Ceramide Activated Protein Phosphatases

神经酰胺激活蛋白磷酸酶

基本信息

批准号：
10208802
负责人：
YUSUF AWNI HANNUN
金额：
$ 36.49万
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/10208802
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.

神经酰胺构成一个与密切相关的分子的家族，该家族起作用生物效应脂质在调节压力反应和生长/死亡中具有作用各种人类癌细胞。我们对神经酰胺的理解中的批判性缺失元素源于缺乏分子定义的作用靶标，并定义神经酰胺的特异性功能。该项目支持的我们的实验室研究已经确定了神经酰胺激活的Ser-thR磷酸酶（CAPP），特别是PP1和 PP2A作为由神经酰胺在体外激活的直接靶标。细胞的研究也显示了各种神经酰胺诱导的刺激（例如TNF，UV，脂肪毒性剂）会影响以神经酰胺依赖性方式对几种底物的去磷酸化。但是，不是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不同的亚细胞隔室中的途径。最近的结果为我们提供了在定义血浆中神经酰胺的特定途径方面的突破膜（PM）。在这里，我们将研究神经酰胺在 PM急性激活PP1Cα，导致Ezrin和其他蛋白质。这导致神经酰胺在调节细胞中的特定作用粘附和迁移。我们将解决以下目的：目标1。定义一个新颖的途径在PM处产生神经酰胺，导致Ezrin dephosphority通过激活 pp1cα。在这里，我们将调查PM神经酰胺调节A的特定假设二聚体pp1c的特定形式介导ezrin的去磷酸化，与筏无关形成。目标2。确定特定的蜂窝程序与分隔的耦合神经酰胺/CAPP。在这里，我们将调查Ceramide PM Ceramide的具体假设与其他隔间中形成的神经酰胺相比，调节细胞粘合剂和迁移。综上所述，这些方法应首次显然导致定义具有特定的神经酰胺作用（PP1）的特定，直接和相关的目标在介导PM神经酰胺对细胞粘附和迁移的影响方面起作用。