Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Eun Kyoung Yim, Guang Peng, Hui Dai, Ruozhen Hu, Kaiyi Li, Yiling Lu, Gordon B. Mills, Funda Meric-Bernstam, Bryan T. Hennessy, Rolf J. Craven, Shiaw Yih Lin

    Research output: Contribution to journalArticle

    133 Scopus citations

    Abstract

    Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

    Original languageEnglish (US)
    Pages (from-to)304-314
    Number of pages11
    JournalCancer Cell
    Volume15
    Issue number4
    DOIs
    StatePublished - Apr 7 2009

    Keywords

    • CELLCYCLE

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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  • Cite this

    Yim, E. K., Peng, G., Dai, H., Hu, R., Li, K., Lu, Y., Mills, G. B., Meric-Bernstam, F., Hennessy, B. T., Craven, R. J., & Lin, S. Y. (2009). Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function. Cancer Cell, 15(4), 304-314. https://doi.org/10.1016/j.ccr.2009.02.012