In the latest issue of the journal Cell (Cell 143, 686-693), MRC Protein Phosphorylation Unit Director Sir Philip Cohen gives his perspective on whether components of the ubiquitin system will become as important drug targets as protein kinases for the pharmaceutical industry in the future. To read his article "Will the ubiquitin system furnish as many drug targets as protein kinases" click here
David Komander, who undertook his PhD jointly between the labs of Dario Alessi and Daan van Aalten between 2002 and 2005, has been admitted into the EMBO Young Investigator Programme (YIP). This is a very prestigious position in which EMBO selects the most promising group leaders from all over Europe each year, who are in the early stages of their independent research careers. EMBO expects these individuals to become the life sciences leaders of the future.
David Komander who is now working at the world renowned MRC Laboratory for Molecular Biology in Cambridge has made an exceptional start to his independent research career having published several significant papers in the area of protein ubiquitylation.
David is the second former PhD student trained in the MRC-PPU to have been selected for the EMBO YIP, John Rouse being the first. Daan van Aalten was also selected to join the EMBO YIP some years ago.
Laura Pearce was awarded her PhD on November 18th on her work characterising the mechanism by which PROTOR regulates mTORC2. Her examiners were Chris Proud of the University of Southampton and Calum Sutherland of Ninewells Hospital, Dundee. Laura plans to undertake her postdoctoral research in the laboratory of Sadaf Farooqi at the University of Cambridge after she completes her work on PROTOR and submits her latest paper in this area. Laura Pearce is Dario Alessi’s 17th student to be awarded a PhD.
The PDK1 kinase has been the focus of great attention since it was discovered over 13 years ago in the MRC Protein Phosphorylation Unit as a key enzyme that activated Akt. Work carried out in Dundee on PDK1 over these years have uncovered most of the known 23 cellular substrates of PDK1 and elucidated how PDK1 is regulated by binding to the PtdIns(3,4,5)P3 second messenger and docking to phosphorylated hydrophobic motifs of its substrates. The structure of PDK1 has also been elucidated and the key roles that PDK1 plays in cancer and insulin signalling been defined in a series of studies with PDK1 hypomorphic as well as tissue specific knockout and knock-in mice lacking the ability to interact with PtdIns(3,4,5)P3 or its AGC kinases phosphorylated at its hydrophobic motif. Importantly this work suggested that inhibitors of PDK1 should protect against cancer, as mice deficient in the PTEN tumour suppressor, expressing reduced levels of PDK1 developed far fewer tumours.
Despite all of this work described in over 70 publications, what was missing was a potent selective inhibitor of PDK1 that could be used to probe the biological roles that this enzyme plays. Over the years many inhibitors of PDK1 have been reported, but everyone we tested turned out to be insufficiently selective or potent to be able to probe the roles of PDK1 in vivo.
In a major breakthrough in this field, GlaxoSmithKline researchers including Jeffrey Axten and M. Phillip DeYoung were able to elaborate the compound GSK-2334450 which turns out to be an amazingly selective and potent (IC50 10 nM) inhibitor of PDK1 which did not inhibit significantly the activity of ~100 other kinases/lipid kinases tested. GlaxoSmithKline kindly provided us with this compound to evaluate and Ayaz Najafov with some help from Eeva Sommer (pictured), set about characterising the cellular efficacy of GSK-2334470. They found that GSK-2334470 potently suppressed activation of many PDK1 substrates including SGK, S6K and RSK, but was less efficient at inhibiting Akt, especially under conditions where large activation of the PI 3-kinase pathway is observed. Further experimentation revealed that this reduced ability to inhibit Akt was probably due to the unusually high efficiency at which Akt is activated by PDK1 on the two dimensional surface of plasma membrane. Studies with GSK-2334470 also revealed striking differences in the kinetics of T-loop dephosphorylation of diverse AGC kinase substrates. Treatment of cells with GSK-2334470 induced potent inhibition and dephosphorylation of the T-loop of Akt, S6K1, SGK isoforms within 5-30 min of GSK233440 treatment whereas equivalent levels of inactivation of RSK isoforms required ~8h.
Overall, these new data define how PDK1 inhibitors affect AGC signalling pathways and suggest that GSK-2334470 will be a useful tool for delineating roles of PDK1 in biological processes. GSK-2334470 also represents a useful addition to our ever-increasing armoury of effective signal transduction inhibitors to dissect biological roles of protein kinases.
To read a copy of our paper describing the GSK-2334470 inhibitor click here
Glycogen breakdown and synthesis plays a critical role in regulating glucose homeostasis. The current issue of Cell Metabolism contains a paper published by Michale Bouskila from Kei Sakamoto's laboratory in the MRC Protein Phosphorylation Unit, which establishes for the first time the key role that allosteric activation of glycogen synthase plays in controlling the accumulation of muscle glycogen. The significance of her study is further discussed in a commentary by Matthew Brady (University of Chicago) in the same issue.
When the blood glucose rises after a meal, insulin is released from the pancreas to signal the body to lower the level of glucose. Insulin achieves this by promoting glucose uptake into muscle and by switching on the action of several enzymes, including glycogen synthase, a key regulator of glycogen formation. It has been known for over 40 years that glycogen synthase is activated allosterically by glucose-6-phosphate (G6P) and by dephosphorylation through insulin-induced inactivation of glycogen synthase kinase-3. However, despite decades of intensive research, the importance of the allosteric regulation of glycogen synthase was unknown due to the lack of a genetic handle on this process. To address this problem Michale first identified a key amino acid residue required for the activation of glycogen synthase by G6P. She then generated a “knock-in” mouse in which the normal form of glycogen synthase was replaced by the G6P-insensitive mutant, which was still capable of being activated normally by dephosphorylation. Strikingly, Michale found that the insulin-stimulated accumulation of muscle glycogen and the muscle glycogen content were both greatly reduced in the knock-in mice. Michale’s work provides compelling evidence that the allosteric activation of glycogen synthase is a major mechanism by which insulin promotes muscle glycogen accumulation in vivo.
On November 1st Hilary Smith delivered her final Ph.D. lecture entitled “Regulation of the E3 Ubiquitin Ligase Pellino in innate immune signalling”, which was followed by a (3.5 hour!) viva conducted by external examiner Luke O'Neill from Trinity College Dublin and internal examiner Ron Hay (College of Life Sciences University of Dundee) at which Hilary defended her thesis. Hilary is the 42nd student to receive her Ph.D. under the supervision of Philip Cohen.
Eris Duro, a PhD student in John Rouse’s team, has discovered a complex of two proteins in human cells, termed MMS22L and TONSL, that plays a vital role in repairing DNA breaks that arise during the process of DNA replication.
