ArticleNature2014
Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 231 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
231 citing papers in PubMed, 365 citations in OpenAlex.
- Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.Journal of cancer research and clinical oncology · 2024Trial
- CCNA2 orchestrates the PI3K/AKT signaling axis to propel prostate cancer metastasis.Translational andrology and urology · 2026Article
- mTORC2 Phosphorylation of GSDME-N Drives Cullin4B-Mediated Proteasomal Degradation to Suppress Pyroptosis and Confer Radioresistance in Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.Science (New York, N.Y.) · 2026Article
- Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.The Biochemical journal · 2026Review
- Review
- DNA-PKcs orchestrates CTLA-4 depletion-induced senescence in cancer cells.Cell death & disease · 2026Article
- Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants.GeroScience · 2026Article
- Low-dose arsenic exposure disrupts rat uterine physiology independent of generation of oxidative stress.Current research in toxicology · 2026Article
- Transcriptional modulation of the PI3K/AKT/mTOR signaling pathway mediated by HPV16Exploration of targeted anti-tumor therapy · 2026Article
- The structural heterogeneity of AKT autoinhibition.Protein science : a publication of the Protein Society · 2026Article
- cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Cell cycle regulation in cancer cells by O-GlcNAcylation.Glycoconjugate journal · 2025Review
- Structural insights of AKT and its activation mechanism for drug development.Molecular diversity · 2025Review
- Citrullination of AKT2 Catalyzed by PAD1 Facilitates the Maintenance of Stemness Characteristics of Ovarian Cancer Stem-Like Cells in Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Stable Cas9 expression regulates cell growth by facilitating mTORC2 activation.Nucleic acids research · 2025Article
- S100 A16 promotes the progression of osteosarcoma by activating the PI3 K/AKT signaling pathway through ANXA2.Scientific reports · 2025Article
- Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes.The Journal of clinical investigation · 2025Article
- PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.The Journal of experimental medicine · 2025Article
- Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
171 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 4 institutions in 1 country.
Funding
Abstract
Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.
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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.