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

不同输出的单独池：TORC1 细胞生长信号通路中的分工

• 批准号: BB/V016334/1
• 负责人: Riko Hatakeyama
• 金额: $ 67.51万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016334%2F1
• 关键词: Separate; pools; distinct; outputs; Division

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.

该项目旨在了解酶TORC 1如何以区室化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调节它们的生长和增殖，以响应波动的环境线索。不这样做会导致严重的疾病，如癌症和糖尿病，以及衰老。细胞生长和代谢的中心调节因子是雷帕霉素复合物1的靶标（TORC 1），一种属于激酶家族的酶。激酶通过用负电荷修饰靶蛋白（“磷酸化”）来控制靶蛋白的功能。TORC 1整合了各种细胞生长信号，包括激素和营养素，反过来又刺激了各种细胞过程。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在人体生理学中的关键重要性及其作为治疗靶点的潜力提供了明确的证据。然而，TORC1信号传导的普遍性和重要性意味着干扰TORC1的治疗具有引起严重副作用（如高血糖症）的高风险。3.我们的目标是什么？该项目旨在揭示TORC 1如何根据特定的刺激差异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TORC 1功能，而不是抑制它们。它将为治疗TORC1相关疾病的更有效方法打开大门，副作用的风险更低。我们的想法从何而来？我之前的研究表明，TORC 1在细胞内的不同位置形成了独立的池，每个池在其空间邻近处磷酸化不同的蛋白质。我用面包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。TORC 1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TORC 1确实在两个亚细胞位置形成了独立的池，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被特异性刺激差异激活。这些结果表明酵母TORC 1通过在核内体和溶酶体的空间上不同的池来划分其功能。在这个项目中我们将做什么？我们将研究内体和溶酶体TORC1库调节细胞反应的分子机制。我们将利用现有的工具和酵母知识，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到哪里？对特异性激活内体或溶酶体TORC1的分子的理解将提示以池特异性方式干扰TORC1的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TORC 1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来对抗癌症、糖尿病和衰老。

项目成果

Pib2 as an Emerging Master Regulator of Yeast TORC1.

PIB2是酵母Torc1的新兴主调节器。

• DOI: 10.3390/biom11101489
• 发表时间: 2021-10-09
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Hatakeyama R

The Yeast Protein Kinase Sch9 Functions as a Central Nutrient-Responsive Hub That Calibrates Metabolic and Stress-Related Responses.

• DOI: 10.3390/jof9080787
• 发表时间: 2023-07-26
• 期刊: JOURNAL OF FUNGI
• 影响因子: 4.7
• 作者: Caligaris, Marco;Sampaio-Marques, Belem;Hatakeyama, Riko;Pillet, Benjamin;Ludovico, Paula;De Virgilio, Claudio;Winderickx, Joris;Nicastro, Raffaele
• 通讯作者: Nicastro, Raffaele

The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1.

• DOI: 10.1371/journal.pgen.1010641
• 发表时间: 2023-02
• 期刊: PLoS genetics
• 影响因子: 4.5