During each cell cycle, the genome is duplicated so that there is enough DNA for two daughter cells when cells divide. A major problem is that the protein machineries responsible for replicating DNA frequently encounter obstacles that block their progression. In addition, the DNA replication machineries often encounters nicks in the DNA backbone, and this causes chromosomes to break and “replication forks” to collapse. This, in turn, can give rise to chromosome translocations, aneuploidy or cell death. It is vital that broken replication forks are detected and repaired efficiently and accurately, so that DNA replication can continue.
MMS22L and TONSL bind rapidly to broken DNA replication forks, and they initiate a process known as “homologous recombination”, an ancient mechanism for repairing broken DNA replication forks. MMS22L and TONSL are required for the loading of the RAD51 recombinase onto DNA ends to initiate homologous recombination. RAD51 loading was also known to require the tumour suppressor BRCA2 that is frequently mutated in breast and ovarian cancers. Furthermore, the consequences of depleting MMS22L and TONSL from cells are remarkably similar to those caused by BRCA2 mutations. This raises the possibility that mutations in MMS22L or TONSL could cause cancers.
Eris’ discovery of the MMS22L–TONSL complex is published in the “Articles in Press” section of the current issue of Molecular Cell.
Saif El-Din Shehata, who recently joined Kei Sakamoto's laboratory in the MRC Protein Phosphorylation Unit as an MSc student, has received the DAAD-Prize, which is awarded annually to the best international student from the Bonn-Rhein-Sieg Universiy of Applied Science, Germany. Saif, who is Egyptian, began his Bachelor’s degree in Pharmacy and Biotechnology in 2005 at the German University in Cairo, but transferred to the Applied Biology programme at Bonn-Rhein-Sieg University in 2007 where he completed his studies. He also received a B.Sc. in Molecular Genetics with 1st class honours from the University of Dundee, which has a partnership with Bonn-Rhein-Sieg University.
Saif said he was very grateful to his parents and many colleagues at the University for their support, but especially to his wife Sherin Saad, who was also present at the awards ceremony on October 23rd 2010.
Philip Cohen will launch the 2010 Dundee Science Festival on Thursday October 28th, with a lecture to the general public entitled "Discovery of new drug targets for the treatment of disease in the 21st century." It will take place at 6pm in the Dalhousie Building Lecture Theatre on the University Campus. Admission is free and does not have to be booked in advance. The lecture will be followed by two weeks of scientific events all over the city aimed at people of all ages and in all walks of life.
Tricia Cohen's gallant attempt to become the first Lady to win the University of Dundee Staff Golf Tournament (the Dow Putter) since the competition started in 1881, came to an end at the 16th hole of Scotscraig Golf Course when she lost 3&2 in the final on October 21st to Robert Ford of the Research and Innovation Services Department. Despite the best efforts and encouragement of her Caddy (Philip Cohen) Tricia could not quite recapture the form that had taken her to the final. We wish Tricia every success in going one better next year!
New exciting postdoctoral opportunity to work on the characterisation of a novel DUB involved in cancer – click here
Sir Philip Cohen, Director of the MRC Protein Phosphorylation Unit, has been named among the `100 most important people in British science’ by The Times newspaper.
Sir Philip is placed at no. 55 in the list, ahead of figures like Ian King, the CEO of British Aerospace (59), Lord Browne, the former CEO of BP (68), Lord Sainsbury, the former Minister of Science (78), Lord Winston, the fertility medicine pioneer and broadcaster (84) and Prince Charles (94).
Number one in the list is Sir Paul Nurse, who will become the President of the Royal Society on December 1st and has just returned to the UK after being the President of the Rockefeller University, New York for the past five years. David Attenborough, the iconic broadcaster on natural history came in at number seven.
The citation in today’s Times mentions Sir Philip’s work on protein phosphorylation that has improved understanding of cancer and other diseases. It also cites his role in transforming Dundee into a hub of medical research and for his pioneering partnerships between academia and business, including the Division of Signal Transduction Therapy at the University of Dundee, the largest such collaboration in Britain.
“It is nice to have been included in this first ever list of the 100 people in Britain that matter in science”. This is apparently going to be published annually from now on alongside similar lists such as The Sunday Times “Rich List.” These lists should not of course be taken too seriously as they are based on the opinions of a small panel of judges, but it is good to see that science and its importance to the UK economy and its culture is now being recognised more widely by the general public.
The list in published in today’s issue of The Times’ Eureka science supplement.
The PhD Association of the College of Life Sciences at Dundee organized a retreat for the current 1st and 2nd year PhD students on Sept 10th-12th at Firbush, situated in the Scottish Highlands about 90 min by car from Dundee.
Approximately 40 students took part, presenting their work at either the oral or poster session. The participants voted Alexander von Wilamowitz-Moellendorff, who works with Kei Sakamoto in the MRC-PPU, as the best speaker of the symposium.
Following the scientific sessions, everyone enjoyed outdoor activities, such as kayaking and hill walking in the beautiful Scottish countryside! The meeting, aimed at facilitating networking between PhD students in different subject areas was voted a big success from both the scientific and social standpoint.
Daniel Fazakerley, who recently received his PhD from the University of Bath, UK, working with Geoffrey Holman, has been awarded a Sir Henry Wellcome Postdoctoral Fellowship. This prestigious four year award provides the most promising newly qualified postdoctoral researchers with an opportunity to work in outstanding laboratories in the UK and overseas to help them to develop into independent scientists. During Daniel’s Fellowship he will first work for three years in David James’s laboratory at the Garvan Institute, Sydney, Australia before transferring for his 4th year to Kei Sakamoto's laboratory in the MRC PPU.
Daniel is interested in understanding how signalling pathways control metabolism and the degree to which these pathways are altered in insulin-resistant or diabetic states. He will combine proteomic approaches measuring how the phosphorylation of many cellular proteins change in response to insulin and exercise, combined with mathematical modeling. The goal is to work out complex protein interactions within cells and identify key components of signalling networks involved in the transition from a healthy to an insulin-resistant state.
The titanic struggle to reach the final of the Dow Putter, the University of Dundee's annual match-play knockout golf tournament, reached a climax on the evening of August 28th when Tricia and Philip Cohen replayed their semi-final on the Downfield Golf Course, Dundee, after their first encounter had ended in a tie. In a fluctuating match, Tricia won the first two holes but had fallen two holes behind by the sixth after Philip had won four holes in a row. Back to level after the 10th, Tricia again fell two behind at the 12th, but rallied strongly to win the next four holes leaving her two up with two to play. Both players made a par threes at the 17th, leaving Tricia the winner 2&1.
