The Phosphoprotein Protein PEA-15 Inhibits Fas- but Increases TNF-R1-Mediated Caspase-8 Activity and Apoptosis

• Published in: Developmental biology 1999-12, Vol.216 (1), p.16-28
• Main Authors: Estellés, Angeles, Charlton, Carol A., Blau, Helen M.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Amino Acid Sequence; Animals; Antibodies - immunology; apoptosis; Apoptosis - drug effects; caspase; Caspase 8; Caspase 9; Caspases - metabolism; death effector domain; Enzyme Activation - drug effects; Fas; fas Receptor - immunology; fas Receptor - metabolism; Gene Expression; Mice; Molecular Sequence Data; Mutation; NF-kappa B - metabolism; phosphoprotein; Phosphoproteins - genetics; Phosphoproteins - pharmacology; Phosphorylation; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction; TNF-α; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1006/dbio.1999.9510

We have characterized a phosphoprotein protein with a death effector domain that has a novel bifunctional role in programmed cell death. The 15-kDa phosphoprotein enriched in astrocytes (PEA-15) inhibits Fas-mediated apoptosis and increases tumor necrosis factor receptor-1 (TNF-R1)-mediated apoptosis in the same cell type in a ligand-dependent manner. Phosphorylation appears to play a role in its differential effects, since point mutations at one or both phosphorylation consensus sites within PEA-15 destroy its effect on Fas-mediated, but not TNF-R1-mediated, apoptosis. Furthermore, the differential effect is evident at the level of caspase-8 activity which is inhibited via Fas activation, but increased via TNF-R1 activation upon PEA-15 expression. These results show that PEA-15 provides a potential mechanism during development for distinguishing between diverse extracellular death-inducing signals that culminate either in apoptosis or in survival.