Surviving apoptosis: life–death signaling in single cells

• TNF family death ligands activate both death and nondeath signaling pathways.
• Cells surviving death stimuli may enter adaptive, death-resistant states.
• Cell-to-cell variability in life–death signaling impacts cell fate decisions.
• The evolutionary advantages of variability in life–death signaling are discussed.

Tissue development and homeostasis are regulated by opposing pro-survival and pro-death signals. An interesting feature of the Tumor Necrosis Factor (TNF) family of ligands is that they simultaneously activate opposing signals within a single cell via the same ligand–receptor complex. The magnitude of pro-death events such as caspase activation and pro-survival events such as Nuclear Factor (NF)-κB activation vary not only from one cell type to the next but also among individual cells of the same type due to intrinsic and extrinsic noise. The molecules involved in these pro-survival and/or pro-death pathways, and the different phenotypes that result from their activities, have been recently reviewed. Here we focus on the impact of cell-to-cell variability in the strength of these opposing signals on shaping cell fate decisions.