Tricia will now meet either Rob Ford (Research and Innovation Services) or Donald Gardiner (Head of College of Life Sciences Stores) in the final where she will attempt to be the first Lady to win the Dow Putter since the event started in the 1880's.
The most eagerly awaited event in the sporting calendar since Serena and Venus Williams played each other in the Wimbledon Tennis Final took play on the afternoon of August 22nd when Tricia and Philip Cohen played their semi-final match in the Dow Putter, the University of Dundee's match play gold tournament. Tricia was ahead nearly all the way but Philip drew level at the 16th and then moved ahead for the first time at the 17th where he got up and down from a bunker in two to make par. However, Tricia rose to the challenge and won the 18th so that the match ended in a tie. A replay over 18 holes will take play in the near future!
See previous news item about Philip and Tricia here
Laura Pearce, a PhD student in Dario Alessi’s lab, has published a paper describing PF-4708671, a highly specific inhibitor of S6K1, a protein kinase activated downstream of the PI 3-kinase-PDK1 and mTOR signalling pathway. There is a lot of interest in S6K1 as it regulates numerous biological processes such as protein synthesis, growth, proliferation and longevity. There has been plenty of speculation that drugs that inhibit S6K1 may have utility in the treatment of cancer, diabetes and obesity.
Pfizer provided PF-4708671 to Laura to characterise as part of her PhD project. This was made possible by the unique Division of Signal Transduction Therapy (DSTT) collaboration between the MRC-PPU and five of the world’s leading pharmaceutical companies which Pfizer is part of. This collaboration is dedicated to accelerating the development of specific inhibitors of kinases for the treatment of disease, as well as for the study of cell signaling.
Laura demonstrated that PF-4708671 suppresses S6K1 activity in cells but does not affect the function of closely related kinases such as S6K2, RSK and Akt. It is likely that PF-4708671 will become a widely deployed research tool to dissect the physiological role of S6K1 in controlling diverse biological processes of relevance to understanding and treatment of many human diseases.
To read a copy of Laura’s paper click here
Autosomal dominant missense mutations within the gene encoding for the Leucine-Rich Repeat protein Kinase 2 (LRRK2) predispose humans to develop Parkinson’s disease. The most frequent mutation (G2019S) enhances kinase activity suggesting inhibitors may be useful for the treatment of Parkinson’s disease.
Numerous drug companies have developed drugs that inhibit LRRK2, but as no downstream substrates of this enzyme have been identified there has been no way to evaluate the effectiveness of these compounds to suppress LRRK2 activity in cell or animal systems.
Nic Dzamko and Jeremy Nichols working in the Alessi lab have published two papers in the Biochemical Journal that provide clues as to how LRRK2 functions and will be of use to drug companies developing inhibitors of LRRK2 for the treatment of Parkinson’s disease. Nic and Jeremy first discovered that LRRK2 is phosphorylated at two residues (Ser910 and Ser935) enabling it to bind isoforms of 14-3-3 . They observed that disrupting 14-3-3 binding by mutating Ser910 and Ser935 caused LRRK2 to accumulate within cytoplasmic aggregates resembling inclusion bodies, rather than being diffusely localised throughout the cytoplasm . Interestingly, Jeremy also observed that five of the six most common pathogenic LRRK2 mutations (namely R1441C, R1441G, R1441H, Y1699C, I2020T) displayed markedly reduced phosphorylation of Ser910/Ser935 and 14-3-3 binding and hence were localised within inclusion bodies . These results suggest that certain pathogenic mutations in LRRK2 disrupt ability of LRRK2 to be phosphorylated at Ser910 and Ser935 through an as yet unknown mechanism that we will investigate in future work.
Another key striking observation was that treatment of cells with two structurally diverse LRRK2 inhibitors (H1152 and sunitinib) induced rapid dephosphorylation of Ser910 and Ser935, resulting in loss of 14-3-3 binding and accumulation of LRRK2 within cytoplasmic inclusion bodies . Nic has found in unpublished work that all other much more specific LRRK2 inhibitors that we have tested also induce the dramatic dephosphorylation of LRRK2 at Ser910/Ser935 leading to loss of 14-3-3 binding and causing LRRK2 to localise within inclusion bodies. Furthermore a mutant of LRRK2 that is resistant to H1152 and Sunitinib termed LRRK2[A2016T] does not become dephosphorylated or localise to inclusion bodies in cells treated with LRRK2 inhibitors .
Nic and Jeremy’s data strongly suggests that LRRK2 does not autophosphorylate at Ser910 or Ser935. The key idea that we are exploring is whether LRRK2 operates as an upstream kinase to activate an as yet unknown downstream kinase that phosphorylates Ser910/Ser935 as part of a negative feedback regulatory loop. Our model of how Ser910/Ser935 phosphorylation is regulated is summarised in the figure.
Our recent results should be of great interest to pharmaceutical companies as they indicate that monitoring phosphorylation of LRRK2 at Ser910 and Ser935 or 14-3-3 binding as well as studying diffuse versus aggregated LRRK2 cytoplasmic localisation can be used to evaluate the relative potency of LRRK2 inhibitors. These assays could be deployed in cell lines, tissues of animals or humans treated with LRRK2 inhibitors. Moreover, for human patients administered LRRK2 inhibitors, phosphorylation status of LRRK2 at Ser910 and Ser935 in blood cells could perhaps be employed as a biomarker of LRRK2 inhibitor activity.
The results described in these papers will also hopefully stimulate future work aimed at understanding how Ser910 and Ser935 phosphorylation is regulated. It would be fascinating to explore whether the Ser910/Ser935 protein kinase might also comprise a drug target for the treatment of Parkinson’s disease.
1 Nichols, R. J., Dzamko, N., Morrice, N. A., Campbell, D. G., Deak, M., Ordureau, A., Macartney, T., Prescott, A. R. and Alessi, D. R. (2010) 14-3-3 binding regulates LRRK2 cytoplasmic localisation and is disrupted by multiple Parkinson’s disease associated mutations. In press in the Biochemical Journal (click here to read paper)
2 Dzamko, N., Deak, M., Henati, F., Reith, A. D., Prescott, A. R., Alessi, D. R. and Nichols, R. J. (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localisation. In press in the Biochemical Journal (click here to read paper)
In among the birds of prey, hip-hop dancers and pipe bands at the Tayport Village Summer Festival on 17th July 2010, the 'Made of Molecules' tent was non-stop busy, featuring three activities on the theme of sugar and diabetes. Carol MacKintosh and Kirsty MacKenzie of the MRC Protein Phosphorylation Unit demonstrated how the pancreas sends insulin signals to our muscles. Angie Nicoll of SCILLs helped Tayporters make over 70 bead bracelets representing a section of the insulin gene code. Linda Morris and David Norman of the College of Life Sciences caused alarm by letting people measure how much sugar was in their favourite fizzy drink.
