Zinc ions activate AKT and promote prostate cancer cell proliferation via disrupting AKT intramolecular interaction

Prostate is a zinc rich organ and the physiological function of the abundant zinc ions is relatively less understood. AKT kinase is a pivotal regulator downstream of cytokines, growth factors and other extracellular stimuli, and the attachment of its PH domain to PtdIns-3,4,5-P3 (PIP3) and the subse...

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Bibliographic Details
Published in:Oncogene 2025-01, Vol.44 (1), p.8-18
Main Authors: Wang, Kangjunjie, Chen, Min, Yan, Shukun, Han, Ying, Yuan, Huairui, Liu, Qiuli, Lu, Dayun, Li, Long, Wang, Kaihua, Liu, Fen, Li, Qianqian, Luo, Dakui, Jiang, Jun, Zhou, Hu, Chen, Yong, Qin, Jun, Gao, Daming
Format: Article
Language:English
Subjects:
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AKT protein
AKT1 protein
Apoptosis
Cell Biology
Cell proliferation
Growth factors
Human Genetics
Internal Medicine
Ions
Medicine
Medicine & Public Health
Mutants
Oncology
Phosphatidylinositol 3,4,5-triphosphate
Phosphorylation
Prostate cancer
Tumors
Zinc
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Summary:Prostate is a zinc rich organ and the physiological function of the abundant zinc ions is relatively less understood. AKT kinase is a pivotal regulator downstream of cytokines, growth factors and other extracellular stimuli, and the attachment of its PH domain to PtdIns-3,4,5-P3 (PIP3) and the subsequent phosphorylation of its kinase domain by PDPK1 are considered important for its activation. Herein, we report a regulatory mechanism of AKT kinase by zinc ions. Mechanistically, zinc ions directly bind to AKT and facilitate AKT activation through disrupting the interaction between PH and kinase domains within AKT molecule. Consistently, AKT1-H89A/E91A mutant (zinc-binding-deficient) fails to respond to zinc ions and exhibits strong interaction between PH and kinase domains, and it is less oncogenic in orthotopic xenograft model of prostate cancer. On the other hand, the AKT1-W80L mutant with minimum intra-molecular interaction between PH and kinase domains shows strong tumor promoting capacity although it could not be further stimulated by zinc ions. Overall, this study reveals a distinctive regulatory mechanism of AKT activation and implies a tumor promoting role of the zinc ions in prostate cancer.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-024-03195-x