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.

神经酰胺是一类密切相关的生物效应分子

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