Anna Zagorska, who until recently was a PhD student in Dario Alessi’s lab, has been awarded the 2010 Tim Hunt prize for Cell Biology for her work on the LKB1 NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. The Tim Hunt prize for Cell Biology is awarded for a significant advance in basic research in any area of cell biology carried out in the College of Life Sciences at the University of Dundee. The award is accompanied by a £500 cash prize.
To read a copy of Anna's paper describing the work for which she was awarded the prize for please click here. For a previous news item describing the mechanisms by which LKB1 NUAK pathway regulates myosin phosphatase complexes please click here
Anna is currently undertaking postdoctoral research in the lab of Greg Lemke at the Salk Institute in San Diego, working on the resolution of the immune system. Anna is the first member of the MRC Protein Phosphorylation Unit to be awarded this prize.
Following the completion of the quarter final round ties in the Dow Putter, the University of Dundee matchplay knockout golf tournament, the MRC Protein Phosphorylation Unit is assured of having a representative in the final, because Tricia Cohen will play Philip Cohen in the semi-final! If Philip wins the tournament he will have won the Dow Putter in four different decades. If Tricia wins, she will be the first lady to win the tournament since it first began in the 1880's, so there is much to play for!
Craig Mackay, a Ph.D. student in John Rouse's team in the MRC Protein Phosphorylation Unit, has discovered a protein, known as FAN1, which plays a vital role in maintaining DNA integrity and thus prevents mutations which can lead to cancers.
Speaking about the discovery, John Rouse said “DNA is like an instruction manual for the proper working of each cell.“ A major problem is that DNA becomes damaged regularly. If DNA damage is not fixed quickly then these instructions are changed and the result is mutations – undesirable changes in DNA – that can cause the cell to become abnormal. This is essentially what causes cancer.
“However, cells are very good at recognising when DNA has become damaged and they are good at finding DNA damage and repairing it. For example, cells can quickly detect breakages in DNA and quickly fix these breaks. Many different factors help this process but we still haven’t identified all of them or exactly how this process works.
“With our findings we have unlocked a major part of the puzzle. We discovered a new protein, FAN1, which is essential for the repair of DNA breaks and other types of DNA damage.
“During repair of DNA damage, DNA `flaps’ are produced that must be trimmed for repair to be completed. These leftover pieces of DNA get in the way during DNA repair and that is why they have to be removed. FAN1 carries out this task, and in this sense it acts like a `molecular scissors’.
“Our study shows that superfluous pieces of DNA are cut by FAN1. Cells that do not have FAN1 are unable to repair DNA breaks and their DNA becomes irreversibly damaged and cells die. This underlines the fundamental importance of FAN1.
“Now that we have identified FAN1 and the role it plays in repairing DNA we can start to develop drugs that inhibit it. This may have a significant effect in cancer, primarily in helping to greatly enhance the efficacy of drugs used in chemotherapy treatments.
“It is pure coincidence that last year we discovered a separate group of proteins called the SLX4 complex that also act as a `molecular toolkit’ for DNA repair and are also required for trimming DNA during DNA repair! The SLX4 complex is another promising drug target.
Most of the work on FAN1 was done by Craig MacKay, a PhD student in John’s team, with help from Anne-Cécile Déclais in the laboratory of Professor David Lilley, based in the College of Life Sciences at Dundee. David is a world-renowned expert on proteins that can cut DNA.
The research, published today in the latest edition of the journal Cell, was funded by the Medical Research Council.
See here for article on FAN1 discovery on BBC website.
Maisie has been honoured as the “Top Fundraising Champion” for her work over the years to raise huge sums of money for the Dundee Diabetes Research Campaign. Over the last three years Maisie has raised over £3000 by participating in various half-marathons and 10k runs around Dundee. This money has gone towards funding vital diabetes research in Dundee and Perth.
Most recently by participating in the Monikie 10k race on Sunday 9th May Maisie raised £1140, completing the race in a personal best time of 1hour 9minutes. Maisie has consistently beaten her personal best in the 10k, her 2009 time being 1hr 11mins and her 2008 time 1hr 13mins.
Maisie was presented her award (a beautiful, engraved silver plate) by Dundee’s most famous Hollywood actor and current rector of Dundee University, Brian Cox. The award ceremony took place today as part of the 2010 Graduation Ceremony, with current principal Pete Downes and past principal Sir Alan Langlands in attendance.
Brian Cox, a Type II diabetic himself, has been a long-time supporter of Dundee University and especially the diabetes research teams. Interestingly Maisie believes her husband may be a second cousin of Brian Cox!
Abdulla Ibrahim, a medical student from the University of Dundee, has been awarded a Pathological Society of Great Britain and Ireland bursary to undertake a research project in Gopal Sapkota's laboratory. The Pathological Society of Great Britain and Ireland is dedicated to enhancing high quality research and education in pathology in its broadest sense. This includes the support and encouragement of research and other activities that further the understanding of disease processes. The prestigious undergraduate bursary scheme enables undergraduate students to work for elective or vacation periods in departments of pathology in universities, medical schools, NHS laboratories or research institutes in the United Kingdom or overseas.
Abdulla, who has been in Gopal Sapkota's laboratory since May 1st 2010, has been investigating the roles and the regulation of distinct splice variants of Smad2, a key mediator of the TGF-beta signals. By undertaking a proteomic approach, Abdulla has identified a few novel proteins, which selectively interact with specific splice variants of Smad2. Currently he is characterising the specificity of the interactions and the roles that these proteins have on TGF-beta pathway.
Elton Zeqiraj, who undertook his PhD in the MRC Unit jointly supervised by Dario Alessi and Daan van Aalten, has been awarded a Sir Henry Wellcome postdoctoral fellowship, which is one of the UK's most prestigious postdoctoral fellowships. The aim of this fellowship is to provide a unique opportunity for the most promising newly qualified postdoctoral researchers to make an early start in developing their independent research careers, working in the best laboratories in the UK and overseas.
During his PhD Elton determined the structure of the heterotrimeric LKB1-STRAD-MO25 complex and worked out the mechanism by which LKB1 was activated by interacting with the STRAD pseudokinase. Elton is now working in the laboratory of Frank Sicheri at the University of Toronto. The award will provide Elton with a sum of £250,000 to pay his salary and research expenses for a period of 4 years. The ambitious project Elton proposes to undertake will involve major collaboration with MRC Unit PI Kei Sakamoto who acts as the UK sponsor together with Frank Sicheri for Elton's fellowship.
