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

磷酸肌苷（PI）是调节多种细胞功能的膜结合信号分子。pi在细胞膜上产生，并影响许多细胞过程，如细胞分裂和迁移。特定pi的空间限制和稳态水平是通过激酶、磷酸酶和磷脂酶的作用来调节的，这些酶特异性地定位于不同的亚细胞区室。因此，磷酸肌肽在不同膜上的分离参与了膜结构的异质性，并产生了具有独特物理和生物特性的离散结构域。大部分PI(4,5)P2富集于质膜，参与几乎所有涉及细胞表面的事件，包括细胞分裂和迁移。然而，对于调节细胞皮层PI(4,5)P2富集的信号网络（PI(4,5)P2稳态）知之甚少。我们最近发现了一种控制Pi(4,5)P2稳态的果蝇肌醇5-磷酸酶dOCRL （Ben El Kadhi et al., Current biology 2011）。我们证明了dOCRL与核内体相关，并且它会使细胞膜上的PI(4,5)P2去磷酸化，从而在质膜上限制这种磷酸肌肽。我们发现这个功能对于细胞分裂的保真度是必要的。虽然Pi(4,5)P2稳态对质膜上发生的许多功能都很重要，但其调控机制在很大程度上仍然未知。在这里，我们的目标是识别和表征控制Pi(4,5)P2细胞稳态的信号通路。具体来说，我们的目标是：(i)确定哪一种控制磷酸肌苷循环的酶与dOCRL协同控制Pi(4,5)P2的稳态。（ii）表征dOCRL / Arf6在调节Pi(4,5)P2稳态中的功能相互作用。这项研究将更好地理解PI(4,5)P2稳态是如何被控制的。我们的中长期目标是整合PI(4,5)P2稳态研究产生的知识，以进一步了解需要维持PI(4,5)P2稳态的细胞功能，如细胞分裂和细胞迁移，这是我们在实验室中深入研究的两个功能。

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.