Understanding how PAR proteins cooperate to establish cell polarity (New Investigator)

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To generate an organism from an initially symmetric one-cell embryo, cells divide and lose their initial symmetry, acquiring structural and functional differences through a process termed cell polarisation. A crucial step in the polarisation of animal cells is the distribution of conserved polarity effectors to discrete domains on the cell surface. From their asymmetric position these key proteins control important events that build an organism, including the generation of the plethora of cell types needed, the organization of tissues into organs and the establishment of embryonic axes that lay the bases for the architectural plan of an animal. Therefore, when the position and function of these polarity effectors is impaired a wide range of diseases can arise including cancer. What ensures the correct localisation and function of these polarity proteins? We recently identified a new way of regulation for these polarity effectors. We found that, like in a manufacturing factory, there is a division of labour for the polarity proteins that will specify a cell domain. They group themselves into distinct protein-complexes, which become specialised in a given function. For the proteins we studied we found that there are at least two distinct protein-complexes, one specialised in the asymmetric distribution of the polarity proteins and the other focused on their activation. A very tight functional coordination between these protein-complexes is required to generate an asymmetric and active domain of polarity proteins that will polarise cells, allowing the development of an organism. We do not know how this important cooperation is achieved; therefore we propose innovative cell biology techniques to identify the players involved and their modes of action. By understanding how cells are polarised we will give insight into key aspects of human embryo development and we will pinpoint events that can go wrong and cause disease. Thus it is important that we identify the mechanisms that control correct cell polarisation; understanding this will, in the long-term, provide new avenues in the design of drugs that can correct errors in these mechanisms of control.