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Dynamic regulation of Ras signaling – a novel way to attenuate PI3K activity in cancer and inflammation

Final Report Summary - PI3KACT (Dynamic regulation of Ras signaling - a novel way to attenuate PI3K activity in cancer and inflammation)


Despite the growing knowledge concerning the inherent mechanisms driving inflammatory and allergic disease, present anti-inflammatory treatments mostly target symptoms or broadly suppress the immune system. Current medication displays little target cell selectivity, causes adverse effects, and impairs host defense.

In allergy, mast cell activation is central to disease progression. We have demonstrated earlier, that phosphoinositide 3-kinase ? (PI3K?) is a central signalling enzyme in hematopoietic cell recruitment and mast cell degranulation. PI3K? is a heterodimer composed of a p110? catalytic and a p84 or p101 adapter subunit. The adapter subunits have distinct expression patterns: p101 is highly expressed in lymphocytes, macrophages and neutrophils, while p84 is the only adapter protein present in mast cells. Moreover, it was recently demonstrated that the p84/p110? PI3K? complex, but not the PI3K?. p101/p110? requires GTP-loaded Ras for its activation. We therefore proposed that the Ras-PI3K? axis could represent a promising target for a specific regulation of mast cell activity.

In this project, we have shown that attenuation of Ras signalling using farnesyltransferase inhibitors (FTIs) interferes with various PI3K?-dependent functions of mast cells, such as the activation of protein kinase B (PKB/Akt), migration, and the release of histamine containing granules. PI3K?-dependent macrophage activation and migration were, however, maintained in the presence of FTIs. Our results demonstrate the important role of Ras in mast cell migration and activation, and represent a proof of concept for cell specific targeting of PI3K?.

Moreover, we described a new mast cell specific phosphorylation event that regulates Ras-PI3K? interaction and therefore activation of mast cells. We have shown that upon IgE/antigen stimulation and Ca2+ influx a residue in the Ras binding domain of PI3K? becomes phosphorylated. This phosphorylation is mediated by PKCß and leads to the abrogation of Ras-PI3K? interaction. Altogether our results reveal a new approach to a fine-tuned control of PI3K?-dependent responses in mast cells, opening novel routes to alleviate allergic disease without general suppression of the immune system.