CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases

Oncogene. 1996 Nov 21;13(10):2087-96.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Caspase 1
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • DNA / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Lymphoma, B-Cell / enzymology
  • Lymphoma, T-Cell / enzymology
  • Mice
  • Signal Transduction
  • Staurosporine / pharmacology
  • fas Receptor / metabolism
  • fas Receptor / pharmacology*


  • Enzyme Inhibitors
  • fas Receptor
  • DNA
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cysteine Endopeptidases
  • Caspase 1
  • Staurosporine