{"doi":"10.17615/75j7-e290","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.","journal":"UNC Libraries","year":2020,"id":110227,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":526001,"name":"U. K. Jinwal","orcid":null,"position":1,"is_corresponding":false},{"id":526002,"name":"J. Dunmore","orcid":null,"position":2,"is_corresponding":false},{"id":526003,"name":"J. Koren","orcid":null,"position":3,"is_corresponding":false},{"id":526004,"name":"C. A. Dickey","orcid":null,"position":4,"is_corresponding":false},{"id":393788,"name":"C. Patterson","orcid":null,"position":5,"is_corresponding":false},{"id":526005,"name":"R. M. Bailey","orcid":null,"position":6,"is_corresponding":false},{"id":525122,"name":"Minjian Sun","orcid":"0009-0001-0588-3717","position":7,"is_corresponding":false},{"id":526006,"name":"L. Petrucelli","orcid":null,"position":8,"is_corresponding":false},{"id":526007,"name":"Y.-J. Zhang","orcid":null,"position":9,"is_corresponding":false},{"id":526008,"name":"B. Monks","orcid":null,"position":10,"is_corresponding":false},{"id":526009,"name":"C. Leon","orcid":null,"position":11,"is_corresponding":false},{"id":526010,"name":"S. Soresh","orcid":null,"position":12,"is_corresponding":false},{"id":526011,"name":"Y.-f. Xu","orcid":null,"position":13,"is_corresponding":false},{"id":526012,"name":"D. Morgan","orcid":null,"position":14,"is_corresponding":false},{"id":526013,"name":"Michael Birnbaum","orcid":null,"position":15,"is_corresponding":false},{"id":526000,"name":"J. Q. Cheng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:12:57.988348Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}