The Lipid Kinase PI4KIIIb Is Highly Expressed in Breast Tumors 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 PI4KIIIb, one of four mammalian PI4Ks, in breast cancer. Although PI4KIIIb protein levels are low in normal breast tissue, we find that approximately 20% of primary human breast tumors overexpress it. Expression of PI4KIIIb in breast carcinoma cells leads to increased Akt activation, dependent on increased PI(3,4,5)P3 production. However, a kinase-inactive version of PI4KIIIb also led to increased Akt activation, and no changes in PI(4)P or PI(4,5)P2 lipid abundancewere detected in the PI4KIIIb-overexpressing cells. This implies that PI4KIIIb regulates PI(3,4,5)P3 and Akt independent of PI(4)P production. We find that the PI4KIIIb-binding protein, Rab11a, a small GTPase that regulates endosomal recycling, is involved in PI4KIIIb-mediated activation of Akt, as RNAi depletion of Rab11a impairs Akt activation. Furthermore, ectopic PI4KIIIb expression alters cellular Rab11a distribution and enhances recruitment of PI4KIIIb and Rab11a to recycling endosomes. This work suggests that PI4KIIIb affects PI3K/Akt signaling through Rab11a and endosomal trafficking, independent of its lipid kinase activity. Thus, PI4KIIIb likely plays a role in breast oncogenesis and that cooperation between Rab11a and PI4KIIIb represents a novel Akt activation pathway. Mol Cancer Res; 12(10); 1492–508. 2014 AACR.