Roles of sphingosine-1 phosphate phosphohydrolase

1 磷酸鞘氨醇磷酸水解酶的作用

• 批准号: 7999977
• 负责人: SARAH SPIEGEL
• 金额: $ 1.57万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-07 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999977
• 关键词: Anabolism; Apoptosis; Attenuated; Biological Availability; Biological Process; Biology; Cardiovascular Diseases; Cell Nucleus; Cell surface; Cells; Ceramides; Cloning; Elements; Endoplasmic Reticulum; Equilibrium; Event; Family; Inflammation; Knowledge; Ligands; Lipids; Malignant Neoplasms; Mediating; Metabolism; Molecular; Phosphoric Monoester Hydrolases; Physiological; Play; Regulation; Research; Role; Signal Transduction; Sphingolipids; Stress; allergic response; angiogenesis; autocrine; cell growth; cell motility; cellular targeting; inorganic phosphate; lipid mediator; mitochondrial autophagy; prototype; receptor; sphingosine 1-phosphate; sphingosine kinase; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase

Sphingosine-1 -phosphate (S1P) is a bioactive lipid produced from the metabolism of sphingolipids that regulates vital biological processes, among which cell growth, survival, and motility are prominent. It is now well established that S1P is the ligand for a family of specific GPCRs, the S1PRs. Its intracellular actions are rar less understood, but it antagonizes apoptosis mediated by ceramide, a stress-induced sphingolipid metabolite. Due to the pivotal roles of S1P, its levels are low and tightly regulated in a spatial-temporal manner by the balance between sphingosine kinase-dependent synthesis and degradation by an endoplasmic reticulum S1P lyase and still not well-characterized phosphohydrolase activities. Cloning of S1P phosphatases, prototypes of a highly conserved class of lipid phosphate phosphohydrolases, will now enable us to use molecular approaches to examine their importance in regulation of sphingolipid metabolites and should help to unravel their physiological functions. It is our hypothesis that S1P phosphatases are not only important in S1P metabolism but also have previously unrecognized roles in regulating ceramide biosynthesis and are gateways that determine the dynamic balance of these two sphingolipids and consequently, cell fate decisions. We will thus examine how S1P phosphatases act as molecular switches between autophagy and mitochondrial-dependent events leading to apoptosis. We will also evaluate the possibility that S1P phosphatases play a role in termination of S1P signaling at the cell surface. If so, this could be an important physiological and pharmacological target for controlling the bioavailability of S1P at the S1PRs. As S1P can act in an autocrine manner, we will examine the notion that S1P phosphatases regulate "inside-out" signaling by reducing intracellular levels of SIP and attenuating signals through its receptors important for cell locomotion. Emphasis will be on regulation by S1P phosphatases of key elements of directed cell movement downstream of S1 PRs. In addition, we will determine the intracellular functions of S1P in the nucleus and identify its direct cellular target(s). Knowledge of how the S1P phosphatases regulate the bioactive lipid mediator S1P and its functions both outside and inside cells not only represents a new research avenue of basic biology, it also has many biomedical implications, especially for cancer, angiogenesis, cardiovascular disorders, inflammation and allergic responses.

鞘氨醇-1-磷酸（S1 P）是由鞘脂代谢产生的生物活性脂质， 调节重要的生物过程，其中细胞生长，存活和运动是突出的。现在 已经确定S1 P是一个特异性GPCR家族（S1 PR）的配体。它的细胞内作用是 很少有人了解，但它能拮抗神经酰胺介导的细胞凋亡，神经酰胺是一种应激诱导的鞘脂 代谢物。由于S1 P的关键作用，其水平较低且在时空上受到严格调控。 通过鞘氨醇激酶依赖性合成和降解之间的平衡， 内质网S1 P裂解酶和仍然没有很好地表征磷酸水解酶活性。的克隆 S1 P磷酸酶是一类高度保守的脂质磷酸水解酶的原型，现在将 使我们能够使用分子方法来研究它们在调节鞘脂代谢物中的重要性 应该有助于揭示它们的生理功能我们假设S1 P磷酸酶不是 不仅在S1 P代谢中很重要，而且在调节神经酰胺中也有以前未认识到的作用 是决定这两种鞘脂动态平衡的通道， 决定细胞的命运。因此，我们将研究S1 P磷酸酶如何作为分子开关 自噬和导致细胞凋亡的细胞依赖性事件之间的联系。我们还将评估 S1 P磷酸酶可能在细胞表面S1 P信号的终止中起作用。如果是这样， 可能是控制S1 P生物利用度的重要生理和药理学靶点， S1PRs。由于S1 P可以自分泌方式发挥作用，我们将研究S1 P磷酸酶 通过降低细胞内SIP水平并通过其减弱信号来调节“由内而外”的信号传导 对细胞运动很重要的受体。重点将是调节S1 P磷酸酶的关键 S1 PRs下游定向细胞运动的元件。此外，我们将确定细胞内 S1 P在细胞核中的功能，并确定其直接的细胞靶点。了解S1 P如何 磷酸酶调节生物活性脂质介质S1 P及其在细胞内外的功能， 它不仅代表了基础生物学的一条新的研究途径，而且具有许多生物医学意义，特别是 用于癌症、血管生成、心血管疾病、炎症和过敏反应。