ArticleProceedings of the National Academy of Sciences of the United States of America2011
Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
What it found
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Who cites it
57 citing papers in PubMed, 90 citations in OpenAlex.
- PHLPP is neither a Phosphatase nor a Tumor Suppressor.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Isoform-specific regulation of PKM by acetylation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural insights of AKT and its activation mechanism for drug development.Molecular diversity · 2025Review
- Fedratinib in chronic kidney disease: antifibrotic potential and renal safety signals from integrated network toxicology and pharmacovigilance.Renal failure · 2025Article
- Live-Cell NanoBRET Assay to Measure AKT Inhibitor Binding to Conformational States of AKT.ACS chemical biology · 2025Article
- AKT1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- AGC family kinase of Entamoeba histolytica: Decoding the members biochemically.PLoS pathogens · 2024Article
- A conserved role for AKT in the replication of emerging flaviviruses in vertebrates and vectors.Virus research · 2024Article
- Altered Metabolism and Inflammation Driven by Post-translational Modifications in Intervertebral Disc Degeneration.Research (Washington, D.C.) · 2024Article
- Combined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathways.Biochemistry and biophysics reports · 2023Article
- Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy.Molecular biomedicine · 2022Review
- Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development.Scientific reports · 2022Article
- Article
- Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor.Journal of medicinal chemistry · 2022Article
- Galvanotactic Migration of Glioblastoma and Brain Metastases Cells.Life (Basel, Switzerland) · 2022Article
- The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy.The Journal of biological chemistry · 2021Article
- Structure of autoinhibited Akt1 reveals mechanism of PIPProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Sensitivity to targeted therapy differs between HER2-amplified breast cancer cells harboring kinase and helical domain mutations in PIK3CA.Breast cancer research : BCR · 2021Article
- Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells.PloS one · 2021Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Phosphorylation of a threonine residue (T308 in Akt1) in the activation loop of Akt kinases is a prerequisite for deregulated Akt activity frequently observed in neoplasia. Akt phosphorylation in vivo is balanced by the opposite activities of kinases and phosphatases. Here we describe that targeting Akt kinase to the cell membrane markedly reduced sensitivity of phosphorylated Akt to dephosphorylation by protein phosphatase 2A. This effect was amplified by occupancy of the ATP binding pocket by either ATP or ATP-competitive inhibitors. Mutational analysis revealed that R273 in Akt1 and the corresponding R274 in Akt2 are essential for shielding T308 in the activation loop against dephosphorylation. Thus, occupancy of the nucleotide binding pocket of Akt kinases enables intramolecular interactions that restrict phosphatase access and sustain Akt phosphorylation. This mechanism provides an explanation for the "paradoxical" Akt hyperphosphorylation induced by ATP-competitive inhibitor, A-443654. The lack of phosphatase resistance further contributes insight into the mechanism by which the human Akt2 R274H missense mutation may cause autosomal-dominant diabetes mellitus.
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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.