Role of PLSCR in Cell Response to Growth Factors

PLSCR 在细胞对生长因子的反应中的作用

• 批准号: 7219407
• 负责人: THERESE WIEDMER
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219407
• 关键词: Adaptor Signaling Protein; Affect; Animals; Antigens; Apoptosis; Attenuated; Avidity; Binding; Blood; Blood Cells; Blood Platelets; Cell Nucleus; Cell Proliferation; Cell membrane; Cell surface; Cells; Cholesterol; Codon Nucleotides; Cytoplasmic Tail; Data; Disruption; EGF gene; Endocytosis; Epidermal Growth Factor Receptor; Epithelial Cells; Erythrocytes; Exhibits; Fibroblasts; Gene Family; Genetic Transcription; Goals; Growth Factor; Growth Factor Receptors; Hematopoietic; Hematopoietic Cell Growth Factors; Injury; Interleukin-3; Leukocytes; Ligands; Localized; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Movement; Mus; Mutation; N-terminal; Nuclear; Nuclear Import; Numbers; Pathway interactions; Phosphatidylserines; Phospholipids; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor; Play; Principal Investigator; Production; Protein Kinase; Protein Tyrosine Kinase; Proteins; Receptor Activation; Receptor Signaling; Recycling; Reporting; Research; Role; SRC gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sphingomyelins; Structure; Thinking; cell injury; cytokine; fetal; granulocyte; insight; intercalation; member; neutrophil; palmitoylation; phospholipid scramblase; physical property; polypeptide; programs; receptor; receptor density; receptor expression; receptor internalization; research study; response; src-Family Kinases; trafficking; uptake

DESCRIPTION (provided by applicant): Phospholipid scramblase 1 (PLSCR1) is a multiply palmitoylated, endofacial plasma membrane protein first identified in red cells, platelets, leukocytes, and other blood cells, which is thought to mediate the transbilayer movement of membrane phospholipids in response to cell activation, injury, or apoptosis. PLSCR1 has been found associated with several growth factor receptors, including epidermal growth factor receptor (EGF-R). PLSCR1 expression is transcriptionally induced by EGF and related growth factors, and it is phosphorylated by tyrosine kinases that are involved in the signal transduction pathways initiated through EGF-R and related receptors. We recently observed that newly synthesized PLSCR1 can localize to the nucleus, and we found nuclear import of PLSCR1 to occur whenever the polypeptide fails to palmitoylate. By contrast, palmitoylated PLSCR1 is a component of plasma membrane lipid "rafts", cholesterol- and sphingomyelin-rich membrane microdomains that are believed to be involved in both assembly of receptor signaling platforms and the endocytic trafficking of activated EGF-R and related receptors from the plasma membrane. We also observed that neutrophil production and maturation in response to select growth factors is impaired in PLSCR1-/-mice, whereas fibroblasts and epithelial cells from these animals exhibit attenuated responses to EGF and related growth factors, with particular effect on EGF-dependent activation of c-Src. In this Project, we aim to elucidate the role of PLSCR1 in the signaling pathways of EGF-R and related growth factor receptors. Our Specific Aims are: Aim1 -- To determine whether the level of expression of plasma membrane PLSCR1 influences cell surface expression, topology, sensitivity to ligand, and/or receptor-initiated activation of signaling kinases by EGF and related growth factors. AIM2 -- To determine whether PLSCR1 influences the localization of EGF-R to membrane lipid rafts, its interactions with key adaptor proteins and signaling kinases, or its endocytic uptake, endosomal trafficking, and degradation following receptor activation. AIM3 - To identify the mechanism by which PLSCR1 traffics into the nucleus, and to determine what role nuclear PLSCR1 might play in the cellular transcription response to cytokine stimulation. We believe that this research will provide new insights into the regulatory control mechanisms that affect signaling by activated growth factor receptors.

描述（由申请人提供）：磷脂爬行酶1（PLSCR 1）是一种多重棕榈酰化的内表面质膜蛋白，首次在红细胞、血小板、白细胞和其他血细胞中发现，被认为介导膜磷脂响应细胞活化、损伤或凋亡的跨双层运动。已发现PLSCR 1与几种生长因子受体相关，包括表皮生长因子受体（EGF-R）。PLSCR 1表达由EGF和相关生长因子转录诱导，并且其被参与通过EGF-R和相关受体启动的信号转导途径的酪氨酸激酶磷酸化。我们最近观察到新合成的PLSCR 1可以定位于细胞核，并且我们发现每当多肽未能棕榈酰化时，PLSCR 1就会发生核输入。相比之下，棕榈酰化PLSCR 1是质膜脂质“筏”、富含胆固醇和鞘磷脂的膜微结构域的组分，所述膜微结构域被认为参与受体信号传导平台的组装和活化的EGF-R和相关受体从质膜的内吞运输。我们还观察到，中性粒细胞的生产和成熟选择生长因子受损PLSCR 1-/-小鼠，而这些动物的成纤维细胞和上皮细胞表现出减弱的EGF和相关生长因子的反应，特别是EGF依赖性激活c-Src的影响。本研究旨在阐明PLSCR 1在EGF-R及相关生长因子受体信号通路中的作用。我们的具体目标是：目的1-确定质膜PLSCR 1的表达水平是否影响细胞表面表达、拓扑结构、对配体的敏感性和/或EGF和相关生长因子对信号激酶的受体启动激活。目的2-确定PLSCR 1是否影响EGF-R定位于膜脂筏，其与关键衔接蛋白和信号激酶的相互作用，或其内吞摄取，内体运输和受体激活后的降解。目的3-确定PLSCR 1进入细胞核的机制，并确定核PLSCR 1在细胞因子刺激的细胞转录反应中可能发挥什么作用。我们相信，这项研究将提供新的见解的调节控制机制，影响信号的激活生长因子受体。