"Identification and characterization of the signaling pathways controlling Pi(4,5)P2 cell homeostasis."

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Phosphoinositides (PI) are membrane-bound signaling molecules that regulate a wide variety of cellular functions. PIs are produced at cellular membranes and influence a number of cellular processes such as cell division and migration. The spatial restriction and steady-state levels of specific PIs are regulated through the actions of kinases, phosphatases and phospholipases, which are specifically localized in different sub-cellular compartments. Therefore, phosphoinositide segregation on different membranes participates to membrane structural heterogeneity and creates discrete domains with unique physical and biological properties. Majority of the PI(4,5)P2 is enriched at the plasma membrane where it participates in nearly all events that involve the cell surface including cell division and migration. However little is known about the signaling network that regulates enrichment of PI(4,5)P2 at the cellular cortex (Pi(4,5)P2 homeostasis). We have recently identified a Drosophila inositol 5-phosphatase, dOCRL, that controls Pi(4,5)P2 homeostasis (Ben El Kadhi et al., Current biology 2011). We demonstrated that dOCRL is associated with endosomes and that it dephosphorylates PI(4,5)P2 on internal membranes to restrict this phosphoinositide at the plasma membrane. We showed that this function was necessary for the fidelity of cytokinesis. While Pi(4,5)P2 homeostasis is important for numerous function occurring at the plasma membrane, its regulation remains largely unknown. Here, we aim to identify and characterize the signaling pathways controlling Pi(4,5)P2 cell homeostasis. Specifically our goals are to (i) To identify which of the enzyme controlling the phosphoinositide cycle collaborates with dOCRL to control Pi(4,5)P2 homeostasis. (ii) To characterize dOCRL / Arf6 functional interactions for the regulation of Pi(4,5)P2 homeostasis. This study will provide a better understanding on how PI(4,5)P2 homeostasis is controlled. Our mid/long-term objective is to integrate the knowledge generated by the study of PI(4,5)P2 homeostasis to further understand cellular functions that require the maintenance of PI(4,5)P2 homeostasis such as cell division and cell migration, two functions we study intensively in the laboratory.