p75 Neurotrophin Receptor-Mediated Apoptosis Involves Biphasic Activation of JNK and Up-regulation of Tumor Necrosis Factor-Alpha-Converting Enzyme/ADAM17

Strategic Insights -

Researchers at Vanderbilt University have made a groundbreaking discovery in the study of tumor necrosis factors. In a recent study published in the Journal of Biological Chemistry, the team led by R.S. Kenchappa found that the p75 neurotrophin receptor has a dual function in the development of the sympathetic nervous system. On one hand, it promotes survival together with TrkA in response to NGF, but on the other hand, it induces cell death upon binding pro or mature brain-derived neurotrophic factor (BDNF). The researchers discovered that the receptor undergoes regulated proteolysis, first by a metalloprotease, and then by gamma-secretase, in response to pro-apoptotic ligands, which is necessary for receptor-mediated neuronal death.

Key Takeaways:

  • The p75 neurotrophin receptor has a dual function in the development of the sympathetic nervous system, promoting survival and inducing cell death.
  • Apoptotic signaling through p75NTR requires activation of the stress kinase, JNK.
  • JNK3 activation is necessary for p75NTR cleavage, but following release of the intracellular domain, there is a secondary activation of JNK3 that is cleavage-dependent.
  • Receptor proteolysis and apoptosis were prevented in sympathetic neurons from jnk3(-/-) mice.
  • Activation of JNK by ectopic expression of MEKK1 induced p75NTR cleavage and cell death.
  • Up-regulation of tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM17 mRNA and protein was observed in wild-type, but not jnk3(-/-) sympathetic neurons.
  • Down-regulation of TACE by RNA interference blocked BDNF-induced p75NTR cleavage and apoptosis, indicating that this metalloprotease is responsible for the initial processing of the receptor.

Statistics:

  • 6 hours: time period after BDNF treatment when proteolysis of the receptor was detected.
  • 26: volume issue of the Journal of Biological Chemistry where the study was published.
  • 2010: publication year of the study.
  • 20358-68: page numbers of the study in the Journal of Biological Chemistry.

Sources:

  • "p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17." Journal of Biological Chemistry, 2010;285(26):20358-68.
  • Vanderbilt University, Center for Molecular Neuroscience.