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Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit

Oncogene volume 31, pages 897–906 (2012)Cite this article

Abstract

The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ-overexpression-mediated Akt phosphorylation, and its potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P=0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by small interfering RNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of phosphoinositide 3-kinase (PI3K). Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3-binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage-independent growth and enhanced stress-induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.

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Acknowledgements

This work is supported by grants from NIH P30-CA 16672 (MDACC); RO1-CA112567, PO1-CA099031 project 4, Department of Defense (DOD) Center of Excellence (BC050006) subproject, DOD Synergistic Award W81XWH-08-1-0712 and Susan G Komen Breast Cancer Foundation Promise Grant KG091020 (D Yu). Dr Dihua Yu is the Hubert L and Olive Stringer Distinguished Chair in Basic Science, MDACC. We thank Dr Lewis Cantley for providing p85 knockout MEFs. We also thank X Du, K Matias, T Chen, J Hannay, S Zhang and S Rehman for reagents, suggestions and manuscript reading.

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  1. C L Neal and J Xu: These authors contributed equally to this paper

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C L Neal, J Xu, P Li, S Mori, J Yang, N N Neal, X Zhou, S L Wyszomierski & D Yu

  2. Cancer Biology Program, the University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    J Xu, J Yang & D Yu

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  1. C L Neal
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  2. J Xu
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  3. P Li
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Correspondence to D Yu.

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Neal, C., Xu, J., Li, P. et al. Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit. Oncogene 31, 897–906 (2012). https://doi.org/10.1038/onc.2011.284

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