For the past four years, five Programme Leaders in the MRC Protein Phosphorylation Unit (Dario Alessi, Simon Arthur, Philip Cohen, Carol MacKintosh and Kei Sakamoto) and four other cell signalling laboratories at the University of Dundee (Doreen Cantrell, Nick Leslie, Calum Sutherland and Colin Watts) have participated in a Research Training Group on “The PI 3-kinase Pathway in Tumour Growth and Diabetes“ with 16 research laboratories at the University of Tübingen coordinated by Florian Lang and Sebastian Wesselborg. Funded by the Deutsche Forschungsgemeinschaft (the equivalent of the Biotechnology and Biological Sciences Research Council in the UK), the aim of the Group is to provide the Ph.D. students in this programme with a multidisciplinary training that will enable them to advance our understanding of the molecular mechanisms by which the PI 3-kinase pathway contributes to tumour progression and diabetes in the future. The Tubingen researchers provide considerable expertise in the fields of apoptosis, oncology and diabetes that combines basic research in cellular and animal models with clinical research on large patient cohorts. The Dundee researchers are well known internationally for their expertise in the biochemistry and molecular biology of the PI 3-kinase signalling pathway.
The success of the programme has recently led the Deutsche Forschungsgemeinschaft to renew the Research Training Group for another 4.5 years until March 31st 2015. In reaching this decision, the Deutsche Forschungsgemeinschaft particularly noted the excellence of the individual partners in Dundee, the unique international reputation of the University of Dundee in signalling biochemistry and the enthusiastic feedback of the German students after spending six months in the Dundee laboratories. The MRC Protein Phosphorylation Unit are looking forward to another period of interaction with Tubingen and to welcoming the next cohort of students from Tubingen in due course when they come to Scotland for their research projects.
Edmond Fischer was yesterday elected a Foreign Member of the Royal Society. In 1955, Eddy Fischer and his colleague Edwin (Ed) Krebs discovered the first example of enzyme regulation by reversible phosphorylation when they found that glycogen phosphorylase was activated by phosphorylation and deactivated by dephosphorylation. We now know that almost all intracellular processes are controlled by reversible phosphorylation and that abnormalities in this process are a cause of consequence of many diseases. For this reason protein kinases, which catalyse the attachment of phosphate to proteins, have become the pharmaceutical industry’s most important class of drug target. The importance of their discovery was recognised in 1992 when Eddy Fischer and Ed Krebs received the Nobel Prize for Medicine or Physiology.
“The Royal Society of London for the Improvement of Natural Knowledge” known simply as The Royal Society is the world’s oldest National Academy of Sciences. It was founded in 1660 by about 12 scientists and granted a Royal Charter by King James 2nd. 44 scientists who are citizens of the UK and British Commonwealth and up to six Foreign Members are elected each year from all branches of sciences. The aim of the Royal Society is to promote excellence in science and Fellows elected in the past include Isaac Newton, Charles Darwin, Albert Einstein, Ernest Rutherford, Dorothy Hodgkin, Francis Crick, James Watson and Stephen Hawking. There are currently more than 60 Nobel Laureates amongst the Society's 1314 Fellows and Foreign Members.
Jeremy Nichols, who has been working as a postdoc in Dario Alessi’s lab for the last three and a half years, is departing to take up a Principal Investigator position at The Parkinson's Institute in Sunnyvale, California.
Whilst in the MRC Unit Jeremy undertook rigorous analysis of the regulation and function of the LRRK2 protein kinase that is frequently mutated in patients with Parkinson’s disease. Jeremy’s work has lead to important tools that enable the analysis of the LRRK2 protein kinase. These include development of optimised peptide substrates such as NICtide that are being used by the pharmaceutical companies to elaborate LRRK2 inhibitors. Jeremy has also identified drugs that inhibit LRRK2 and generated mutants of this enzyme that are insensitive to these drugs. Jeremy has two further exciting studies that are being submitted at the moment and further information will appear on the MRC News page regarding these once they are published.
The Parkinson’s Institute is one of the world’s only centres that focuses exclusively on basic and clinical research on Parkinson’s disease under one roof. This should provide Jeremy with a very stimulating environment to establish his independent research group to continue dissecting the signalling pathways controlled by the LRRK2 protein kinase. Jeremy takes up his position at the Parkinson’s Institute in May 2010 and his new email address is email@example.com. Jeremy is the tenth Alessi lab member to be appointed as a group leader in an academic establishment.
It was a busy time for Carol MacKintosh’s group when Catherine Johnson became the second of her students to be awarded a PhD within a week. On Tuesday 30th March, Catherine gave a lively account of her project on “Dual engagement of 14-3-3 proteins with doubly phosphorylated targets” and capably fielded many questions from her audience. Her recent paper on this subject was highlighted a ‘hot paper’ in the Biochemical Journal and can be accessed here. Catherine’s examiners were Professors Alastair Aitken of the Centre for Integrative Biology, University of Edinburgh and Mike Stark of the Wellcome Centre for Gene Regulation and Expression, University of Dundee. They continued the in-depth questioning all afternoon until Catherine emerged successful, with a big grin. Catherine was fêted with gifts and congratulations from her friends and colleagues, as the party got underway. A freak blizzard hit the Scottish Borders that evening, and we were all relieved to hear that Alastair Aitken made it home there safely, albeit at 2 am!
Olof Olsson, a student with Carol MacKintosh successfully defended his PhD thesis on “Novel targets of EGF- and phorbol ester-stimulated phosphorylation and 14-3-3 binding” on 26th March. In the tradition of Swedish PhD vivas, Olof’s family travelled from Sweden to attend Olof’s lecture and being clinicians his parents appreciated the implications of Olof’s exciting discoveries of a subset of proteins that connect growth factor signaling to the regulation of cell migration and gene transcription. We thank Professors Bengt Hallberg of the Faculty of Medicine, University of Umeå and Colin Watts of the Division of Molecular Physiology University of Dundee for putting Olof through his paces in a three hour ‘viva’ exam on his thesis. Then the celebration party could begin, featuring a video of notable events in Olof’s Dundee scientific and social life in Dundee.
Over the two weeks of the 2010 Edinburgh International Science Festival, 1300 children were entertained and educated by six Scottish MRC Units' activities making cells, viruses, DNA bracelets and test-tube babies, and testing how body symmetry correlates with response times. Protein Phosphorylation is challenging to convey to 5 to 12-year-olds, but our Unit rose to the occasion with The Cell Signalling Challenge, a puzzle representing how the pancreas signals to our muscles "Get ready sugar is coming", and how insulin and exercise help get the signal through in people with diabetes. Thanks to our students and postdocs for their enthusiastic participation. We all enjoyed the light bulb moments when children 'got it', and were surprised at how many people have diabetic dogs.
