.lastname: Yankee
authors.forename: K E
authors.initials: KE
authors.lastname: Draves
authors.forename: M K
authors.initials: MK
authors.lastname: Ewings
authors.forename: E A
authors.initials: EA
authors.lastname: Clark
authors.forename: J D
authors.initials: JD
authors.lastname: Graves
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C409587:GRAP2 protein, human; C498726:Mona protein, mouse; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases