Effects of phosphatidylserine and oligomerization on activation mechanisms of TAM receptors

项目摘要 许多控制细胞生存、生长和分化的信号是由受体激活而启动的 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，以及将信号携带到细胞内以引发所需 回应。然而，浸泡这些蛋白质的细胞膜的组成也可以 在信号响应中起直接作用。目前的研究建议解释如何与特定的 通讯细胞膜中的脂质影响受体酪氨酸家族的受体激活 激活剂。受体组成了一个独特的受体酪氨酸激酶家族，不是由生长因子激活的， 而是被认为在激活细胞时直接与暴露的脂类相互作用的配体。然而，潜在的 控制脂质诱导受体激活的机制还知之甚少。拟议的研究将 使用生化和生物物理方法相结合的方法来研究脂质如何产生的分子细节 可能与信号蛋白相互作用，诱导变化，然后转化为细胞内反应。 这些研究将从机制上定义脂质介导的受体激活，并提供重要的见解 这可能用于开发治疗癌症、病毒和自身免疫性疾病的新疗法。我们的 具体目标主要解决两个问题：(1)对的PtdSer刺激有什么要求-- 依赖的吞噬作用？(2)PtdSer与/配体复合体的结合如何诱导细胞活化 受体？这项工作将在凯瑟琳·弗格森博士的实验室中进行支持和创新 在新的耶鲁癌症生物研究所的研究环境。这家伙将有机会获得一大笔 耶鲁大学校园各个部门的资源，包括几个核心研究设施和 专注于提供工具和培训以推动耶鲁社区内的研究的中心 以及更远的地方。

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.