title: Assembly of the FKBP51-PHLPP2-AKT signaling complex in cerebral ischemia/reperfusion injury in rats.
abstract: The imbalance of cell pro-death and pro-survival signaling pathways determines the neuronal fate during cerebral ischemia/reperfusion (I/R) injury. However, the biological mechanisms regulating the balance between activation of the pro-death or the pro-survival signaling pathways remain unclear. In this study, a rat model of I/R injury was established using four-vessel occlusion followed by different times of reperfusion. I/R injury did not affect the level of FK506 binding protein 51 (FKBP51), PH domain and leucine rich repeat protein phosphatases (PHLPP)-2, and AKT, but induced assembly of the FKBP51-PHLPP2-AKT signaling complex, as indicated by the enhancement of interactions among these compounds following reperfusion. Using an antisense oligonucleotide, PHLPP2 expression was effectively inhibited. Critically, the inhibition of PHLPP2 prohibited the interactions of FKBP51, PHLPP2 and AKT, reversed the decrease of p-AKT expression and increased the expression of p-JNKs and p-c-Jun elicited by I/R injury. In addition, PHLPP2 inhibition reversed I/R-injury-induced Caspase-3 cleavage and loss of pyramid neurons in the CA1 region of hippocampus. The results of the current study indicate that the assembly of the FKBP51-PHLPP2-AKT signaling complex plays a critical role in mediating cell death in I/R injury. The inhibition of PHLPP2 via antisense oligonucleotide treatment may be an effective method to prohibit the assembly of the FKBP51-PHLPP-AKT signaling complex, thus balancing the cell pro-survival and pro-death signaling pathways ultimately mitigating cell death in I/R injury.
authors.affiliation: The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China. Electronic address: wxeqq@163.com.
authors.forename: Xiu-E
authors.initials: XE
authors.lastname: Wei
authors.affiliation: Liaocheng Hospital, Liaocheng 252000, China.
authors.forename: Feng-Yu
authors.initials: FY
authors.lastname: Zhang
authors.affiliation: The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
authors.forename: Qing-Xiu
authors.initials: QX
authors.lastname: Zhang
authors.affiliation: The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
authors.forename: Liang-Qun
authors.initials: LQ
authors.lastname: Rong
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; C541124:PHLPP2 protein, rat; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins
keywords: Cell death; FKBP51–PHLPP–AKT signaling complex; PHLPP2; p-AKT; p-JNKs