"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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528871
• 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.

磷脂酰肌醇（PI）是膜结合的信号分子，调节各种细胞功能。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通过激酶、磷酸酶和磷脂酶的作用来调节，这些酶特异性地定位于不同的亚细胞区室中。因此，磷脂酰肌醇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学性质的离散结构域。大多数PI（4，5）P2在质膜处富集，在那里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，关于调节细胞皮层处PI（4，5）P2富集的信号网络（PI（4，5）P2稳态）知之甚少。我们最近已经鉴定了控制Pi（4，5）P2稳态的果蝇肌醇5-磷酸酶dOCRL（Ben El Kadhi等人，Current biology 2011）。我们证明了dOCRL与内体相关，并且它使内膜上的PI（4，5）P2去磷酸化以限制质膜上的磷酸肌醇。我们表明，该功能对于胞质分裂的保真度是必要的。虽然Pi（4，5）P2稳态对于在质膜处发生的许多功能是重要的，但其调节在很大程度上仍然未知。在这里，我们的目标是确定和表征控制Pi（4，5）P2细胞稳态的信号通路。具体而言，我们的目标是（i）鉴定控制磷酸肌醇循环的酶中的哪一种与dOCRL协作以控制Pi（4，5）P2稳态。(ii)表征dOCRL /Arf 6在调节Pi（4，5）P2稳态中的功能相互作用。这项研究将提供一个更好的了解PI（4，5）P2稳态是如何控制的。我们的中期/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，这两种功能我们在实验室中深入研究。