title: Akt and CHIP coregulate tau degradation through coordinated interactions.
abstract: A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.
authors.affiliation: Department of Molecular Pharmacology and Physiology and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA. cdickey1@health.usf.edu
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Bobby
authors.initials: B
authors.lastname: Monks
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Bailey
authors.forename: Judith
authors.initials: J
authors.lastname: Dunmore
authors.forename: Sareh
authors.initials: S
authors.lastname: Soresh
authors.forename: Carlos
authors.initials: C
authors.lastname: Leon
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000544:Alzheimer Disease; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D016875:tau Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C122043:Mark2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt