title: PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways.
abstract: The proline-rich Akt substrate of 40kDa (PRAS40) protein is not only a substrate of the protein kinase Akt but also a component of the mTOR complex 1 (mTORC1), thus it links the Akt and the mTOR pathways. We investigated the potential protective role of PRAS40 in cerebral ischemia and its underlying mechanisms by using rats with lentiviral over-expression of PRAS40 and mice with PRAS40 gene knockout (PRAS40 KO). Our results show that gene transfer of PRAS40 reduced infarction size in rats by promoting phosphorylation of Akt, FKHR (FOXO1), PRAS40, and mTOR. In contrast, PRAS40 KO increased infarction size. Although the PRAS40 KO under normal condition did not alter baseline levels of phosphorylated proteins in the Akt and mTOR pathways, PRAS40 KO that underwent stroke exhibited reduced protein levels of p-S6K and p-S6 in the mTOR pathway but not p-Akt, or p-PTEN in the Akt pathway. Furthermore, co-immunoprecipitation suggests that there were less interactive effects between Akt and mTOR in the PRAS40 KO. In conclusion, PRAS40 appears to reduce brain injury by converting cell signaling from Akt to mTOR.
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Weiying
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kovacina
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA. Electronic address: hzhao@stanford.edu.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018014:Gene Transfer Techniques; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C516104:Akt1s1 protein, rat; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C508191:proline-rich Akt substrate, 40 kDa protein, mouse; C074639:Foxo1 protein, rat; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt; Focal cerebral ischemia; PRAS40; PTEN; Stroke; mTOR