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Converting Enzyme
Family Proteases, and a Dense Membrane Fraction
* Division of Cellular Immunology, We have begun to explore the mechanisms
of apoptosis using a cell-free system based on extracts
from Xenopus eggs. Nuclei assembled or placed in
these extracts undergo the morphological changes typical of apoptosis and eventually disintegrate. We used this system to investigate the potential involvement in
apoptosis of proteins containing Src homology 2 (SH2)
domains, which are known to interact with specific tyrosine-phosphorylated ligands. SH2 domains from a
number of signaling proteins, including Lck, Src, and
Abl, inhibited apoptosis when present at concentrations of 10-100 nM. The inhibition was dependent on
specific interaction with endogenous tyrosine-phosphorylated ligands. A synthetic peptide ligand for Src family
SH2 domains also inhibited apoptosis in a phosphotyrosine-dependent manner. Kinetic analysis defined
three phases in the apoptotic process occurring in this
cell-free system. SH2 domains and ceramide act
throughout the first 60-90 min of the process (the "initiation" phase). Next, Bcl-2, interleukin-1 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego,
California 92121
converting
enzyme family(CPP32-like) proteases, and the heavy membrane fraction act in a period occurring ~90-120
min after the start of incubation (the "sentencing"
phase). In the final phase ("execution"), the process of
active nuclear destruction ensues.
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