Akt and CHIP coregulate tau degradation through coordinated interactions
Open accessAbstract
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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AKT phosphorylates and enhances PAR-1 activity.
“AKT phosphorylates and enhances PAR-1 activity (125).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [125]
The Results report that Akt binds PAR1/MARK2 and increases PAR1-associated phosphorylation of tau; the Discussion describes possible regulation of PAR1/MARK2 activity. Neither section shows that Akt phosphorylates PAR1 itself, and the Results leave open whether Akt activates PAR1 or instead makes tau more accessible to it (page numbers unavailable). (LLM, conf=0.88)
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- Authors
- Dickey, C. A., Koren, J., Zhang, Y.-J., Xu, Y.-F., Jinwal, U. K., Birnbaum, M. J., Monks, B., Sun, M., Cheng, J. Q., Patterson, C., Bailey, R. M., Dunmore, J., Soresh, S., Leon, C., Morgan, D., & Petrucelli, L.
- Affiliations
- University of South Florida (US)
- Mayo Clinic (US)
- Howard Hughes Medical Institute (US)
- University of North Carolina at Chapel Hill (US)
- *Department of Molecular Pharmacology and Physiology and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-03-04
- Volume
- 105
- Issue
- 9
- Pages
- 3622-3627
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2265134
- OpenAlex
- W2075401349
- Cited by
- 226
- References
- 21
- Citations by year
- 2026: 15 · 2025: 11 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 10 · 2018: 15 · 2017: 15 · 2016: 11 · 2015: 10 · 2014: 18 · 2013: 9 · 2012: 16
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Alzheimer's Association
- American Federation for Aging Research
- CurePSP
- National Institutes of Health (AG17216)
- National Institute on Aging (K99AG031291, R01-AG17216-08, R00AG031291, P01AG017216, K99-AG31291)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK56886, R01DK056886)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Akt, CHIP, tau degradation, tau phosphorylation, HSP90, ubiquitination, Alzheimer's disease, tau aggregation, protein quality control
- MeSH terms
- Alzheimer Disease, Animals, Phosphorylation, tau Proteins, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, HSP90 Heat-Shock Proteins, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-akt, Mice
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