Elton Zeqiraj took some time out from his new postdoc position in Frank Sicheri’s lab at the University of Toronto to return to Dundee to collect the Howard Elder prize. This prize was awarded to Elton for his PhD work characterising the structure of the heterotrimeric LKB1-STRAD-MO25 complex (click here for further information on the prize).
The prize was awarded to Elton by Mike Ferguson, Dean of Research at the College of Life Sciences. For a video of the award ceremony click here.
Anna Zagórska, a PhD student working in Dario Alessi’s lab, has published a paper describing a new pathway by which the LKB1 tumour suppressor might regulate cell adhesion and polarity. Anna discovered that the key regulator of this pathway is an LKB1 activated protein kinase termed NUAK1. Anna observed that the NUAK1 kinase interacts with the myosin phosphatase complex by virtue of its ability to directly bind to the PP1 catalytic subunit via three highly conserved GILK motifs. Anna found that upon stimuli that induce cell detachment, NUAK1 phosphorylates the MYPT1 regulatory subunit of the myosin phosphatase complex, promoting interaction with 14-3-3 isoforms and thereby inhibiting myosin phosphatase complex activity. This enhances phosphorylation of myosin light chain, thereby leading to activation of crucial non-muscle myosin motor proteins that play vital roles in regulating the cytoskeleton as well as cell adhesion and polarity. Anna was able to validate and confirm the importance of her findings using LKB1 and NUAK1 knock-out cell lines (kindly provided by Mariko Hirano and Shinichi Aizawa, Kobe, Japan) as well as a NUAK1 inhibitor (BX795). Using these reagents Anna demonstrated that loss of the LKB1-NUAK1 pathway markedly enhanced cell adhesion and impaired cell detachment.
Anna’s data indicate NUAK1 plays a major role in controlling cell adhesion and functions as a regulator of myosin phosphatase complexes. These findings also suggest that the LKB1 tumour suppressor influences the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes. These results define a new function for LKB1 in decreasing cell adhesion through inhibition of myosin phosphatase activity and indicate that NUAK1 may contribute to tumor invasion by activating cytoskeletal motor proteins and thereby promoting cell detachment.
A dramatic picture of a NUAK1 deficient fibroblast taken by Alan Prescott was selected as the cover of this week’s science signalling (click here)
This study was also of particular interest to Dario Alessi, as his first project as a postdoc in 1991 in Philip Cohen’s lab in Dundee was to purify the myosin phosphatase complex from Chicken Gizzard. After several years work in the cold room Dario purified and identified peptides that belonged to the myosin phosphatase complex that enabled the cloning of the different subunits of this enzyme including MYPT1. Click here to see Dario’s original paper.
Dario then decided to work on protein kinases rather than phosphatases as he was unsure how interesting studying myosin phosphatase complexes would be. This was arguably a mistake as there has been an explosion of papers describing essential roles for regulation of myosin phosphatases in controlling cytoskeleton, cell structure and polarity. Myosin phosphatase complexes also function as master phosphatases acting on many substrates other than myosin light chain. Myosin phosphatases also regulated by phosphorylation by many trendy well-studied protein kinases such as Rock.
Anna is now undertaking postdoctoral research at the Molecular Neurobiology Laboratory, in Greg Lemke's lab at the Salk Institute, La Jolla, California.
To read a copy of Anna’s paper that has made the cover story of Science Signaling click here
To hear a podcast about this work click here
Elton Zeqiraj, who trained for his PhD in the MRC Protein Phosphorylation Unit, co-supervised by Dario Alessi and Daan van Aalten (September 2005 - October 2009) has been awarded a very highly sought-after and competitive Long-Term/Cross-Disciplinary Fellowship from the Human Frontiers Science Programme (HFSP). This will fund Elton’s research in the laboratory of Frank Sicheri in Toronto.
Elton had a very successful PhD where he crystallised the heterotrimeric LKB1-STRAD-MO25 complex and discovered the mechanism by which the STRAD pseudokinase by folding into an active conformation is able to interact with and activate LKB1. It is now becoming realised that many other pseudokinases, as well as active protein kinases, e.g. BRAF, may be able to trigger downstream signalling responses simply by being able to bind to targets when they are folded into the active conformation.
A University of Dundee scientist has been named as the world’s most quoted biochemist over the past 10 years in a survey that also identifies a colleague as among the top 20 in the field globally.
The research papers published by Sir Philip Cohen, Director of the Medical Research Council Protein Phosphorylation Unit and of the SCottish Institute for ceLL Signalling (SCILLS) at Dundee, were mentioned 10, 378 times over the past decade by other scientists in their research publications (termed citations).
The survey is based on data provided by Thomson Reuters from its Essential Science Indicators between January 1st 1999 and October 31st 2009.
Commenting on the survey, Sir Philip said, “I first entered these scientific ‘pop charts’ many years ago when I was named as the 126th most quoted scientist for papers published between the years of 1973 and 1984.
“It is gratifying to see that, so many years later, other biochemists around the world still enjoying reading my papers and that they find them sufficiently important to be worth mentioning in their own publications.”
The survey listed the top 20 biochemists in the world in terms of citations per published paper. Arranged in this way, Sir Philip ranked 18th in the world, while his colleague Professor Dario Alessi, the Deputy Director of the MRC Protein Phosphorylation Unit at the University of Dundee, was two places above him at 16th.
Professor Alessi was cited 78.04 times per paper (68 papers, 5,307 citations) during the period, while Sir Philip was cited 75.20 times per paper (138 papers, 10,378 citations).
There were two other UK-based scientists listed in the top 20, Professor Chris Dobson of University of Cambridge and Dr Rolf Apweiler of the European Bioinformatics Institute, Cambridge. Eleven biochemists from the USA, two from Japan, two from Germany and one from Switzerland were the other nationalities represented in the top 20.
Citations are regarded as one of the most important measures of excellence in basic research because they indicate the extent to which other scientists recognise its quality and use it in their own research.
The table, published in the latest edition of Times Higher Education, surveys journal articles indexed by Thomson Reuters. In total, 7,002 authors published papers in biochemistry between January 1999 and October 2009. Of these, 2,432 published 50 or more papers during the period surveyed.
Ian Ganley and Matthias Trost who have recently been appointed as programme leaders at the MRC PPU each have a PhD project available for October 2010.
