title: Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury.
abstract: 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.
authors.affiliation: Department of Neurobiology and Biophysics, University of Science and Technology of China, Hefei, Anhui, China.
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Xiao-Tian
authors.initials: XT
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Yin
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000037:antagonists & inhibitors; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006624:Hippocampus / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D000079424:Tumor Necrosis Factor Inhibitors; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D048948:14-3-3 Proteins; D053148:Caspase 3; D020169:Caspases; D045304:Cytochromes c; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D048057:Mitogen-Activated Protein Kinase 10; D018696:Neuroprotective Agents; D051059:PTEN Phosphohydrolase; D017027:Protein Tyrosine Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D000079424:Tumor Necrosis Factor Inhibitors; D014443:Tyrosine; D014638:Vanadates; D051028:bcl-2-Associated X Protein; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C505662:Faslg protein, rat; C505410:Casp3 protein, rat; C499134:Rac1 protein, rat