Effects of phosphatidylserine and oligomerization on activation mechanisms of TAM receptors

磷脂酰丝氨酸和寡聚化对 TAM 受体激活机制的影响

• 批准号: 10084164
• 负责人: Chrystal Starbird
• 金额: $ 6.86万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084164
• 关键词: Address; Adhesions; Adult; Affect; Apoptosis; Apoptotic; Autoimmune Diseases; Binding; Biochemical; Biological Assay; Biological Models; Biophysics; Blood Coagulation Factor; Bone Marrow; Cancer Biology; Cell Adhesion; Cell Differentiation process; Cell Survival; Cell membrane; Cell surface; Cells; Cellular Assay; Cellular Membrane; Cessation of life; Communities; Complex; Cryoelectron Microscopy; Development; Differentiation and Growth; Disease; Elements; Embryonic Development; Environment; Epidermal Growth Factor Receptor; Event; Extracellular Domain; Family; Growth; Growth Factor; Homeostasis; Individual; Inflammation; Institutes; Investigation; Laboratories; Length; Ligands; Lipids; Malignant Neoplasms; Mediating; Membrane; Membrane Lipids; Molecular; Molecular Conformation; N-terminal; Outcome; Output; Phagocytosis; Phosphatidylserines; Phospholipids; Phosphotransferases; Play; Property; Protein S; Proteins; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recombinants; Research; Resources; Role; Signal Transduction; Signaling Protein; Site; Specificity; Stimulus; Structural Models; Structure; Surface; System; Testing; Thrombosis; Training; Transmembrane Domain; Vesicle; Virus Diseases; Work; X-Ray Crystallography; activation product; base; biophysical techniques; cell motility; design; dimer; extracellular; innovation; insight; macrophage; member; migration; new therapeutic target; novel therapeutics; phosphatidylserine receptor; receptor; receptor binding; research facility; response; tool

Project Summary Many signals that control the survival, growth and differentiation of cells are initiated by activation of receptor tyrosine kinases on the surface of the cell. Studies of cellular responses to stimuli often focus on the ligands or proteins that perceive the signal, and the protein receptors that carry the signal into the cell to elicit the desired response. However, the composition of the cellular membranes in which those proteins are submerged can also play a direct role in the signaling response. The current study proposes to elucidate how interaction with specific lipids in the membranes of communicating cells affect receptor activation in the TAM family of receptor tyrosine kinases. TAM receptors comprise a unique family of receptor tyrosine kinases activated not by growth factors, but by ligands that are proposed to directly interact with exposed lipids in activating cells. However, the underlying mechanisms that govern lipid induced receptor activation are poorly understood. The proposed research will employ a combination of biochemical and biophysical methods to investigate the molecular details of how lipids may interact with signaling proteins to induce changes that are then converted into an intracellular response. These studies will mechanistically define lipid-mediated TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer, viral and autoimmune diseases. Our Specific Aims address two main questions: (1) What are the requirements for PtdSer stimulation of TAM- dependent phagocytosis? (2) How does binding of PtdSer to the TAM/ligand complex induce activation of the receptor? This work will take place in the laboratory of Dr. Kathryn Ferguson in the supportive and innovative research environment at the new Yale Cancer Biology Institute. The fellow will have access to a wealth of resources at the various departments across the Yale campuses, including several core research facilities and centers that focus on providing tools and training to advance the research of those within the Yale community and beyond.

项目摘要 许多控制细胞存活、生长和分化的信号都是通过受体的激活来启动的 细胞表面的酪氨酸激酶。细胞对刺激反应的研究通常集中在配体或 感知信号的蛋白质，以及携带信号进入细胞以引发所需信号的蛋白质受体。 反应然而，浸没这些蛋白质的细胞膜的组成也可以 在信号反应中发挥直接作用。目前的研究旨在阐明如何与特定的相互作用， 通讯细胞膜中的脂质影响受体酪氨酸的TAM家族中的受体活化 激酶。TAM受体包括不被生长因子激活的受体酪氨酸激酶的独特家族， 而是通过被提出与暴露的脂质直接相互作用以激活细胞的配体。然而，底层 对控制脂质诱导的受体活化的机制知之甚少。拟议的研究将 采用生物化学和生物物理学方法相结合的方法来研究脂质 可能与信号蛋白相互作用，以诱导变化，然后转化为细胞内的反应。 这些研究将从机制上定义脂质介导的TAM受体激活，并提供重要的见解 其可用于开发癌症、病毒和自身免疫性疾病的新疗法。我们 具体目的解决两个主要问题：（1）TAM的PtdSer刺激要求是什么？ 依赖性吞噬作用？(2)PtdSer与TAM/配体复合物的结合如何诱导 受体？这项工作将在凯瑟琳·弗格森博士的实验室进行， 耶鲁大学癌症生物学研究所的研究环境。这家伙将有机会获得丰富的 资源在耶鲁大学校园的各个部门，包括几个核心研究设施， 中心，专注于提供工具和培训，以促进耶鲁社区内的研究 以及更远的地方