title: Crosstalk Between MAPK/ERK and PI3K/AKT Signal Pathways During Brain Ischemia/Reperfusion.
abstract: The epidermal growth factor receptor (EGFR) is linked to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Raf/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK1/2) signaling pathways. During brain ischemia/reperfusion, EGFR could be transactivated, which stimulates these intracellular signaling cascades that either protect cells or potentiate cell injury. In the present study, we investigated the activation of EGFR, PI3K/AKT, and Raf/MAPK/ERK1/2 during ischemia or reperfusion of the brain using the middle cerebral artery occlusion model. We found that EGFR was phosphorylated and transactivated during both ischemia and reperfusion periods. During ischemia, the activity of PI3K/AKT pathway was significantly increased, as judged from the strong phosphorylation of AKT; this activation was suppressed by the inhibitors of EGFR and Zn-dependent metalloproteinase. Ischemia, however, did not induce ERK1/2 phosphorylation, which was dependent on reperfusion. Coimmunoprecipitation of Son of sevenless 1 (SOS1) with EGFR showed increased association between the receptor and SOS1 in ischemia, indicating the inhibitory node downstream of SOS1. The inhibitory phosphorylation site of Raf-1 at Ser259, but not its stimulatory phosphorylation site at Ser338, was phosphorylated during ischemia. Furthermore, ischemia prompted the interaction between Raf-1 and AKT, while both the inhibitors of PI3K and AKT not only abolished AKT phosphorylation but also restored ERK1/2 phosphorylation. All these findings suggest that Raf/MAPK/ERK1/2 signal pathway is inhibited by AKT via direct phosphorylation and inhibition at Raf-1 node during ischemia. During reperfusion, we observed a significant increase of ERK1/2 phosphorylation but no change in AKT phosphorylation. Inhibitors of reactive oxygen species and phosphatase and tensin homolog restored AKT phosphorylation but abolished ERK1/2 phosphorylation, suggesting that the reactive oxygen species-dependent increase in phosphatase and tensin homolog activity in reperfusion period relieves ERK1/2 from inhibition of AKT.
authors.affiliation: Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, P. R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Du
authors.affiliation: Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, P. R. China.
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.affiliation: Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Rong
authors.affiliation: Faculty of Life Science, The University of Manchester, UK Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain University of Nizhny Novgorod, Russia.
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.affiliation: Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, P. R. China hkkid08@yahoo.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D002545:Brain Ischemia / Q000201:enzymology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D020244:Infarction, Middle Cerebral Artery; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology; D020837:SOS1 Protein / Q000378:metabolism
chemical_list: D020837:SOS1 Protein; D019869:Phosphatidylinositol 3-Kinases; C483803:Egfr protein, rat; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; EGF receptor; ERK; PTEN; Raf-1; brain ischemia