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

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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.