Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt

Quanguang Zhang, D. Han, J. Xu, Q. Lv, R. Wang, X. H. Yin, T. L. Xu, G. Y. Zhang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Activation of Akt/protein kinase B has been recently reported to play an important role in ischemic tolerance. We here demonstrate that the decreased protein expression and phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) underlie the increased Akt-Ser-473 phosphorylation in the hippocampal CA1 subfield in ischemic preconditioning (IPC). Co-immunoprecipitation analysis reveals that Akt physically interacts with Rac1, a small Rho family GTPase required for mixed lineage kinase 3 (MLK3) autophosphorylation, and both this interaction and Rac1-Ser-71 phosphorylation induced by Akt are promoted in preconditioned rats. In addition, we show that Akt activation results in the disassembly of the plenty of SH3s (POSH)-MLK3-Rac1 signaling complex and down-regulation of the activation of MLK3/c-Jun N-terminal kinase (JNK) pathway. Akt activation 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. The expression of Fas ligand is also decreased in the CA1 region. Akt activation protects against apoptotic neuronal death as shown in TUNEL staining following IPC. Intracerebral infusion of LY294002 before IPC reverses the increase in Akt phosphorylation and the decrease in JNK signaling activation, as well as the neuroprotective action of IPC. Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance.

Original languageEnglish (US)
Pages (from-to)431-444
Number of pages14
JournalNeuroscience
Volume143
Issue number2
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

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Mitogen-Activated Protein Kinase 10
Ischemic Preconditioning
Phosphorylation
Phosphotransferases
Chromosomes, Human, Pair 10
Proto-Oncogene Proteins c-akt
rho GTP-Binding Proteins
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Fas Ligand Protein
1-Phosphatidylinositol 4-Kinase
Monomeric GTP-Binding Proteins
JNK Mitogen-Activated Protein Kinases
In Situ Nick-End Labeling
Cytochromes c
Phosphoric Monoester Hydrolases
Immunoprecipitation
Caspase 3
Serine
Down-Regulation
Ischemia

Keywords

  • Akt
  • MLK3
  • POSH
  • Rac1
  • apoptosis
  • ischemic preconditioning

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. / Zhang, Quanguang; Han, D.; Xu, J.; Lv, Q.; Wang, R.; Yin, X. H.; Xu, T. L.; Zhang, G. Y.

In: Neuroscience, Vol. 143, No. 2, 01.12.2006, p. 431-444.

Research output: Contribution to journalArticle

Zhang, Quanguang ; Han, D. ; Xu, J. ; Lv, Q. ; Wang, R. ; Yin, X. H. ; Xu, T. L. ; Zhang, G. Y. / Ischemic preconditioning negatively regulates plenty of SH3s-mixed lineage kinase 3-Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt. In: Neuroscience. 2006 ; Vol. 143, No. 2. pp. 431-444.
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AU - Han, D.

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AU - Lv, Q.

AU - Wang, R.

AU - Yin, X. H.

AU - Xu, T. L.

AU - Zhang, G. Y.

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AB - Activation of Akt/protein kinase B has been recently reported to play an important role in ischemic tolerance. We here demonstrate that the decreased protein expression and phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) underlie the increased Akt-Ser-473 phosphorylation in the hippocampal CA1 subfield in ischemic preconditioning (IPC). Co-immunoprecipitation analysis reveals that Akt physically interacts with Rac1, a small Rho family GTPase required for mixed lineage kinase 3 (MLK3) autophosphorylation, and both this interaction and Rac1-Ser-71 phosphorylation induced by Akt are promoted in preconditioned rats. In addition, we show that Akt activation results in the disassembly of the plenty of SH3s (POSH)-MLK3-Rac1 signaling complex and down-regulation of the activation of MLK3/c-Jun N-terminal kinase (JNK) pathway. Akt activation 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. The expression of Fas ligand is also decreased in the CA1 region. Akt activation protects against apoptotic neuronal death as shown in TUNEL staining following IPC. Intracerebral infusion of LY294002 before IPC reverses the increase in Akt phosphorylation and the decrease in JNK signaling activation, as well as the neuroprotective action of IPC. Our results suggest that activation of pro-apoptotic MLK3/JNK3 cascade can be suppressed through activating anti-apoptotic phosphoinositide 3-kinase/Akt pathway induced by a sublethal ischemic insult, which provides a functional link between Akt and the JNK family of stress-activated kinases in ischemic tolerance.

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