Ceramide Activated Protein Phosphatases

神经酰胺激活蛋白磷酸酶

• 批准号: 10734669
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 39.54万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734669
• 关键词: Acute; Address; Adhesions; Apoptosis; Basic Science; Biochemical; Biological Assay; Cell Adhesion; Cell Death; Cell membrane; Cell physiology; Cells; Ceramidase; Ceramides; Cessation of life; Development; Elements; Enzymes; Event; Family; Generations; Goals; Grant; Growth; Human; Hydroxylation; In Vitro; Length; Lipids; Measures; Mediating; Membrane; Membrane Microdomains; Metabolism; Molecular; Pathway interactions; Phorbol Esters; Phosphoric Monoester Hydrolases; Production; Productivity; Protein Dephosphorylation; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Protein translocation; Proteins; Publishing; Quantitative Evaluations; Regulation; Role; Scheme; Signal Pathway; Signal Transduction; Sphingolipids; Sphingomyelinase; Sphingosine; Stimulus; TNF gene; Time; acid sphingomyelinase; biological adaptation to stress; cancer cell; cell fixing; cell growth; cell motility; combinatorial; experimental study; ezrin; liquid chromatography mass spectrometry; migration; novel; programs; response; senescence; stem; targeted cancer therapy; tumor progression

Ceramide constitutes a family of closely related molecules that function as bioeffector lipids with roles in the regulation of stress responses and growth/death of various human cancer cells. Critical missing elements in our understanding of ceramide stem from the lack of defining compartment-specific functions of ceramides and from lack of molecularly- defined targets of action. Studies in our lab supported by this project have identified ceramide-activated Ser–Thr phosphatases (CAPPs), specifically PP1 and PP2A as direct targets activated by ceramide in vitro. Recent results have provided us a breakthrough in defining a specific pathway of ceramide generation at the plasma membrane (PM). Here, we will investigate the hypothesis that ceramide generated at the PM acutely activates PP1α that leads to the dephosphorylation of distinct proteins, launching a distinct program of regulation of cell adhesion and migration. We are also developing a novel assay to quantitate PM ceramide specifically. With this breakthrough, we will address these aims: Aim 1. Develop a quantitative assay to measure ceramide generation at the PM and define key enzymes of ceramide metabolism in this compartment (steady state). Aim 2. Define stimulus-induced formation of PM ceramide and the mechanisms involved. Aim 3. Define biochemical mechanisms of regulation of PP1a by PM ceramide. Taken together, these approaches should result, for the first time, in clearly defining a specific, direct, and relevant target for ceramide action (PP1) with a specific function in mediating the effects of PM ceramide on cell adhesion and migration.

神经酰胺构成一个与生物效应的密切相关的分子家族 脂质在调节压力反应和各种人的生长/死亡中的作用 癌细胞。我们对神经酰胺的理解中的批判性缺失元素源于 缺乏神经酰胺的定义隔室特异性功能，并且缺乏分子 定义的动作目标。该项目支持的我们的实验室研究已经确定 神经酰胺激活的Ser-Thr磷酸酶（CAPP），特别是PP1和PP2A直接 靶标在体外被神经酰胺激活。最近的结果为我们带来了突破 在质膜（PM）上定义神经酰胺生成的特定途径。这里， 我们将研究在PM急性激活下产生神经酰胺的假设 PP1α导致不同蛋白质的去磷酸化，启动了一个独特的程序 细胞粘附和迁移的调节。我们也正在开发一种新颖的测定 专门定量PM神经酰胺。通过这一突破，我们将解决这些目标： 目标1。开发定量测定，以测量PM的神经酰胺的产生，并 定义神经酰胺代谢的关键酶（稳态）。目标2。 定义刺激诱导的PM神经酰胺的形成和所涉及的机制。目标3。 定义PM Ceramide对PP1A调节的生化机制。在一起， 这些方法应首次明确定义特定，直接和 神经酰胺作用的相关目标（PP1）具有介导效果的特定功能 PM神经酰胺在细胞粘附和迁移方面。

项目成果

ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding.

• DOI: 10.1016/j.isci.2023.107145
• 发表时间: 2023-07-21
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Al-Rashed, Fatema;Haddad, Dania;Al Madhoun, Ashraf;Sindhu, Sardar;Jacob, Texy;Kochumon, Shihab;Obeid, Lina M.;Al-Mulla, Fahd;Hannun, Yusuf A.;Ahmad, Rasheed
• 通讯作者: Ahmad, Rasheed