Award details

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

Reference	BB/N015886/1
Principal Investigator / Supervisor	Dr Simon Cook
Co-Investigators / Co-Supervisors
Institution	Babraham Institute
Department	Signalling
Funding type	Research
Value (£)	341,874
Status	Completed
Type	Research Grant
Start date	04/07/2016
End date	30/11/2019
Duration	41 months

Abstract

ERK5 is unusual in consisting of a kinase domain (KD), similar to ERK1/2, and a C-terminal domain with an NLS and transcriptional transactivation domain (TAD) that can autonomously bind chromatin and promote gene expression. The relationship between the KD and TAD is poorly understood. ERK5 controls angiogenesis & neural differentiation in the developing embryo. It also promotes B cell survival, inflammation, cardiovascular disease and fibrosis so there is widespread interest in finding ERK5 inhibitors (ERK5i). We have been involved in an ERK5 drug discovery programme that has identified nanomolar ERK5i. In the course of this work we have found that: 1. Whilst ATP-competitive ERK5is completely inhibit the isolated ERK5 KD, they cause the paradoxical, kinase-independent activation of the ERK5 TAD in full length ERK5. 2. ERK5 inhibition reduces cell migration and reverses the epithelial-to-mesenchymal transition suggesting that ERK5 may be important in cell movement, wound repair and conceivably tumour cell invasion. We suggest that binding of ERK5is inhibits kinase activity but also elicits a conformational change that exposes the ERK5 TAD allowing ERK5 to enter the nucleus to drive gene expression. Understanding these dual effects is critical to understanding how ERK5 functions and exerts its biological effects. It is also critical if we are to understand how best to employ ERK5 kinase inhibitors that are being developed for a variety of indications. Is it most important to inhibit the KD or the TAD? To inform these issues we will define how ERK5i-dependent inhibition of the ERK5 KD elicits activation of the ERK5 TAD, identify genomic targets of the ERK5 KD and ERK5 TAD signalling functions and investigate the role of ERK5 (KD and TAD domains) in EMT. Our basic biology study may have far reaching implications for colleagues studying diseases where ERK5 is implicated and where the significance of paradoxical ERK5 TAD activation has not even been considered.

Summary

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.

Impact Summary

The primary impact will come from new knowledge of mechanisms of signal transduction, related to the role of ERK5 in various biological contexts (see Academic beneficiaries). Impacts on industry and other stakeholders: 1. Industry: All major pharmaceutical companies remain interested in protein kinases as drug targets for a variety of diseases. Several of these companies have active ERK5 inhibitor programmes (AstraZeneca, Boehringer Ingelheim, etc) and ERK5 is being positioned for a variety of indications including cancer, inflammation, fibrosis and cardiovascular disease. ERK5 is clearly druggable and this proposal developed out of a collaboration with the University of Newcastle including Astex Pharmaceuticals and CRT as commercial partners. Our research will therefore be relevant to a range of BioPharma companies contributing to UK economic competitiveness and we have clear pathway to progress this. 2. BBSRC: Within the BBSRC 2010 Strategic Plan this work maps to BBSRC Strategic Priority 3: Basic Bioscience Underpinning Health. In particular 'basic molecular science underpinning the translation of knowledge about drug targets into chemical and biological tools and drugs'. Relevant areas include: new tools in chemical biology, lipidomics and genomics; molecular cell biology, chemical biology and biochemistry to drive the discovery and validation of new drug targets or selective pharmaceuticals. The project exemplifies the use of Partnerships, with contributions across sectors (Institutes, Universities, Industry). Within the BBSRC Strategic Plan 2013/14 refresh this research maps to Strategic Research Priority 3 - Bioscience For Health - and is relevant to the Societal Grand Challenge of 'maintaining health across the whole lifecourse' and the Key Priority 'Generate new knowledge of the biological mechanisms of development and the maintenance of health across the lifecourse'. In particular, our work on 'signalling mechanisms will provide new insights to potential strategies for health monitoring and intervention, including drug targets and pharmaceuticals', consistent with the aspiration that 'basic bioscience funded by BBSRC underpins the pharmaceutical and healthcare industries'. 3. Healthcare and 3rd sector charities: ERK5 is implicated in a variety of processes that promote disease and infirmity in old age and is therefore of interest to the health sector. ERK5 is implicated in myogenesis and adipogenesis. Age-related loss of muscle mass significantly impairs quality of life in the elderly. Similarly, adipocytes are critical regulators of metabolism and are involved in a variety of metabolic diseases including obesity. In addition, ERK5 is directly implicated in inflammation, fibrosis and cardiovascular disease - all of which have ageing as a key risk factor. Thus understanding how ERK5 functions may contribute to future intervention strategies aimed at these problems. In addition, ERK5 is amplified in some cancers and our new results studying EMT suggest a role in metastases. Thus, our basic biology will be of interest to a variety of disease charities as well as the healthcare professions. Training: This project will provide further training for key researchers (Lochhead & Cook) in new scientific skills in growth areas (chemical genomics/chemical biology, genomics, bioinformatics). It will build on Lochheads's excellent organisational skills, honed in industry, providing training for her future contribution to UK science & economic output. Science & Society: We will continue to contribute to public STEM (science, technology, engineering and maths) understanding through our public engagement activities. Indeed, Lochhead has been closely involved in Cook lab public engagement activities, communicating her knowledge and enthusiasm to the next generation of scientists and informing interested adults through activities such as science exhibitions and science visits to schools and local community groups.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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