CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases.
Triggering of CD95 (APO-1/Fas) on different T- and B-cell lines resulted in the induction of a number of kinases (35 kDa, 38 kDa, 46 kDa and 54 kDa) that phosphorylate c-Jun and to a lesser extent Histone H1. Activation of these kinases was independent of protein biosynthesis and preceded apoptotic DNA degradation. The kinase activation pattern was specific for CD95 triggering since a variety of physical or chemical inducers of T- and B-cell apoptosis activated different kinases. The kinase activities at 46 and 54 kDa contained members of the stress-activated family of protein kinases (JNK/SAPK). Activation of the CD95-specific set of kinases was prevented by treating cells with the ICE-inhibiting peptide N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) or by overexpression of the cow pox virus serpin CrmA. However, despite inhibition of ICE-like proteases the death signal was readily initiated at the cell membrane since a CD95 death-inducing signaling complex (DISC) was formed. Thus, our results demonstrate that ICE-like proteases in the CD95 pathway function downstream of the DISC but upstream of SAP kinases.
Cahill
M A
MA
Institute for Molecular Biology, Hannover Medical School, Germany.
Peter
M E
ME
Kischkel
F C
FC
Chinnaiyan
A M
AM
Dixit
V M
VM
Krammer
P H
PH
Nordheim
A
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D020170:Caspase 1; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology; D016399:Lymphoma, T-Cell / Q000201:enzymology; D051379:Mice; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D019014:fas Receptor; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D019311:Staurosporine