Separate pools for distinct outputs: Division of labour in the TORC1 cell growth signalling pathway

该项目旨在了解TORC1酶如何以分区的方式控制细胞功能的不同方面。什么是TORC1？我们身体的单个细胞根据波动的环境信号调节它们的生长和增殖。如果不这样做，就会导致严重的疾病，如癌症和糖尿病，以及衰老。雷帕霉素复合体1 （TORC1）是细胞生长和代谢的中心调节因子，是一种属于激酶家族的酶。激酶通过带负电荷修饰靶蛋白（“磷酸化”）来控制靶蛋白的功能。TORC1整合了包括激素和营养物质在内的各种细胞生长信号，进而刺激多种细胞过程。2. 为什么TORC1很重要，突出的问题是什么？TORC1抑制剂显示出抗癌和抗衰老作用，为TORC1在人体生理学中的重要作用及其作为治疗靶点的潜力提供了明确的证据。然而，TORC1信号的普遍性和重要性意味着干扰TORC1的治疗有很高的风险引起严重的副作用，如高血糖。3. 我们的目标是什么？该项目旨在揭示基于特定刺激的TORC1如何差异地控制特定的细胞过程。了解分子机制将使我们能够选择性地操纵特定的TORC1功能，而不是抑制它们。这将为更有效地治疗torc1相关疾病、降低副作用风险打开大门。我们的想法从何而来？我之前的研究表明，TORC1在细胞内的不同位置形成单独的池，每个池磷酸化其空间邻近的不同蛋白质。我用面包师的酵母测试了这种可能性，这是一种为实验研究提供主要技术优势的系统。TORC1的大多数结构和功能特征在酵母和人类之间是共享的，因此我们在酵母中发现的也可能适用于我们的细胞。我发现酵母TORC1确实在两个亚细胞位置形成单独的池，称为内体和溶酶体。此外，我发现这两个池磷酸化不同的靶蛋白。重要的是，我的初步证据表明，内体和溶酶体TORC1在特定刺激下被不同的激活。这些结果表明酵母TORC1通过在核内体和溶酶体中不同的空间池来划分其功能。在这个项目中我们要做什么？我们将研究通过内体和溶酶体TORC1池调节细胞反应的分子机制。我们将利用酵母现有的工具和知识，并将我们的研究扩展到人类细胞。这个项目将来会把我们带向何方？了解特异性激活内体或溶酶体TORC1的分子将为以池特异性方式干扰TORC1提供有吸引力的药物靶点。它将使我们能够选择性地操纵所需的TORC1功能子集，从而设计出全新的、更有效的、无副作用的治疗策略，以对抗癌症、糖尿病和衰老。

This project aims to understand how the enzyme TORC1 controls different aspects of cellular functions in a compartmentalized manner.1. What is TORC1?Individual cells of our body modulate their growth and proliferation in response to fluctuating environmental cues. Failure to do so causes serious diseases such as cancer and diabetes, as well as aging. A central regulator of cell growth and metabolism is the Target of Rapamycin Complex 1 (TORC1), an enzyme belonging to the kinase family. Kinases control functioning of target proteins by modifying them with negative charge ("phosphorylation"). TORC1 integrates various cell growth signals including hormones and nutrients, and in turn, stimulates diverse cellular processes. 2. Why is TORC1 important, and what is the outstanding problem?Inhibitors of TORC1 show anti-cancer and anti-aging effects, providing clear evidence of the critical importance of TORC1 in human physiology and its potential as a therapeutic target. However, the prevalence and importance of TORC1 signaling means therapies that interfere with TORC1 have a high risk of causing serious side effects such as hyperglycemia. 3. What is our goal?The proposed project aims to uncover how TORC1 differentially controls specific cellular processes, based on the particular stimulus. Understanding the molecular mechanisms will enable us to selectively manipulate specific TORC1 functions, rather than inhibiting them all. It will open the door to more efficient ways of treating TORC1-related diseases, with lower risk of side effects.4. Where does our idea come from?My previous research suggests that TORC1 forms separate pools at different locations inside the cell, each of which phosphorylates distinct proteins in its spatial proximity. I tested this possibility using baker's yeast, a system that offers major technical advantages for experimental investigation. Most structural and functional features of TORC1 are shared between yeast and human, so what we discover in yeast is also likely to be true for our cells. I discovered that yeast TORC1 indeed forms separate pools at two subcellular locations called endosomes and lysosomes. Moreover, I found that these two pools phosphorylate distinct target proteins. Importantly, my preliminary evidence suggests that endosomal and lysosomal TORC1 are differentially activated by specific stimuli. These results show that yeast TORC1 compartmentalizes its functions via spatially distinct pools at endosomes and lysosomes.5. What will we do in this project?We will investigate the molecular mechanisms through which endosomal and lysosomal TORC1 pools regulate cellular responses. We will take advantage of available tools and knowledge in yeast, and also extend our study to human cells.6. Where will this project take us in the future?Understanding of the molecules that specifically activate either endosomal or lysosomal TORC1 will suggest attractive drug targets for interfering with TORC1 in a pool-specific manner. It will enable us to selectively manipulate a desired subset of TORC1 functions, and thereby design completely novel, more efficient and side effect-free therapeutic strategies against cancer, diabetes and aging.