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Deciphering the functional role of actin-spectrin-based membrane skeleton in subcellular compartmentalization of signaling proteins and cell signal transduction

破译基于肌动蛋白-血影蛋白的膜骨架在信号蛋白的亚细胞区室化和细胞信号转导中的功能作用

基本信息

批准号：
10673679
负责人：
Ruobo Zhou
金额：
$ 38.82万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

项目摘要

Project Summary/Abstract: Receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and cell adhesion molecules (CAMs) are three major families of cell surface proteins in all eukaryotic cells, and together represent the primary first responders for cells to respond an extracellular stimulus and initiates a variety of signaling pathways to subsequently regulate cell proliferation and differentiation, promote cell survival, and modulate cellular metabolism and cell-to-cell communication. Mutations affecting these signaling pathways result in many human syndromes and diseases, such as various types of neurodegenerative disorders and cancer. The clinical importance of these signaling proteins has motivated the development of targeted therapies designed to block the activation of the membrane receptors and the downstream signal transduction. Increasing evidence has suggested that there is significant signaling crosstalk among these three membrane protein families at the plasma membrane level and these proteins can form highly organized membrane micro- or nano-clusters with unique biochemical and biophysical properties, dictating the signaling outcome. However, the molecular mechanisms by which how such crosstalk and compartmentalization of membrane-associated signaling proteins are initiated and maintained to modulate the sensitivity and specificity of the downstream signaling remain largely elusive. Our recent discovery of a newly identified actin-spectrin-based membrane-associated periodic skeleton (MPS) structure being a signaling platform for RTK transactivation by GPCRs and CAMs in neurons provides molecular insights into how the cooperative action among these cell surface proteins can be coordinated to give rise to the downstream signaling. The objective of this proposal is to combine super-resolution imaging, cell and molecular biology tools, and mass spectrometry analyses, to investigate the distinctively physical molecular mechanisms responsible for the MPS-mediated cell signaling, by identifying the key molecular interactions responsible for the MPS-dependent assembly and disassembly of the signaling protein clusters (i.e., signaling protein complexes) and examining the roles of liquid-liquid phase separation, receptor endocytosis, and contact sites between the plasma membrane and intracellular membrane-bound intracellular organelles in the MPS- mediated cell signaling in neurons. As the spectrin-actin based MPS structures likely exist in other differentiated cell types such as lymphocytes and thereby control lymphocyte development and activation, our analyses will also be extended to examine the role of the MPS in lymphocyte signaling during immune responses Our proposed research will not only broaden our fundamental understanding of cell signal transduction controlled by the membrane skeleton and the phase separation behaviors of signaling proteins in neurons and immune cells, but also help suggest potential drug targets for human diseases including neurodegenerative diseases and cancer.

项目摘要/摘要：受体酪氨酸激酶 (RTK)、G 蛋白偶联受体 (GPCR) 和细胞粘附分子 (CAM) 是所有真核细胞中细胞表面蛋白的三个主要家族，它们共同代表了最初的第一个家族细胞响应细胞外刺激并启动多种信号通路随后调节细胞增殖和分化，促进细胞存活，并调节细胞新陈代谢和细胞间通讯。影响这些信号通路的突变导致许多人类综合症和疾病，例如各种类型的神经退行性疾病和癌症。临床上这些信号蛋白的重要性推动了旨在阻断的靶向疗法的开发膜受体的激活和下游信号转导。越来越多的证据表明表明这三个膜蛋白家族之间存在显着的信号串扰质膜水平，这些蛋白质可以形成高度组织的膜微米或纳米簇独特的生化和生物物理特性决定了信号传导结果。然而，分子膜相关信号蛋白的串扰和区室化的机制被启动和维持以调节下游信号传导的敏感性和特异性仍然在很大程度上难以捉摸。我们最近发现了一种新发现的基于肌动蛋白-血影蛋白的膜相关周期骨架 (MPS) 结构是神经元中 GPCR 和 CAM 进行 RTK 反式激活的信号平台，提供了分子洞察如何协调这些细胞表面蛋白之间的合作作用以提供上升到下游信号。该提案的目标是将超分辨率成像、细胞和分子生物学工具和质谱分析，以研究独特的物理分子通过识别关键的分子相互作用，负责 MPS 介导的细胞信号传导的机制负责信号蛋白簇的 MPS 依赖性组装和分解（即信号传导蛋白质复合物）并检查液-液相分离、受体内吞作用和接触的作用 MPS-中质膜和细胞内膜结合的细胞内细胞器之间的位点介导神经元中的细胞信号传导。由于基于血影蛋白-肌动蛋白的 MPS 结构可能存在于其他分化的细胞类型，例如淋巴细胞，从而控制淋巴细胞的发育和激活，我们的分析将也可以扩展到检查 MPS 在免疫反应期间淋巴细胞信号传导中的作用拟议的研究不仅将拓宽我们对细胞信号转导控制的基本理解神经元和免疫细胞中信号蛋白的膜骨架和相分离行为，还有助于提出人类疾病的潜在药物靶点，包括神经退行性疾病和癌症。