Regulation of midbody formation and function by phosphorylation

通过磷酸化调节中间体的形成和功能

基本信息

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

项目摘要

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（蛋白质）控制和执行，蛋白质的蛋白质受到翻译后修饰（PTM）的调节。可逆的PTM（例如磷酸化）对于控制几乎每个细胞和发育过程的许多信号通路和网络的适当活动至关重要。磷酸化和去磷酸化是通过相反的酶：激酶介导的，它们在其靶标底物中添加磷酸基团，而磷酸酶则将其去除。这些磷酸根的添加或去除调节蛋白质的活性，定位和关联。蛋白质组学领域的最新进展导致了许多蛋白质的鉴定，这些蛋白质在不同的细胞环境中受磷酸化调节。然而，体内功能研究揭示了激酶和反破坏磷酸酶之间的复杂相互作用，这些相互作用在很大程度上未知。因此，了解激酶和磷酸酶调节蛋白质如何调节特定生物学事件中蛋白质和蛋白质复合物的功能是生物科学研究中未来的主要挑战之一。此外，由于许多人类疾病经常改变磷酸化，因此对激酶和磷酸酶交叉调节的详细知识以及在正常条件下的功能可以提供一个框架，以揭示磷酸化机制和途径在病理条件下改变了如何改变了未来临床疗法的设计。细胞分裂末端的两个子细胞。中体对于完成细胞分裂至关重要，并且与各种后过程有关，包括细胞命运，多能，根尖 - 基质极性，组织组织，细胞增殖，脑发育以及纤毛和腔体形成。此外，中体蛋白质与人类疾病有关，包括癌症和脑发育受损（小头畸形）。我们计划采用一种跨学科方法，涉及创新和先进方法的组合，包括基因编辑，定量蛋白质组学，生物信息图和高分辨率多维成像，以揭示磷酸化如何调节中体蛋白质的功能，动态和关联的功能。我们的发现将为中体蛋白的调节提供关键的见解，并有助于了解该细胞器如何介导细胞中如此多的重要功能。此外，我们的结果将为开发癌症和某些神经系统疾病等人类疾病的靶向疗法铺平道路。我们的研究将在细胞分裂研究（包括医学学科）的研究之外的许多研究领域产生深远的影响。