For further information on their PhD projects click here and click here for how to apply for a PhD
Two new postdoc positions have become available in Dario Alessi's lab. Click here for details.
The Medical Research Council (MRC) Protein Phosphorylation Unit at the University of Dundee has made a second major appointment within a week, having recruited Dr Matthias Trost as a new Programme Leader.
Dr Trost, who is currently working as a Research Associate at the Institute for Research in Immunology and Cancer, Montreal, Canada, will take up his post in Dundee in August. Born and brought up in Freiburg, Germany, he obtained a BSc in Chemistry from the University of Manchester in 1996 and a Diploma in Chemistry from the Albert-Ludwig University of Freiburg, in 2001.
He then carried out postgraduate research at the German Research Centre for Biotechnology in Braunschweig, from where he received a PhD in 2004. He moved to the University of Montreal in 2005 to carry out postdoctoral research and was promoted to Research Associate in 2007.
Commenting on his appointment and research programme Dr Trost said, "I am very excited and grateful to be appointed to the MRC Protein Phosphorylation Unit where I will be able to work among some of the best researchers in the world.
“The MRC Unit and the College of Life Science in Dundee offer a world-class research environment while keeping a very collegial atmosphere which will help me to establish fruitful collaborations. With my work, I will try to understand how pathogenic bacteria survive in the immune cells that are specialised in killing these microbes, by interfering with signalling cascades.
“I hope that my work will help us to identify molecular mechanisms of infectious diseases such as tuberculosis, and provide new drug targets in the future. On a personal level, my partner and I are looking forward to coming to Scotland as we have always enjoyed the beautiful landscapes and friendliness of the people.”
The appointment of Dr Trost represents the second major recruitment thatr the MRC Protein Phosphorylation Unit has announced recently. Last week it was confirmed that Dr Ian Ganley from the Memorial Sloan Kettering Cancer Center, New York, will take up a post as a Programme Leader within the Unit in August.
Commenting on the appointment of Dr Trost, Sir Philip Cohen, Director of the MRC Protein Phosphorylation Unit said, “We are extremely pleased to have recruited Matthias.
“His research on how white blood cells prevent infection by “eating” pathogenic bacteria when they invade the body is an extremely interesting and important topic, and his great expertise in the technology of mass spectrometry will enable Matthias to initiate important new research collaborations with other Programme Leaders in our Unit.”
This latest appointment means the MRC Protein Phosphorylation Unit now comprises 10 Programme Leaders and 130 scientific and support staff.
Dr Trost met his partner, Dr Katharina Trunk, when they were studying chemistry in Freiburg. Dr Trunk also holds a PhD in the life sciences, which she obtained at the Technical University of Braunschweig, Germany. She is currently working as a postdoctoral fellow at the Institute for Research in Immunology and Cancer in Montreal, Canada. The couple have a one-year-old son called Linus.
It is with great sadness that we report the death of Edgar da Cruz e Silva on March 2nd 2010 after a long battle against cancer. Edgar, who worked in the Protein Phosphorylation Group from 1983-1988, just before it became the MRC Protein Phosphorylation Unit, was Tricia Cohen's first Ph.D. student. He was the first person to carry out cDNA cloning using oligonucleotide screening at the University of Dundee, which he exploited to determine the sequence of the catalytic subunit of phosphorylase kinase. The cDNA libraries that he made were also used to isolate the first clones of protein phosphatase 1 and, with his wife Odete (also a Ph.D. student in Tricia's group), the first clones of protein phosphatase 4. After a year as a postdoc in Tricia’s lab, Edgar then spent eight years carrying out postdoctoral research on protein phosphatases at the Rockefeller University, New York with Paul Greengard, who received a Nobel Prize in 2000 for his work on dopamine signaling in the brain. Edgar and Odete moved to the University of Aveiro in Portugal in 1996, where they became founder members of the Centre for Cellular Biology. Over the next 14 years Edgar, who was appointed Professor and later the Director of the Centre, did much to build up strength in biology in Aveiro that put it on the scientific map. Tricia and Philip Cohen visited the Department on several occasions and, with Carol MacKintosh, attended the Europhosphatase 2007 conference in Aveiro, which Edgar organised and ran superbly, despite having been diagnosed with cancer a year before it took place. Edgar was a warm and generous person, and a committed and talented scientist, who will be sadly missed by the cell signaling community. The Unit sends its sincerest condolences to Odete and their two children Cristóvão and David.
The Medical Research Council Protein Phosphorylation Unit at the University of Dundee has made a key scientific appointment with the recruitment of Dr Ian Ganley from the Memorial Sloan Kettering Cancer Center, New York, USA.
Dr Ganley, who is currently working as a postdoctoral fellow at the USA’s premier institute for cancer research, will relocate to Dundee in August to take up his position as a Programme Leader.
He obtained a Master’s degree from the University of Oxford in 1997 and after working for one year at Oxford Glycosciences Ltd, moved to the University of Cambridge from where he obtained his Ph.D. in 2002. He then carried out postdoctoral research at Stanford University in California for five years before moving to New York in 2007.
Commenting on his appointment, Dr Ganley said, “The decision to join the MRC Protein Phosphorylation Unit was an easy one to make. The international reputation of the Unit is well deserved as not only are the facilities world-class, but the researchers are too. The Unit, and its position in the University of Dundee, creates a superb collegiate environment that fosters collaboration and scientific interactions, something that is very important to me as a scientist in the early stages of my career. This is a place where significant and valuable scientific discoveries are made and I am proud and eager to contribute to the great science being done here.”
Sir Philip Cohen, Director of the MRC Protein Phosphorylation Unit, said, “We are extremely fortunate to have recruited Ian. He is working on a process called `autophagy’, in which damaged and unwanted components of living cells are broken down to their individual components and recycled for use elsewhere. Recent work has indicated that when this process goes wrong, it can cause cancer, heart and liver disease and degeneration of the brain. It may also be a cause of aging.
“Ian’s research is focused on how the process of ‘autophagy’ is regulated at the molecular level with the long-term aim of exploiting this information to develop novel drugs to treat disease.
“I am confident that Ian’s recruitment will create many opportunities for productive interactions with other research teams in the MRC Protein Phosphorylation Unit and College of Life Sciences at the University of Dundee. With Ian’s appointment the size of the MRC Protein Phosphorylation Unit will increase to nine Programme Leaders and 125 scientific and support staff.”
Dr Ganley’s wife, Dr Emma Hill is currently the Executive Editor of the Journal of Cell Biology, one of the world’s leading scientific journals. When she moves to Dundee, Emma will become the Adminstrative Head of the new Dundee Cancer Centre.
