THE ART OF SCIENCE
is communicating effectively
About the lab
The lab is headed by Adrian Saurin and you can find out more about his research background and philosophy in this online interview:
We address fundamental questions about chromosome segregation in an effort to understand why this process goes wrong so frequently in tumour cells. We also focus on some basic cell signalling questions that have widespread implications outside of cell division. Some of the main questions that motivate our research are highlighted below.
If this is your first visit to the site you may want to look here first. There you can find the philosophy and background to our research in very simple terms.
We also feel passionately that science should be open and accessible to all. Therefore, on this website you will find short 2-minute video clips to explain our work in simple terms.
How are protein phosphorylation signals controlled?
The simple textbook answer is that kinases and phosphatases work antagonistically to switch phosphorylation signals on and off. This description is not only far too simplistic, in many cases it is also misleading. These enzymes work antagonistically to switch individual molecules on and off, but they also work very much together to define the signals. This 'cooperativity' allows for tight control of the amplitude, localisation, timing and shape of phosphorylation signals. In this way, a variety of different outputs can then be used to control complex biological responses.
Read our latest review on this topic here.
Click here for a short video description of this review.
I am common to all phosphorylation sites but hardly anything is known about me. What am I?
In just over 60 years of protein phosphorylation research, we have identified over half a million phosphorylation sites and discovered that this process regulates almost all aspects of cell biology.
Considering these facts, it is perhaps surprising that we would still struggle to answer one fundamental question that could be applied to any one of those half a million phosphorylation sites: how does each substrate molecule behave dynamically in time? We may known a lot about the average behaviour of all molecules for any given substrate, but in each case the individual molecules could be flickering on an off at different rates and we would be largely unaware. It is important to uncover this information because the rate of phosphorylation-dephosphorylation on individual molecules can have important functional implications.
Read our latest article on this here
Click here for a short video description of this review.
In this commentary we also put forward a new hypothesis to explain how fast phosphorylation-dephosphorylation dynamics could lead to the rapid binding and release of protein cargo. This is a new area of research in lab and if you would like to study this, particularly in the context of mitotic checkpoint signalling, then please get in contact.
How do protein phosphatases achieve specificity?
We work on two serine/threonine phosphatases, PP1 and PP2A-B56, to understand how they achieve specificity during mitosis. These enzymes exhibit very little specificity in vitro, they localise to an almost identical molecular space during mitosis (i.e. the same subcomplex on kinetochores), and yet they manage to dephosphorylate different substrates and control distinct processes. We are investigating how they achieve such exquisite specificity because this will help us to understand how chromosome segregation is regulated and it may also reveal how these different phosphatase complexes achieve specificity in other contexts.
We are also examining the issue of isoform specificity, since both PP1 and PP2A-B56 exist in multiple different isoforms that each perform very specialised roles during mitosis. Very little is currently known about phosphatase isoform-specificity in any context.
How is cell division regulated?
A reductionist approach to cell biology over the past few decades has revealed the core parts that control cell division. The next big challenge is to understand how these parts are assembled in a way that allows cells to divide with incredible accuracy and precision. This requires us to learn how the parts are interconnected, and in particular, how they work together to ensure mitosis is coordinated, reliable and robust. To meet this challenge we are using an interdisciplinary mix of quantitative cell biology, biochemistry, synthetic biology and systems biology (in collaboration with colleagues in Milan).
We showed previously how two kinases and two phosphatases work together to generate a responsive spindle checkpoint signal. In this case, it is the particular way in which these enzymes are coupled together that allows the checkpoint signal to be responsive (i.e. to switch states quickly). This demonstrates how studying the network as a whole can be more informative than investigating the individual parts in isolation.
Read our manuscript on this here.
Why does cell division fail so frequently in cancer?
In some respects the answer to this question is known - frequent errors in division cause chromosomal instability (CIN), which enables tumours to quickly evolve, metastasise and evade chemotherapy. What isn't clear, however, is how cell division is deregulated in a way that allows this to occur. We are trying to understand this because it may reveal new ways to tackle cancer. For example, preventing the errors in mitosis could limit tumour evolution, or alternatively, enhancing them may induce lethal levels of aneuploidy in tumour cells.
Read our latest review on this here to find out why a kinase-phosphatase imbalance could underlie CIN.
Can phosphatases be exploited therapeutically?
Small molecules targeting the catalytic site of phosphatases have had only limited success in the past; mainly because these catalytic subunits are often shared between many different holoenzyme complexes. We believe that understanding how the phosphatase holoenzymes achieve specificity, which principally occurs through regulatory domain interactions, is the key to unlocking new ways to modulate their activity. This was demonstrated recently by the seminal discovery of a small molecule compound that can inhibit specific PP1 regulatory complexes to treat neurodegenerative diseases (Das et al. Science 2015). Similar selective inhibitors of mitotic phosphatase complexes - PP1-KNL1 or PP2A-B56 - could have important therapeutic implications: for example, we have shown previously that genetic inhibition of these complexes causes the same catastrophic mitotic effects as paclitaxel (one of the best-selling anti-cancer drugs), but importantly, without causing any of the undesirable effects on microtubules (read more about this here).
Why are second generation anti-mitotic drugs so ineffective in the clinic?
Paclitaxel (taxol) is still one of the best selling anti-cancer drugs that targets microtubules to inhibit cell division. This has stimulate a huge investment from the drug industry to develop new drugs that inhibit mitosis specifically without causing the undesirable 'off-target' effects on microtubules. Many of these compounds have now progressed into the clinic and, generally speaking, they have been a huge disappointment. We are trying to understand why taxol is still so much better than these drugs by combining biological experiments with mathematical modelling (in collaboration with colleagues in Dundee and Edinburgh). The idea is that taxol has a unique property of becoming 'trapped' inside cells which may allow it to persist for much longer inside slow growing tumours. This could potentially explain why it is much more effective in human diseases, but relatively similar to new drugs in animal models where tumours frequently grow much quicker.
Why are CDK4/6 inhibitors so effective in the clinic?
CDK4/6 inhibitors are an exciting new class of anti-cancer drug that arrest the cell cycle in G1-phase. They are licenced to treat the most common subtype of metastatic breast cancer (HR+) and they are currently undergoing clinical trials against a variety other tumour types. To understand how these drugs work, it is important to explain why pausing the cell cycle in G1 has long-lasting effect on tumour growth: i.e. why is this cytotoxic and not simply cytostatic? We demonstrated recently that when cells are arrested in G1 they downregulate replisome components, which causes incomplete DNA replication and DNA damage when cells are released from that arrest. This implies that CDK4/6 inhibitors may cause genotoxic stress to induce permanent cell cycle withdrawal, perhaps explaining why they have long-lasting anti-cancer activity. You can read this study here. We followed up this article with two further studies that explain mechanistically the cause of this genotoxic stress. When cells arrest in G1 they continue to grow in size, skewing the proteome and leading to toxicity and cell cycle exit - see here. Importantly, this grow is driven by oncogenes, and therefore cancer cells are primed for toxic growth when arrested in G1 - see here. Our recent work shows how this has hindered the search for CDK4/6 biomarkers - see here.