Fas ligation induces apoptosis and Jun kinase activation independently of CD45 and Lck in human T cells.
Stimulation through the Fas/APO-1 receptor results in apoptosis through an incompletely characterized signaling pathway. More is known regarding signal transduction events that occur after ligation of the T-cell antigen receptor (TCR). It has been shown that TCR stimulation requires both the membrane tyrosine phosphatase, CD45, and the Src-family kinase, Lck, to result in cellular activation. Although prior studies suggest a role for protein tyrosine kinases and phosphatases in Fas signaling, we report here that Fas ligation induces apoptosis in T cells deficient in either CD45 or Lck. Further, in normal and CD45- or Lck-deficient cell lines, Fas stimulation results in activation of Jun kinase (JNK), a proposed mediator of stress activation pathways. Previous studies have also demonstrated a role for endogenous ceramide release in Fas-mediated apoptosis. We show that stimulation with a synthetic ceramide analog results in JNK activation as well as apoptosis, suggesting ceramide release occurs proximal to JNK activation in Fas signaling. Our data suggest that although CD45 and Lck are not required for Fas signaling, JNK activation may play an important role transducing distal signals that lead to apoptosis after Fas ligation.
Latinis
K M
KM
Department of Immunology, University of Iowa, Iowa City 52242, USA.
Koretzky
G A
GA
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013012:Sorbitol / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*; D019061:src-Family Kinases / Q000172:deficiency / Q000502:physiology*
C064769:N-acetylsphingosine; D016755:Proto-Oncogene Proteins c-jun; D019014:fas Receptor; D013012:Sorbitol; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens; D013110:Sphingosine