Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: A protective mechanism against ischemic brain injury

Quan Guang Zhang, Xiao Tian Wang, Dong Han, Xiao Hui Yin, Guang Yi Zhang, Tian Le Xu

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The overall goal of this study was to determine the molecular basis by which mixed-lineage kinase 3 (MLK3) kinase and its signaling pathways are negatively regulated by the pro-survival Akt pathway in cerebral ischemia. We demonstrated that tyrosine phosphorylation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) underlies the increased Akt-Ser473 phosphorylation by orthovanadate. Co-immunoprecipitation analysis revealed that endogenous Akt physically interacts with Rac1 in the hippocampal CA1 region, and this interaction is promoted on tyrosine phosphatase inhibition. The elevated Akt activation can deactivate MLK3 by phosphorylation at the Ser71 residue of Rac1, a small Rho family of guanidine triphosphatases required for MLK3 autophosphorylation. Subsequently, inhibition of c-Jun N-terminal kinase 3 (JNK3) results in decreased serine phosphorylation of 14-3-3, a cytoplasmic anchor of Bax, and prevents ischemia-induced mitochondrial translocation of Bax, release of cytochrome c and activation of caspase 3. At the same time, the expression of Fas-ligand decreases in the CA1 region after inhibition of c-Jun activation. The neuroprotective effect of Akt activation is significant in the CA1 region after global cerebral ischemia. Our results suggest that the activation of the pro-apoptotic MLK3/JNK3 cascade induced by ischemic stress can be suppressed through activation of the anti-apoptotic phosphatidylinositol 3-kinase/Akt pathway, which provides a direct link between Akt and the family of stress-activated kinases.

Original languageEnglish (US)
Pages (from-to)1886-1898
Number of pages13
JournalJournal of Neurochemistry
Issue number6
StatePublished - Sep 2006
Externally publishedYes


  • Akt
  • Hippocampus
  • Mixed-lineage kinase 3
  • Neuronal death
  • Orthovanadate
  • Rac1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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