ArticleBiochemistry2008
Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain.
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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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
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis.Frontiers in cell and developmental biology · 2020Pooled it
- Cell surface liposome binding (CLiB) allows lipid-binding probe engineering via high-throughput screening.Nature cell biology · 2026Article
- The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects.Frontiers in oncology · 2026Review
- AKT1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Discovering Deleterious Single Nucleotide Polymorphisms of Human AKT1 Oncogene: An In Silico Study.Life (Basel, Switzerland) · 2023Article
- Article
- Article
- The PH Domain and C-Terminal polyD Motif of Phafin2 Exhibit a Unique Concurrence in Animals.Membranes · 2022Article
- The AKT1E17K Allele Promotes Breast Cancer in Mice.Cancers · 2022Article
- Structure of autoinhibited Akt1 reveals mechanism of PIPProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia.Nature communications · 2021Article
- Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation.Pharmaceutics · 2021Article
- The Role of mTOR Signaling as a Therapeutic Target in Cancer.International journal of molecular sciences · 2021Review
- Akt Is S-Palmitoylated: A New Layer of Regulation for Akt.Frontiers in cell and developmental biology · 2021Article
- Characterization of AKT Somatic Mutations in Chinese Breast Cancer Patients.Cancer management and research · 2021Article
- A Crosstalk Between Dual-Specific Phosphatases and Dual-Specific Protein Kinases Can Be A Potential Therapeutic Target for Anti-cancer Therapy.Advances in experimental medicine and biology · 2021Article
- Control of Akt activity and substrate phosphorylation in cells.IUBMB life · 2020Review
- Lipid-dependent Akt-ivity: where, when, and how.Biochemical Society transactions · 2019Review
- Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K.Biomolecules · 2019Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The protein kinase AKT1 regulates multiple signaling pathways essential for cell function. Its N-terminal PH domain (AKT1 PH) binds the rare signaling phospholipid phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)], resulting in plasma membrane targeting and phosphoactivation of AKT1 by a membrane-bound kinase. Recently, it was discovered that the Glu17Lys mutation in the AKT1 PH domain is associated with multiple human cancers. This mutation constitutively targets the AKT1 PH domain to the plasma membrane by an unknown mechanism, thereby promoting constitutive AKT1 activation and oncogenesis. To elucidate the molecular mechanism underlying constitutive plasma membrane targeting, this work compares the membrane docking reactions of the isolated wild-type and E17K AKT1 PH domains. In vitro studies reveal that the E17K mutation dramatically increases the affinity for the constitutive plasma membrane lipid PI(4,5)P(2). The resulting PI(4,5)P(2) equilibrium affinity is indistinguishable from that of the standard PI(4,5)P(2) sensor, PLCdelta1 PH domain. Kinetic studies indicate that the effects of E17K on PIP lipid binding arise largely from electrostatic modulation of the dissociation rate. Membrane targeting analysis in live cells confirms that the constitutive targeting of E17K AKT1 PH to plasma membrane, like PLCdelta1 PH, stems from PI(4,5)P(2) binding. Overall, the evidence indicates that the molecular mechanism underlying E17K oncogenesis is a broadened target lipid selectivity that allows high-affinity binding to PI(4,5)P(2). Moreover, the findings strongly implicate the native Glu17 side chain as a key element of PIP lipid specificity in the wild-type AKT1 PH domain. Other PH domains may employ an analogous anionic residue to control PIP specificity.
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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.