MECHANISM & REGULATION OF RECEPTOR G PROTEIN SIGNALING

G蛋白依赖的信号通路调节由许多激素、炎症介质、神经递质和感觉刺激触发的生物过程，从而协调成人一系列不同的细胞、组织和器官功能。这些途径也调节胚胎发育。G蛋白信号通路的紊乱与许多人类疾病有关，包括癌症、心力衰竭、哮喘和内分泌紊乱。G蛋白信号通路是当今临床药物中超过一半的靶点。因此，G蛋白信号通路的基础研究将继续揭示新的疾病机制，并推动用于治疗各种人类疾病的新型治疗剂的发现进程。该项目的长期目标是阐明受体和G蛋白在控制真核细胞增殖、分化和形态发生的细胞-细胞信号通路中的作用机制。两个主要的挑战是确定受体如何激活G蛋白，以及信号通路的下游成分如何调节细胞的运动和形态发生。为了回答这些问题，本项目使用酿酒酵母的交配信息素反应途径作为模型，直接适用于包括人类在内的许多其他真核生物的细胞。对酵母中G蛋白信号的研究揭示了新的机制，后来被证明用于人类细胞。提出了以下具体目标：1.受体如何激活G蛋白？2.寡聚是否调节受体组装、转运到质膜、信号传递或下调？3.PAK家族激酶如何调节肌动蛋白细胞骨架组织？

G protein dependent signaling pathways regulate biological processes triggered by many hormones, inflammatory mediators, neurotransmitters and sensory stimuli, thereby coordinating a diverse array of cell, tissue and organ functions in the adult. These pathways also regulate embryonic development. Perturbations of G protein signaling pathways are associated with many human diseases, including cancer, heart failure, asthma and endocrine disorders. G protein signaling pathways are the targets of more than half of the drugs used today in clinical medicine. Therefore, basic research of G protein signaling pathways will continue to reveal novel disease mechanisms and fuel the discovery process for novel therapeutic agents used to treat a variety of human diseases. The long term goal of this project is to delineate the mechanisms whereby receptors and G proteins function in cell-cell signaling pathways that control the proliferation, differentiation and morphogenesis of eukaryotic cells. Two major challenges are to determine how receptors activate G proteins, and how downstream components of the signaling pathway regulate cell motility and morphogenesis. To answer these questions, this project uses the mating pheromone response pathway of the yeast S. cerevisiae as a model that is directly applicable to cells of many other eukaryotic organisms including humans. Studies of G protein signaling in yeast have revealed novel mechanisms that later have been shown to be used in human cells. The following specific aims are proposed: 1. How do receptors activate G proteins? 2. Does oligomerization regulate receptor assembly, trafficking to the plasma membrane, signaling, or downregulation? 3. How do PAK family kinases regulate actin cytoskeletal organization?