title: Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function.
abstract: The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Fitzgerald
authors.forename: M D
authors.initials: MD
authors.lastname: Camprubi
authors.forename: L
authors.initials: L
authors.lastname: Dunn
authors.forename: H-C
authors.initials: HC
authors.lastname: Wu
authors.forename: N Y
authors.initials: NY
authors.lastname: Ip
authors.forename: R
authors.initials: R
authors.lastname: Kruger
authors.forename: L M
authors.initials: LM
authors.lastname: Martins
authors.forename: N W
authors.initials: NW
authors.lastname: Wood
authors.forename: H
authors.initials: H
authors.lastname: Plun-Favreau
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse