New insights into the function of the protein kinase DYRK1B, an ERK1/2 target gene

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The cells in our body are constantly subjected to changes in their environment and they contain an extensive network of signalling pathways that coordinate appropriate responses. For example, exposure to noxious chemicals will activate signal pathways that allow repair of cellular damage and promote cell survival. In the developing embryo, cells may receive stimuli or cues telling them to divide (so called growth factors) or they may receive cues telling them to cease dividing and undergo 'differentiation', a process in which cells acquire the characteristics of specialized cell types that make up the discrete tissues in our adult bodies such as nerves, blood cells or muscles. This process of cell division and differentiation is not only important in the developing embryo but also throughout our adult lives in responding to cell and tissue damage. For example, if we tear a muscle, special 'stem cells' in the muscle start to divide and then differentiate into new muscle cells to repair muscle tissue. As we get older this process become less efficient and our capacity to repair and renew tissues is reduced. This accounts for the progressive decline in our ability to recover from injuries that pose little problem to our younger selves.For cells to respond to growth or damage cues they must activate key growth and repair proteins; this often involves increasing the abundance of these proteins. The genetic information for these proteins is stored in discrete pieces of DNA termed genes, which reside on chromosomes in the nucleus. When a cell receives a growth or damage signal these genes are 'transcribed' into messenger RNA (mRNA) molecules, which are in turn 'translated' into the relevant proteins. This whole complex process is orchestrated by signalling pathways, which control every step. Control is the key word here. If the cells divide too much during the repair response they may become cancerous; if they do not divide enough then muscle repair may be defective.The signalling pathways controlling cell division and differentiation typically involve cascades of enzymes called protein kinases. These enzymes 'tag' other proteins with a phosphate group (a process called phosphorylation) and this changes the activity, abundance or localisation of the protein. The tagged protein is referred to as the 'substrate' of the protein kinase enzyme. This project concerns a protein kinase called DYRK1B.DYRK1B is one of a small family of protein kinases that are poorly understood but are believed to be very important. For example, the closely related DYRK1A may be important in Down Syndrome whilst DYRK1B itself may be a cancer-causing gene. Importantly, the abundance of DYRK1B increases substantially during the switch from cell division to cell differentiation. However we are currently ignorant about how DYRK1B controls these processes because we know very few proteins that are DYRK1B substrates (i.e. that are tagged with phosphate by DYRK1B).We have now identified a group of proteins that are phosphorylated by DYRK1B. These proteins are involved in controlling the abundance of the mRNA molecules that are ultimately translated into growth and repair proteins. In this project we will define how DYRK1B controls these proteins, the importance of this for regulating mRNA abundance and the role that DYRK1B plays in muscle differentiation using cells that can be stimulated to change into muscle in the lab.The results of this study should tell us more about the normal role of DYRK1B in muscle differentiation, which is important in the elderly where muscle repair can be defective. It may also be relevant in other models of differentiation where DYRK1B may be important including fat cells, which is relevant to the rise in obesity. Finally, the ability of DYRK1B to control cell division may be important in cancer. To help us maximize the impact of our research we will work with other scientists in these area.