Defining the role of ERK5 kinase and ERK5 transcriptional activities in cell migration and EMT using novel ERK5 inhibitors

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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. 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 in the immune system or our skin. This process of cell division and differentiation continues in adults in certain tissues; which constantly renew themselves such as our skin. For cells to respond to growth or differentiation cues they must activate key growth or differentiation proteins; this often involves increasing the abundance of these proteins. The genetic information for these proteins is stored in discrete pieces of DNA (genes), which reside on chromosomes in the nucleus. When a cell receives a growth signal these genes are 'read' by 'transcription factors', discrete proteins that bind to DNA and transcribe the DNA information the into messenger RNA (mRNA) molecules, which are in turn 'translated' into the relevant proteins. This coupled process of transcription and translation is called 'gene expression'.This whole complex process is orchestrated by signalling pathways, which control every step. Control is the key word here. For example, if the cells divide too much or fail to differentiate correctly they may become cancerous. 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 ERK5. 1. There is much interest in finding drugs that block ERK5 activity (ERK5 inhibitors or ERK5i) as they may help to treat inflammation, cardiovascular disease or cancer. Indeed, we have been working with a team of scientists to identify new ERK5i that inhibit ERK5 kinase activity. However, to our surprise they actually promote gene reading or transcription. The ERK5 protein is unusual in that it has two quite different functional regions or domains. The first is the kinase domain, which phosphorylates substrates; the second is a transcription factor domain, which binds DNA to read genes. Our results suggest that when an ERK5i inhibits the kinase domain it causes structural changes that activate the transcription factor domain. So one aim is to understand at the molecular level how this happens and whether this is a good thing or a bad thing for designing ERK5 inhibitors.2. Second, we want to identify the genes that ERK5 binds to so we can better understand the role of ERK5 - and specifically the two functional domains of ERK5 - in gene expression. 3. Our recent experiments have suggested that ERK5 activity is important in regulating a differentiation process called epithelial-to-mesenchymal transition (or EMT). EMT is important during development of the embryo, during wound repair and for cancer cells to spread around the body and invade new sites - a process called metastases. Indeed, we have found that blocking ERK5 activity reverses EMT and prevents the movement of cells. So a final aim of this project is to understand how ERK5 controls this EMT process and whether it is controlled by the kinase domain or the gene reading domain of ERK5.This study should tell us more about the normal role and regulation of ERK5. ERK5 may also be important in clinical conditions (inflammation, cardiovascular disease, cancer) so our results may have wider impacts and we will work with scientists in these areas to progress this.