A PP2A Regulatory Nexus Modulating Hippo Signalling and Growth

PP2A 调节 Hippo 信号传导和生长的调节关系

• 批准号: BB/T004576/1
• 负责人: Paulo Baptista Ribeiro
• 金额: $ 67.24万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT004576%2F1
• 关键词: PP2A; Regulatory; Nexus; Modulating; Hippo

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.

组织在发育和成年期间的生长是细胞增殖、分化和死亡之间微妙平衡的结果。了解调节组织生长的机制是生物学中尚未回答的关键问题之一。越来越清楚的是，生长与组织结构密切相关，在病理条件下，组织结构受到严重影响，导致组织异常。河马通路是控制组织生长的最重要的信号级联信号之一，它对组织结构的变化做出反应。这一信号级联过程包括几个步骤，其中一些步骤是由蛋白质介导的，蛋白质的功能可以通过附着不同的化学和生化实体来改变，这一过程被称为翻译后修饰。磷酸化是细胞中一种这样的翻译后过程，它包括磷酸基团与其他蛋白质的结合。这是一个可逆的过程，涉及一个复杂的蛋白质机制，将修饰附加到其他蛋白质上或从其他蛋白质中移除。磷酸化通过影响蛋白质的稳定性、细胞内的定位或功能来改变蛋白质的性质。我们以前发现，作为大型蛋白质复合体的一部分，磷酸酶PP2A阻断了河马途径的活性。最近，在详细研究组织结构如何控制河马信号时，我们发现PP2A磷酸酶在组织生长调节中还有额外的作用，在某些条件下，它可以激活而不是阻止河马信号。然而，目前还不清楚是什么信号和机制控制了PP2A是否激活或阻断了河马通路。我们将以果蝇为模式生物，研究PP2A是如何调控组织生长的。果蝇是一种极其灵活和高度相关的生物工具，由于其易于操作和快速的生命周期，已被广泛应用于遗传学研究。许多已知对人类发育很重要的基因是在果蝇基因研究的结果下首次被识别和描述的。由于果蝇和哺乳动物之间基因的显著保守，果蝇研究的结果已经转化为我们对人类重要生物过程的理解的进步。因此，我们的工作还将检测果蝇中识别的基因在人类组织培养细胞中的功能，以精确研究这一过程的分子细节。该项目将揭示磷酸酶PP2A是如何控制组织生长的，以及是什么信号调节其活性，并将其功能从促进生长蛋白转换为生长抑制蛋白，反之亦然。我们将在正常发育条件下和组织对其结构变化做出反应的情况下研究这一关键问题。我们将结合使用遗传学和生物化学方法来揭示相关基因的功能，方法是将它们关闭，并确定细胞的增殖能力是否受到损害，并产生合适大小的组织。我们将阐明磷酸酶PP2A的活性是如何调节的，控制其活性的信号是什么，以及如何利用它。许多参与组织生长的基因在人类疾病中发生突变，导致发育异常和癌症。因此，识别与组织生长调节有关的基因可能对未来的治疗干预具有潜在的意义。此外，由于我们将研究我们感兴趣的基因在组织损伤反应中的作用，我们的项目也将与未来对组织再生和组织工程的研究非常相关。