Regulation of midbody formation and function by phosphorylation

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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.