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

“控制 Pi(4,5)P2 细胞稳态的信号通路的识别和表征。”

• 批准号: 386426-2012
• 负责人: Carréno, Sébastien
• 金额: $ 1.89万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=595938
• 关键词: Identification; characterization; signaling; pathways; controlling

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.

磷酸肌醇 (PI) 是膜结合信号分子，可调节多种细胞功能。 PI 在细胞膜上产生，影响许多细胞过程，例如细胞分裂和迁移。特定 PI 的空间限制和稳态水平通过激酶、磷酸酶和磷脂酶的作用进行调节，这些酶、磷酸酶和磷脂酶专门位于不同的亚细胞区室中。因此，不同膜上的磷酸肌醇分离参与膜结构异质性，并产生具有独特物理和生物学特性的离散域。大部分 PI(4,5)P2 富集在质膜上，它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，人们对调节细胞皮层 PI(4,5)P2 富集（Pi(4,5)P2 稳态）的信号网络知之甚少。我们最近发现了一种果蝇肌醇 5-磷酸酶 dOCRL，它控制 Pi(4,5)P2 稳态（Ben El Kadhi 等人，Current Biology 2011）。我们证明 dOCRL 与内涵体相关，并且它使内膜上的 PI(4,5)P2 去磷酸化，以限制这种磷酸肌醇在质膜上。我们证明该功能对于胞质分裂的保真度是必要的。虽然 Pi(4,5)P2 稳态对于质膜上发生的众多功能很重要，但其调节仍然很大程度上未知。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) 确定哪种控制磷酸肌醇循环的酶与 dOCRL 协作来控制 Pi(4,5)P2 稳态。 (ii) 表征 dOCRL / Arf6 调节 Pi(4,5)P2 稳态的功能相互作用。这项研究将有助于更好地理解 PI(4,5)P2 稳态是如何控制的。我们的中长期目标是整合 PI(4,5)P2 稳态研究产生的知识，进一步了解需要维持 PI(4,5)P2 稳态的细胞功能，例如细胞分裂和细胞迁移，这是我们在实验室深入研究的两个功能。