title: A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2.
abstract: Accumulating evidence indicates that dysfunction of mitochondria is a common feature of Parkinson disease. Functional loss of a familial Parkinson disease-linked gene, BRPK/PINK1 (PINK1), results in deterioration of mitochondrial functions and eventual neuronal cell death. A mitochondrial chaperone protein has been shown to be a substrate of PINK1 kinase activity. In this study, we demonstrated that PINK1 has another action point in the cytoplasm. Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. Rictor, a specific component of mTORC2, was phosphorylated by overexpression of PINK1. Furthermore, overexpression of PINK1 enhanced cell motility. These results indicate that PINK1 exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of mTORC2.
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakaguchi
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Futami
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamada
authors.forename: Ken
authors.initials: K
authors.lastname: Kataoka
authors.forename: Nam-ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011471:Prostatic Neoplasms; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002352:Carrier Proteins; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors; D000099202:PTEN-Induced Putative Kinase; C493245:CRTC2 protein, human; C492571:RICTOR protein, human