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Functional inhibition of PI3K by the βGBP molecule suppresses Ras–MAPK signalling to block cell proliferation

Oncogene volume 26, pages 7709–7714 (2007)Cite this article

Abstract

The mechanisms of signal transduction from cell surface receptors to the interior of the cell are fundamental to the understanding of the role that positive and negative growth factors play in cell physiology and in human diseases. Here, we show that a functional link between phosphatidylinositol-3-OH kinase (PI3K) and Ras is suppressed by the β-galactoside binding protein (βGBP) molecule, a cytokine and a negative cell-cycle regulator. Ras–mitogen-activated protein kinase (MAPK) signalling is blocked by βGBP owing to its ability to inhibit the p110 catalytic subunit of PI3K, whose basal activity is required for Ras activation. Functional inhibition of p110 by βGBP results in downregulation of PI3K activity, suppression of Ras-GTP loading, consequent loss of MAPK activation and block of cell proliferation. This study sheds light on the molecular mechanisms whereby βGBP can control cell proliferation and, by extension, may potentially control tumorigenesis by controlling PI3K.

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Acknowledgements

We thank Jun Hirabayashi for H-Gal-1 cDNA in pET21 plasmid, Len Stephens for the gift of antibodies to p110γ, Beth Drees and Paul Neilsen for cooperation in developing the PI3K assay, Pat Warne for technical assistance, Kate Kirwan for art work and John Stirling for critical reading of the manuscript.

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Authors and Affiliations

  1. Pharmaceutical Science Research Division, Cell Signalling and Growth Laboratory, King's College London, London, UK

    V Wells & L Mallucci

  2. Signal Transduction Laboratory, London Research Institute, Lincoln's Inn Fields Laboratories, Cancer Research UK, London, UK

    J Downward

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  1. V Wells
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  2. J Downward
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  3. L Mallucci
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Correspondence to L Mallucci.

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Wells, V., Downward, J. & Mallucci, L. Functional inhibition of PI3K by the βGBP molecule suppresses Ras–MAPK signalling to block cell proliferation. Oncogene 26, 7709–7714 (2007). https://doi.org/10.1038/sj.onc.1210580

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