Regulation of midbody formation and function by phosphorylation

通过磷酸化调节中间体的形成和功能

• 批准号: BB/W01372X/1
• 负责人: Pier Paolo D'Avino
• 金额: $ 83.2万
• 依托单位: University of Cambridge
• 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%2FW01372X%2F1
• 关键词: Regulation; midbody; formation; function; phosphorylation

All biological processes are controlled and executed by a class of molecules, the proteins, whose functions are regulated in both space and time by post-translational modification (PTMs). Reversible PTMs, such as phosphorylation, are essential for the proper activity of many signalling pathways and networks that control almost every cellular and developmental process. Phosphorylation and de-phosphorylation are mediated by opposing enzymes: kinases, which add phosphate groups to their target substrates, and phosphatases that instead remove them. The addition or removal of these phosphate groups regulate the activity, localisation and association of proteins. Recent advances in the field of proteomics have led to the identification of many proteins that are regulated by phosphorylation in different cellular contexts. However, in vivo functional studies have revealed the existence of complex interplays between kinases and counteracting phosphatases that are largely unknown. Therefore, understanding how protein regulation by kinases and phosphatases regulates the function of proteins and protein complexes in specific biological events represents one of the main future challenges in bioscience research. In addition, as phosphorylation is often altered in many human diseases, detailed knowledge of kinases and phosphatases cross-regulation and functions in normal conditions could provide a framework for revealing how phosphorylation mechanisms and pathways are altered in pathological conditions and aid the design of future clinical therapies.The goal of our research project is to understand how phosphorylation controls the formation and functions of an organelle, the midbody, that forms between the two daughter cells at the end of cell division. The midbody is essential for completion of cell division and has been implicated in various post-division processes, including cell fate, pluripotency, apical-basal polarity, tissue organisation, cell proliferation, brain development, and cilium and lumen formation. In addition, midbody proteins have been linked to human diseases, including cancer and impaired brain development (microcephaly). We plan to employ an interdisciplinary approach involving a combination of innovative and advanced methodologies, including gene editing, quantitative proteomics, bioinformatics, and high resolution multi-dimensional imaging, to unravel how phosphorylation regulates the function, dynamics and association of midbody proteins. Our findings will provide key insights into the regulation of midbody proteins and help understand how this organelle mediate so many important functions in cells. Furthermore, our results will pave the way for the development of targeted therapies for human diseases like cancer and some neurological conditions. Our study will have a far-reaching impact in many research areas beyond the study of cell division and including medical disciplines.

所有生物过程均由一类分子（即蛋白质）控制和执行，其功能通过翻译后修饰 (PTM) 在空间和时间上进行调节。可逆的 PTM（例如磷酸化）对于控制几乎所有细胞和发育过程的许多信号通路和网络的正常活动至关重要。磷酸化和去磷酸化是由相反的酶介导的：激酶将磷酸基团添加到其目标底物上，而磷酸酶则将其去除。这些磷酸基团的添加或去除可调节蛋白质的活性、定位和缔合。蛋白质组学领域的最新进展已经鉴定出许多在不同细胞环境中受磷酸化调节的蛋白质。然而，体内功能研究揭示了激酶和抵消磷酸酶之间存在复杂的相互作用，而这些相互作用在很大程度上是未知的。因此，了解激酶和磷酸酶的蛋白质调节如何调节特定生物事件中蛋白质和蛋白质复合物的功能是生物科学研究未来的主要挑战之一。此外，由于磷酸化在许多人类疾病中经常发生改变，因此对正常条件下激酶和磷酸酶交叉调节和功能的详细了解可以提供一个框架，揭示磷酸化机制和途径在病理条件下如何改变，并有助于设计未来的临床疗法。我们研究项目的目标是了解磷酸化如何控制细胞器（中间体）的形成和功能，该细胞器在细胞之间形成。 细胞分裂末期有两个子细胞。中体对于完成细胞分裂至关重要，并且与各种分裂后过程有关，包括细胞命运、多能性、顶端-基底极性、组织组织、细胞增殖、大脑发育以及纤毛和管腔形成。此外，中体蛋白与人类疾病有关，包括癌症和大脑发育受损（小头畸形）。我们计划采用跨学科方法，结合创新和先进的方法，包括基因编辑、定量蛋白质组学、生物信息学和高分辨率多维成像，来揭示磷酸化如何调节中间体蛋白的功能、动力学和关联。我们的研究结果将为中体蛋白的调节提供重要见解，并有助于了解这种细胞器如何介导细胞中如此多的重要功能。此外，我们的结果将为癌症和某些神经系统疾病等人类疾病的靶向治疗的开发铺平道路。我们的研究将对细胞分裂研究之外的许多研究领域产生深远的影响，包括医学学科。