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Ceramide Activated Protein Phosphatases

神经酰胺激活蛋白磷酸酶

基本信息

批准号：
10434893
负责人：
YUSUF AWNI HANNUN
金额：
$ 35.76万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-12 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434893
关键词：
Actins Acute Address Adhesions Apoptosis Basic Science Biochemical Biological Cell Adhesion Cell Compartmentation Cell Cycle Regulation Cell Death Cell membrane Cell physiology Cells Ceramides Cessation of life Coupled Development Elements Enzymes Event Family Generations Goals Growth Human Hydroxylation In Vitro Lipids Mediating Membrane Metabolism Molecular Nature Pathway interactions Phosphoric Monoester Hydrolases Production Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Regulation Role Scheme Signal Pathway Specificity Sphingolipids Sphingomyelinase Stimulus TNF gene Time biological adaptation to stress cancer cell cell growth cell growth regulation cell motility combinatorial dimer ezrin liquid chromatography mass spectrometry migration novel programs prototype radixin protein response senescence stem targeted cancer therapy tumor progression

项目摘要

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 stems from the lack of molecularly-defined targets of action and from defining compartment-specific functions of ceramides. 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. Studies in cells have also shown that various ceramide-inducing stimuli (e.g. TNF, UV, lipotoxic agents) induce dephosphorylation of several substrates in a ceramide-dependent manner. However, not all stimuli induce all dephosphorylations, presumably due to their activation of distinct pathways in distinct subcellular compartments. 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 PP1cα that leads to the dephosphorylation of ezrin and other proteins. This results in a compartment-specific role for ceramide in regulating cell adhesion and migration. We will address these aims: Aim 1. Define a novel pathway of ceramide generation at the PM leading to ezrin dephosphorylation though activation of PP1cα. Here we will investigate the specific hypothesis that PM ceramide regulates a specific form of dimeric PP1c to mediate ezrin dephosphorylation, independent of raft formation. Aim 2. Identify specific cellular programs coupled to compartmentalized ceramide/CAPPs. Here we will investigate the specific hypothesis that PM ceramide, in contrast to ceramide formed in other compartments, regulates cell adhesion and migration. 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.

神经酰胺构成了一系列密切相关的分子，其功能如下：生物效应脂质在应激反应和生长/死亡的调节中发挥作用各种人类癌细胞。我们对神经酰胺的理解中缺失的关键元素源于缺乏分子定义的行动目标和定义神经酰胺的区室特异性功能。我们实验室的研究受到该项目的支持已经鉴定出神经酰胺激活的丝氨酸-苏氨酸磷酸酶 (CAPP)，特别是 PP1 和 PP2A 作为体外神经酰胺激活的直接靶标。细胞研究还表明各种神经酰胺诱导刺激（例如 TNF、紫外线、脂毒剂）会诱导以神经酰胺依赖性方式对几种底物进行去磷酸化。然而，不所有刺激都会诱导所有去磷酸化，大概是由于它们激活了不同的不同亚细胞区室中的通路。最近的结果为我们提供了在定义等离子体中神经酰胺生成的特定途径方面取得突破膜（PM）。在这里，我们将研究神经酰胺在以下位置产生的假设： PM 急剧激活 PP1cα，导致埃兹蛋白和其他物质去磷酸化蛋白质。这导致神经酰胺在调节细胞中发挥特定的作用粘附和迁移。我们将实现以下目标：目标 1. 定义一条新颖的途径 PM 处产生神经酰胺，通过激活 ezrin 去磷酸化 PP1cα。在这里，我们将研究 PM 神经酰胺调节的具体假设介导埃兹蛋白去磷酸化的二聚体 PP1c 的特定形式，与筏无关形成。目标 2. 识别与区室化耦合的特定细胞程序神经酰胺/CAPP。在这里我们将研究 PM 神经酰胺的具体假设，与其他区室中形成的神经酰胺相比，调节细胞粘附和迁移。总而言之，这些方法应首次产生明确的结果定义一个具体的、直接的和相关的神经酰胺作用目标（PP1）介导 PM 神经酰胺对细胞粘附和迁移的影响。