ArticleeLife2022
PH domain-mediated autoinhibition and oncogenic activation of Akt.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 29 citations in OpenAlex.
- The proximal lipid phase of PI3K signaling is confined to the plasma membrane.bioRxiv : the preprint server for biology · 2026Article
- Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.The Biochemical journal · 2026Review
- A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant.The Journal of biological chemistry · 2026Article
- Review
- The structural heterogeneity of AKT autoinhibition.Protein science : a publication of the Protein Society · 2026Article
- Single-molecule lipid biosensors mitigate inhibition of endogenous effector proteins.The Journal of cell biology · 2025Article
- Single molecule Lipid Biosensors Mitigate Inhibition of Endogenous Effector Proteins.bioRxiv : the preprint server for biology · 2025Article
- Article
- Latent allosteric control of protein interactions by ATP-competitive kinase inhibitors.Current opinion in structural biology · 2024Review
- Capturing Autoinhibited PDK1 Reveals the Linker's Regulatory Role, Informing Innovative Inhibitor Design.Journal of chemical information and modeling · 2024Article
- Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease.Scientific reports · 2024Article
- Article
- Kaposi's sarcoma-associated herpesvirus viral protein kinase augments cell survival.Cell death & disease · 2023Article
- A Novel FYVE Domain-Containing Protein Kinase, PsZFPK1, Plays a Critical Role in Vegetative Growth, Sporangium Formation, Oospore Production, and Virulence inJournal of fungi (Basel, Switzerland) · 2023Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Akt is a Ser/Thr protein kinase that plays a central role in metabolism and cancer. Regulation of Akt's activity involves an autoinhibitory intramolecular interaction between its pleckstrin homology (PH) domain and its kinase domain that can be relieved by C-tail phosphorylation. PH domain mutant E17K Akt is a well-established oncogene. Previously, we reported that the conformation of autoinhibited Akt may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu et al., 2020). Here, we discover unexpectedly that a single mutation R86A Akt exhibits intensified autoinhibitory features with enhanced PH domain-kinase domain affinity. Structural and biochemical analysis uncovers the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity. Our studies also shed light on the molecular basis for E17K Akt activation as an oncogenic driver.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.