title: Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.
abstract: In Alzheimer disease (AD), the microtubule-associated protein tau is highly phosphorylated and aggregates into characteristic neurofibrillary tangles. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) 1 and 2, members of the sterile 20 family of kinases, have been shown to regulate microtubule stability and organization. Here we show that tau is a good substrate for PSK1 and PSK2 phosphorylation with mass spectrometric analysis of phosphorylated tau revealing more than 40 tau residues as targets of these kinases. Notably, phosphorylated residues include motifs located within the microtubule-binding repeat domain on tau (Ser-262, Ser-324, and Ser-356), sites that are known to regulate tau-microtubule interactions. PSK catalytic activity is enhanced in the entorhinal cortex and hippocampus, areas of the brain that are most susceptible to Alzheimer pathology, in comparison with the cerebellum, which is relatively spared. Activated PSK is associated with neurofibrillary tangles, dystrophic neurites surrounding neuritic plaques, neuropil threads, and granulovacuolar degeneration bodies in AD brain. By contrast, activated PSKs and phosphorylated tau are rarely detectible in immunostained control human brain. Our results demonstrate that tau is a substrate for PSK and suggest that this family of kinases could contribute to the development of AD pathology and dementia.
authors.affiliation: Division of Cancer Studies, King's College London, New Hunt's House, Guy's Campus, Great Maze Pond, London SE1 1UL, London.
authors.forename: Ignatius A
authors.initials: IA
authors.lastname: Tavares
authors.forename: Dona
authors.initials: D
authors.lastname: Touma
authors.forename: Steven
authors.initials: S
authors.lastname: Lynham
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Megan
authors.initials: M
authors.lastname: Schober
authors.forename: Mirsada
authors.initials: M
authors.lastname: Causevic
authors.forename: Ritu
authors.initials: R
authors.lastname: Garg
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Richard
authors.initials: R
authors.lastname: Killick
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodi
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Jonathan D H
authors.initials: JD
authors.lastname: Morris
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002522:Chlorocebus aethiops; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases; C115483:TAO1 protein kinase; D020930:MAP Kinase Kinase Kinases
keywords: Alzheimer Disease; Kinase; MAP Kinases (MAPKs); MAPs; Neurodegenerative Diseases; Neurofibrillary Tangles; PSK Kinases; Phosphorylation; Signal Transduction; Tau