Overview and broad aims
Our cells are constantly exposed to environmental challenges. Some of these are ‘normal’; for example, insulin responds to changes in nutrient status. But others are ‘stressful’, causing damage to DNA, proteins and lipids. Healthy ageing requires that cells are resilient, able to detect and adapt to these challenges to remain viable and functional. Failure to adapt can undermine cell, tissue and organ function in later life.
Signalling refers to the network of biochemical pathways inside cells that are activated by growth factors and hormones (normal) or by the accumulation of damaged or misfolded proteins (stressful) and orchestrate the cell’s response. We are studying how these pathways are regulated and how they change cell behaviour (growth, division, death). Notably, these pathways harbour drug targets for a range of age-related diseases.
Progress and research highlights in 2023 and 2024
One key signalling pathway that is activated by growth factors receptor tyrosine kinases (RTKs) and nutrients is the phosphoinositide 3-kinase (PI3K) pathway, which controls cell metabolism and growth. In healthy tissues this pathway is controlled by insulin and related growth factors. This pathway is deregulated in cancer. Using a mouse model of prostate cancer we have used mass spectrometry to understand how the components of the PI3K pathway change in cancer. We find that the IRS proteins, major components of the PI3K pathway, are downregulated and replaced by a protein called PLEKHS1 that sustains PI3K signalling in prostate cancer ().
Activation of RTKs leads to the activation of the protein kinases ERK1 and ERK2 and promotes cell survival and cell division. This pathway is frequently activated in cancer due to mutation of ERK1/2 pathway components, making ERK1/2 attractive drug targets. We have discovered nearly all ERK inhibitors (ERKi) not only inhibit these protein kinases but also drive the degradation of the most abundant ERK2 enzyme. Since ERK2 has been proposed to have kinase-independent, non-catalytic functions, the ability to degrade the enzyme may impart such ERKi with superior drug-like properties ().
Whilst RTKs phosphorylate proteins on tyrosine residues to propagate signals for cell division, growth and motility, the receptor protein tyrosine phosphatases (RPTPs) remove phosphate from tyrosine and have been suggested to simply act in opposition to RTKs. We have shown that Protein Tyrosine Phosphatase Receptor Type K (PTPRK) suppresses invasive behaviour in colorectal cancer cells. In vivo PTPRK supports recovery from inflammation-induced colitis and functions as a tumour suppressor in the mouse colon and colorectal cancer xenografts. Remarkably, and contrary to
the prevailing dogma, PTPRK suppresses cancer phenotypes independent of its catalytic function suggesting that it acts as a signalling scaffold ().
Proteins control every aspect of cellular life and the timely synthesis, folding, stabilisation, trafficking and degradation of proteins (proteostasis) is critical for health. The evolution of our research programme now provides critical mass for proteostasis research.
Using advanced mass spectrometry techniques, we have identified proteins which are stabilised by the molecular chaperone heat shock protein 90 (HSP90). This study reveals the selective effect of HSP90 inhibitors, identifies new components of the HSP90- dependent proteome and provide a rich data resource for the HSP90 and proteostasis communities ().
Lysosomes are key sites of degradation and recycling of damaged or unwanted proteins and foreign organisms. Maintenance of lysosome function is critical for lifelong health and we have recently described a novel pathway, Conjugation of ATG8s to Single Membranes (or CASM), that responds to lysosome damage by recruiting a protein called ATG2, a lipid transfer protein central to lysosome repair ().
Aggregation of proteins is a driver of normal age-related decline and certain diseases. Both in disease and during ageing, proteins selectively aggregate in certain tissues and not others. We have described a novel safety mechanism that selectively targets newly synthesised proteins to suppress their aggregation and associated proteotoxicity ().
Impact highlights
During 2023-24 the Signalling programme has continued its close work with the biotech and pharmaceutical sector. Studies on PI3K remodelling in cancer suggest that PLEKHS1 and related proteins may be potential drug targets in prostate cancer and this will be explored in collaboration with AstraZeneca. Understanding how ERKi drive the degradation of ERK2 and the consequences of this is being progressed in collaboration with PhoreMost. In addition to PTPRK, studies from the Sharpe lab are rewriting the PTP rule book, suggesting new opportunities to understand and drug this enzyme class; these are being progressed with AstraZeneca, Cancer ̨Íåswag Horizons and Oppilotech.
Our work on proteostasis, ubiquitylomics, senescence and ageing is also attracting industrial collaborations including AstraZeneca, PhoreMost and Stemnovate. Furthermore, we have led the launch of the UK Proteostasis Network hosting the first very successful conference here at ̨Íåswag.
Looking ahead
We will study how signalling mechanisms sense and adapt to different types of stress across the life course. A major focus will be on pathways which regulate 'proteostasis across the life course' - with colleagues in our Epigenetics and Immunology programmes. We will also reveal new molecular understanding of how reactive oxygen species and PTPases regulate epithelial barrier integrity, how the PI3K network is rewired during ageing, how the V-ATPase transduces lysosomal stress and the role of phase-separation in the induction of autophagy. We will use this knowledge to identify new opportunities for therapeutic intervention to mitigate age-related physiological decline.