Endosomes are now recognized as important sites for regulating signal transduction. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates both endocytic kinetics and receptor signaling in breast cancer cells. PI4KIIIβ generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of breast cancers. However, the molecular mechanism by which PI4KIIIβ promotes breast cancer is unclear. We demonstrate that ectopic PI4KIIIβ expression increases the rates of both endocytic internalization and recycling. PI4KIIIβ deletion reduces endocytic kinetics accompanied by a concomitant decrease in activity of the Rab11a GTPase, a protein required for endocytic function. Finally, we find that PI4KIIIβ activates IGF-IRβ signaling dependent on endosome function. Regulation of endocytic function by PI4KIIIβ is independent of its kinase activity but requires interaction with the Rab11a. This suggests that PI4KIIIβ controls endosomal kinetics and signaling by directly modulating Rab11a function. Our work suggests a novel regulatory role for PI4KIIIβ in endosome function and plasma membrane receptor signaling.
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