References
Query Results -- Details
MGI Accession ID: MGI:3776678
J Number: J:132677
Other Accession IDs:
Title: Akt and CHIP coregulate tau degradation through coordinated interactions.
Authors: Dickey CA; Koren J; Zhang YJ; Xu YF; Jinwal UK; Birnbaum MJ; Monks B; Sun M; Cheng JQ; Patterson C; Bailey RM; Dunmore J; Soresh S; Leon C; Morgan D; Petrucelli L
Journal: Proc Natl Acad Sci U S A
Volume: 105
Issue: 9
Date: 2008 Mar 4
Year: 2008
Pages: 3622-7
Review Status: Peer Reviewed
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.
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