RGD Reference Report - Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway. - Rat Genome Database

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Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway.

Authors: Delgado-Esteban, M  Martin-Zanca, D  Andres-Martin, L  Almeida, A  Bolanos, JP 
Citation: Delgado-Esteban M, etal., J Neurochem. 2007 Jul;102(1):194-205. Epub 2007 Feb 14.
RGD ID: 2292536
Pubmed: PMID:17302912   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2007.04450.x   (Journal Full-text)

Peroxynitrite is usually considered as a neurotoxic nitric oxide-derivative. However, an increasing body of evidence suggests that, at low concentrations, peroxynitrite affords transient cytoprotection, both in vitro and in vivo. Here, we addressed the signaling mechanism responsible for this effect, and found that rat cortical neurons in primary culture acutely exposed to peroxynitrite (0.1 mmol/L) rapidly elicited Akt-Ser(473) phosphorylation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway with wortmannin or Akt small hairpin RNA (shRNA) abolished the ability of peroxynitrite to prevent etoposide-induced apoptotic death. Endogenous peroxynitrite formation by short-term incubation of neurons with glutamate stimulated Akt-Ser(473) phosphorylation, whereas Akt shRNA enhanced the vulnerability of neurons against glutamate. We further show that Akt-Ser(473) phosphorylation was consequence of the oxidizing, but not the nitrating properties of peroxynitrite. Peroxynitrite failed to nitrate or phosphorylate neurotrophin tyrosine kinase receptors (Trks), and it did not modify the ability of brain-derived neurotrophic factor (BDNF), to phosphorylate its cognate receptor, TrkB; however, peroxynitrite enhanced BDNF-mediated Akt-Ser(473) phosphorylation. Finally, we found that peroxynitrite-stimulated Akt-Ser(473) phosphorylation was associated with an increased proportion of oxidized phosphoinositide phosphatase, PTEN, in neurons. Moreover, peroxynitrite prevented the increase of apoptotic neuronal death caused by over-expression of PTEN. Thus, peroxynitrite exerts neuroprotection by inhibiting PTEN, hence activating the anti-apoptotic PI3K/Akt pathway in primary neurons.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to inorganic substance  IEP 2292536 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pten  (phosphatase and tensin homolog)


Additional Information