A PP2A Regulatory Nexus Modulating Hippo Signalling and Growth

点击翻译按钮获取中文摘要

The growth of tissues during development and adult life is the result of a fine balancing act between cell proliferation, differentiation and death. Understanding the mechanisms that regulate tissue growth is one of the key unanswered questions in biology. It is increasingly clear that growth is tightly connected with tissue structure and that, in pathological conditions, tissue structure is severely affected, leading to tissue abnormalities.The Hippo pathway is one of the most important signalling cascades controlling tissue growth, and it responds to alterations in tissue architecture. This signalling cascade includes several steps, some of which are mediated by proteins whose function can be modified by the attachment of different chemical and biochemical entities, in a process termed post-translational modification. Phosphorylation is one such post-translational process in the cell, which consists of the attachment of a phosphate group to other proteins. This is a reversible process that involves a complex machinery of proteins that attach or remove the modification from other proteins. Phosphorylation changes the properties of proteins by affecting their stability, localisation in the cell or function.We have previously found that the phosphatase PP2A blocks the activity of the Hippo pathway as part of a large protein complex. Recently, when studying in detail how tissue structure controls Hippo signalling, we discovered that the PP2A phosphatase has an additional role in the regulation of tissue growth and, in certain conditions, it can activate rather than block Hippo signalling. However, it is still unknown what are the signals and mechanisms that control whether PP2A activates or blocks the Hippo pathway.Using the fruit fly Drosophila as a model organism, we will investigate how tissue growth is regulated by the phosphatase PP2A. The fruit fly is an extremely flexible and highly relevant biological tool that has been widely used in genetic studies due to its ease of manipulation and fast life cycle. Many of the genes known to be important for human development were first identified and characterised as a result of fruit fly genetic studies. Due to the remarkable conservation of genes between flies and mammals, findings from fruit fly studies have been translated to advances in our understanding of important biological processes in humans. Thus, our work will also examine the function of genes identified in Drosophila in human tissue culture cells to precisely study the molecular details of the process.This project will reveal how the phosphatase PP2A controls tissue growth and what are the signals that regulate its activity and switch its function from a growth-promoting to a growth-suppressive protein, and vice versa. We will study this crucial question both in normal developmental conditions and when tissues respond to changes in their architecture. We will use a combination of genetic and biochemical approaches to uncover the function of the genes involved by switching them off and determining whether cells are impaired in their ability to proliferate and give rise to tissues of the correct size.We will elucidate how the activity of the phosphatase PP2A is regulated, what are the signals that control its activity, and how it can be exploited. Numerous genes involved in tissue growth are mutated in human disease, leading to developmental abnormalities and cancer. Therefore, identification of genes involved in the regulation of tissue growth may be potentially relevant for future therapeutic interventions. In addition, as we will study the role of our genes of interest in the context of the response to tissue damage, our project will also be very relevant for future studies into tissue regeneration and tissue engineering.