The lipid kinase PI4KIIIbeta is highly expressed in breast tumours and activates Akt in cooperation with Rab11a.

Emerging evidence now implicates phosphatidylinositol 4-kinases (PI4K), enzymes that generate PI(4)P from phosphatidylinositol (PtdIns), in cancer. In this study we investigate the role of PI4KIIIbeta, one of four mammalian PI4Ks, in breast cancer. While PI4KIIIbeta protein levels are low in normal breast tissue, we find that approximately 20% of primary human breast tumours overexpress it. Expression of PI4KIIIbeta in breast carcinoma cells leads to increased Akt activation, dependent on increased PI(3,4,5)P3 production. However, a kinase-inactive version of PI4KIIIbeta also led to increased Akt activation and no changes in PI(4)P or PI(4,5)P2 lipid abundance were detected in the PI4KIIIbeta-overexpressing cells. This implies that PI4KIIIbeta regulates PI(3,4,5)P3 and Akt independently of PI(4)P production. We find that the PI4KIIIbeta binding protein, Rab11a, a small GTPase that regulates endosomal recycling, is involved in PI4KIIIbeta-mediated activation of Akt, as RNAi depletion of Rab11a impairs Akt activation. Furthermore, ectopic PI4KIIIbeta expression alters cellular Rab11a distribution and enhances recruitment of PI4KIIIbeta and Rab11a to recycling endosomes. This work suggests that PI4KIIIbeta affects PI3K/Akt signalling through Rab11a and endosomal trafficking, independent of its lipid kinase activity. Implications: PI4KIIIbeta likely plays a role in breast oncogenesis and that cooperation between Rab11a and PI4KIIIbeta represents a novel Akt activation pathway.

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