title: ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons.
abstract: Proneurotrophins and mature neurotrophins activate different signaling pathways with distinct effects on their target cells: proneurotrophins can induce apoptotic signaling via p75(NTR), 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 p75(NTR) by proNGF and TrkB signaling by BDNF elicited apoptosis despite TrkB phosphorylation. Apoptosis induced by p75(NTR) 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 p75(NTR)-mediated death, demonstrating that PTEN is a crucial factor mediating the balance between p75(NTR)-induced apoptotic signaling and Trk-mediated survival signaling in brain neurons.
authors.affiliation: Department of Biological Science, Rutgers University, Newark, New Jersey 07102, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Song
authors.forename: Marta
authors.initials: M
authors.lastname: Volosin
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Cragnolini
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Wilma J
authors.initials: WJ
authors.lastname: Friedman
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D008297:Male; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011247:Pregnancy; D011498:Protein Precursors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000502:physiology*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C514218:pro-nerve growth factor, rat; C068313:Ngfr protein, rat; D020813:Receptor, trkB; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat