ProNGF Induces PTEN via p75NTR to Suppress Trk-Mediated Survival Signaling in Brain Neurons

Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75NTR, whereas mature neurotrophins activate Trk receptors to influence survival and differentiation. Here, we demonstrate that the PTEN (phosphatase and tensin homolog deleted on chromosome 10) phosphatase represents a novel switch between the survival and apoptotic signaling pathways in rat CNS neurons. Simultaneous activation of p75NTR by proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75NTR required suppression of TrkB-induced phosphoinositide-3 kinase signaling, mediated by induction of PTEN, for apoptosis to proceed. Inhibition of PTEN restored the ability of BDNF to phosphorylate Akt and protect cultured basal forebrain neurons from proNGF-induced death. In vivo, inhibition or knockdown of PTEN after pilocarpine-induced seizures protected CNS neurons from p75NTR-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75NTR-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.

• Publication year

  2010

• Venue

  Journal of Neuroscience

• Publication date

  2010-11-17

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.2581-10.2010PMID 21084616PMCID PMC2996105
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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