ArticleProceedings of the National Academy of Sciences of the United States of America2012
Disruption of PH-kinase domain interactions leads to oncogenic activation of AKT in human cancers.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 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
94 citing papers in PubMed, 148 citations in OpenAlex.
- AKT mutant allele-specific activation dictates pharmacologic sensitivities.Nature communications · 2022Trial
- Effect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor: NCI-MATCH Subprotocol EAY131-Y Nonrandomized Trial.JAMA oncology · 2021Trial
- Results of an abbreviated phase-II study with the Akt Inhibitor MK-2206 in Patients with Advanced Biliary Cancer.Scientific reports · 2015Trial
- Computational analysis of the structural and functional impact of the deleterious nsSNPs in the humanBiochemistry and biophysics reports · 2026Article
- The structural heterogeneity of AKT autoinhibition.Protein science : a publication of the Protein Society · 2026Article
- Challenging AlphaFold in predicting proteins with large-scale allosteric transitions.Communications chemistry · 2025Article
- Pulmonary sclerosing pneumocytoma with rapid progression: a case description of serial images.Quantitative imaging in medicine and surgery · 2025Article
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- Live-Cell NanoBRET Assay to Measure AKT Inhibitor Binding to Conformational States of AKT.ACS chemical biology · 2025Article
- AKT and DUBs: a bidirectional relationship.Cellular & molecular biology letters · 2025Review
- Article
- AKT1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Zinc ions activate AKT and promote prostate cancer cell proliferation via disrupting AKT intramolecular interaction.Oncogene · 2025Article
- Prioritizing cancer therapeutic genes using BioRank: A biologically-informed PageRank framework.Computational and structural biotechnology journal · 2025Article
- AKT kinases as therapeutic targets.Journal of experimental & clinical cancer research : CR · 2024Review
- Autoinhibited Protein Database: a curated database of autoinhibitory domains and their autoinhibition mechanisms.Database : the journal of biological databases and curation · 2024Article
- Genomic Characterization of Preclinical Prostate Cancer Cell Line Models.International journal of molecular sciences · 2024Article
- Network-based prediction approach for cancer-specific driver missense mutations using a graph neural network.BMC bioinformatics · 2023Article
- CircFam190a: a critical positive regulator of osteoclast differentiation via enhancement of the AKT1/HSP90β complex.Experimental & molecular medicine · 2023Article
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Molecular cancer · 2023Review
34 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
27 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH-KD interface and found that most of them lead to constitutive activation of AKT. Such mutations are likely another mechanism by which activation may occur in human cancers and other diseases. In support of this likelihood, we found somatic mutations in AKT1 at the PH-KD interface that have not been previously described in human cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively active, leading to oncogenic signaling. Additionally, our studies show that the AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors, consistent with the requirement for an intact PH-KD interface for allosteric inhibition. These results have important implications for therapeutic intervention in patients with AKT mutations at the PH-KD interface.
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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.