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bioRxiv · 10.1101/2020.02.10.942177

Activation of Rab11a and endocytosis by Phosphatidylinositol 4-kinase III beta promotes oncogenic signaling in breast cancer

MacDonald, S.·Harding, K.·Bilodeau, P.·de Souza, C.·Campa, C.·Hirsch, E.·Auer, R.·Lee, J.
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Abstract

Endosomes are now recognized as important sites for regulating signal transduction. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIII{beta}) regulates both endocytic kinetics and receptor signaling in breast cancer cells. PI4KIII{beta} generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of breast cancers. However, the molecular mechanism by which PI4KIII{beta} promotes breast cancer is unclear. We demonstrate that ectopic PI4KIII{beta} expression increases the rates of both endocytic internalization and recycling. PI4KIII{beta} 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 PI4KIII{beta} activates IGF-IR{beta} signaling dependent on endosome function. Regulation of endocytic function by PI4KIII{beta} is independent of its kinase activity but requires interaction with the Rab11a. This suggests that PI4KIII{beta} controls endosomal kinetics and signaling by directly modulating Rab11a function. Our work suggests a novel regulatory role for PI4KIII{beta} in endosome function and plasma membrane receptor signaling.

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MacDonald, S., Harding, K., Bilodeau, P., de Souza, C., Campa, C., Hirsch, E., Auer, R., Lee, J.. 2020-02-11. Activation of Rab11a and endocytosis by Phosphatidylinositol 4-kinase III beta promotes oncogenic signaling in breast cancer. https://doi.org/10.1101/2020.02.10.942177

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