PH domain-mediated autoinhibition and oncogenic activation of Akt
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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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Viennet, T. (2025) · Journal of Structural Biology · doi:10.1016/j.jsb.2025.108192
Self-citationDong, J., Li, J., Zhu, Z. L., Zhang, H., Sun, C., Gao, F., & Ye, X. (2026) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2026.105547
Tian, D., wei, L., Zhao, Y.-H., Zhao, C., Luo, X., Feng, J., & Zhao, S. (2026) · Industrial Crops and Products · doi:10.1016/j.indcrop.2026.123102
The proximal lipid phase of PI3K signaling is confined to the plasma membranePreprint
Ricci, M. M. C., Patel, H., Montoya, M. J., Jayasuriya, K. L., Rectenwald, A., Motter, M. A. K., Wills, R. C., & Hammond, G. R. V. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.08.723799
BindingDB (2025) · UC San Diego · doi:10.7270/q20v8jd8
- Authors
- Bae, H., Viennet, T., Park, E., Chu, N., Salguero, A., Eck, M. J., Arthanari, H., & Cole, P. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Eck, Michael J
- Arthanari, Haribabu
- Cole, Philip A
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-08-15
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9417420
- OpenAlex
- W4291552265
- Cited by
- 31
- References
- 63
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 7
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R01CA74305, R35CA242461, K22CA241105, R50 CA221830)
- Claudia Adams Barr Program (Grant)
- National Institutes of Health (EB002026)
- Kwanjeong Educational Foundation (Fellowship)
- National Institute of General Medical Sciences (R01GM136859)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Akt, pleckstrin homology domain, autoinhibition, allosteric regulation, kinase domain
- MeSH terms
- Pleckstrin Homology Domains, Oncogenes, Phosphorylation, Signal Transduction, Proto-Oncogene Proteins c-akt
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