Regulated cell death: signaling and mechanisms

Annu Rev Cell Dev Biol. 2014;30:337-56. doi: 10.1146/annurev-cellbio-100913-013226. Epub 2014 Aug 13.


Cell turnover is a fundamental feature in metazoans. Cells can die passively, as a consequence of severe damage to their structural integrity, or actively, owing to a more confined biological disruption such as DNA damage. Passive cell death is uncontrolled and often harmful to the organism. In contrast, active cell death is tightly regulated and serves to support the organism's life. Apoptosis-the primary form of regulated cell death-is relatively well defined. Necroptosis-an alternative, distinct kind of regulated cell death discovered more recently-is less well understood. Apoptosis and necroptosis can be triggered either from within the cell or by extracellular stimuli. Certain signaling components, including several death ligands and receptors, can regulate both processes. Whereas apoptosis is triggered and executed via intracellular proteases called caspases, necroptosis is suppressed by caspase activity. Here we highlight current understanding of the key signaling mechanisms that control regulated cell death.

Keywords: RIP; TNF; apoptosis; caspase; death receptor; necroptosis; receptor interacting protein; tumor necrosis factor.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / physiology
  • Caspases / physiology
  • Cell Death / physiology*
  • Death Domain Receptor Signaling Adaptor Proteins / physiology
  • Enzyme Activation
  • Humans
  • Models, Biological
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology
  • Receptors, Death Domain / physiology
  • Receptors, Tumor Necrosis Factor / physiology
  • Signal Transduction / physiology
  • Tumor Necrosis Factors / physiology


  • Apoptosis Regulatory Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Receptors, Death Domain
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspases