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

点击翻译按钮获取中文摘要

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.