On Wednesday March 10th, Sir Philip Cohen, the Director of the MRC Protein Phosphorylation Unit and the Scottish Institute for Cell Signaling, will give the MRC Basic Science Lecture at the Annual Meeting of the American Society of Toxicology, Salt Lake City, Utah, USA. Sponsored since 1995 by the MRC Toxicology Unit, which is based at the University of Leicester, England, the aim of the lecture is to showcase research being carried out by UK scientists who have an involvement with the UK Medical Research Council. Previous speakers have included the Nobel Laureates Sir John Walker and Robert Horvitz. Established by Lewis Smith, when he was the Director of the MRC Toxicology Unit, the lectureship covers the speaker's travel and accommodation and provides an honorarium of US$10,000. Sir Philip will also be made an Honorary Member of the American Society for Toxicology at the opening session of the meeting on the evening of Sunday March 6th.
Elton Zeqiraj an MRC Unit PhD student jointly supervised by Dario Alessi and Daan van Aalten has been awarded the 2009 Howard Elder Prize for Cancer Research for his spectacular PhD research that has lead to the resolution of the three dimensional structure of the LKB1:STRADa:MO25a. To read Elton’s award-winning paper click here.
Elton’s PhD research project was generously supported by TENOVUS Scotland. The committee selecting Elton for this award was composed of Ninewells-based researchers Paul Clarke, Steve Keyse and John Hayes. They commented that “Elton’s work is not only a superb and important piece of work with clear relevance to cancer, but we also selected Elton because he clearly contributed a great deal to the success of the project.”
Much research in the MRC Protein Phosphorylation Unit over the last 11 years has focused on understanding the LKB1 tumour suppressor protein kinase that is frequently mutated in many human cancers. It is now clear that LKB1 exerts its cancer suppressing effects by activating a group of other ~14 kinases comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses cell growth under conditions of low cell energy Activation of AMPK-related kinases by LKB1 appears to regulate cell polarity and contribute to inhibiting inappropriate expansion of tumour cells.
A fascinating feature of LKB1 is that it is activated by an unusual allosteric mechanism involving interaction with an inactive pseudokinase termed STRAD and a scaffolding protein termed MO25. Prior to Elton’s work how STRAD and MO25 cooperate to activate LKB1 was not known. For his PhD project Elton courageously took up the challenge to crystallize the complete LKB1:STRAD:MO25 heterotrimeric complex. This was an extremely challenging project. Elton worked tirelessly for over 3 years attempting to express many constructs in both bacterial and insect cell systems to generate sufficient complex to permit crystallographic analysis. This effort paid off at the beginning of the 4th year of his PhD project when he succeeded in crystallising and solving the structure of the complete heterotrimeric LKB1:STRAD:MO25 complex expressed in insect cells using a baculovius expression system. A stunning movie of the crystal structure of the heterotrimeric LKB1 crystal structure can be viewed in YouTube.
With lots of help from Beatrice Filippi, Elton analysed the effect that over 100 mutations in interesting regions of the LKB1 complex had on complex assembly and activity. These data provide a remarkable molecular insight of how LKB1 is activated by binding to STRAD and MO25. The pseudokinase STRAD subunit despite being catalytically inactive binds ATP and adopts a closed conformation typical of active protein kinases. LKB1 interacts with STRAD as a pseudosubstrate. LKB1 is maintained in an active conformation by forming a web of interactions with both STRAD and MO25.
The finding that STRAD despite being catalytically inactive, exerts its biological function by folding into an active conformation and binding LKB1 in the same manner as an active kinase would interact with a substrate, is likely to be relevant to understanding the evolution and function of other poorly studied pseudokinases (of which there are ~40 encoded by the human genome). It also suggests that active protein kinases could exert physiological responses by binding to substrates without necessarily needing to phosphorylate them. Finally, another very important aspect of Elton’s study is that the structure of the LKB1 complex also reveals how ~60 different LKB1 mutations found in diverse human cancers impair LKB1 function.
The Howard Elder Prize was endowed by Dr Alison Burt in memory of her father (Dr Howard Elder, a former medical graduate of the University of Dundee) 25 years ago. The prize is awarded to a PhD student or postdoctoral researcher in the College of Life Sciences deemed to have published the most significant paper in an area related to cancer research. Elton is now undertaking Postdoctoral Research in Frank Sicheri’s laboratory at the Samuel Lunenfeld Research institute, Toronto Canada. He hopes to return to Dundee to collect his award in April 2010.
This is the second year in a row that the Howard Elder Prize has been awarded to an MRC Unit researcher working in the Alessi lab as last years prize went to Xu Huang for his work in defining the importance of the LKB1 pathway in modulating tumourigenesis.
Fatema Rafiqi for her PhD project, chose to study the role of the protein kinase SPAK that that had previously been discovered to be activated by the WNK1 kinase by an ex-MRC Unit PhD student, Alberto Vitari. Mutations that increase expression of WNK1 result in Gordon’s Syndrome, a rare genetic disorder that is characterized by hypertension and hyperkalemia (high serum potassium). In order to address whether WNK regulated blood pressure via SPAK, Fatema generated a genetically modified mouse in which WNK1 can no longer switch SPAK on.
Excitingly, Fatema found with considerable help of Kevin O’Shaughnessy’s lab in Cambridge as well as Aleksandar Jovanovict lab that the genetically modified SPAK mice have dramatically reduced blood pressure. In addition, there is reduced phosphorylation and expression of the kidney blood-pressure regulating ion cotransporters NCC and NKCC2, that Ciaran Richardson in the MRC Unit had previously shown to be phosphorylated and activated by SPAK. Consistent with these data, plasma and urine electrolyte measurements indicate that the mice display symptoms of salt wasting in particular when under a low-sodium diet.
This study is important as it provides strong genetic evidence that the WNK- SPAK-NCC/NKCC2 signalling network comprises a fundamental regulatory pathway involved in controlling blood pressure. Furthermore, our data suggest that drugs that inhibit SPAK kinase would be effective at lowering blood pressure by reducing the activity and expression of NCC and NKCC2. A recent
genome-wide association study revealed that intronic SNPs within the human SPAK gene (also known as STK39) could be linked to 20% of the population and lead to increased blood pressure. Together with our results the take home message is that SPAK is a master regulator of blood pressure in humans.
To read Fatema’s paper click here.
Emma Carrick successfully defended her thesis on the 7th January with Peter Roepstorff from the University of Southern Denmark and Dimitris Xirodimas as her examiners. Peter is semi-retired and is really the godfather of proteomics in Europe, having spent over 40 years using mass spectrometry to analyse proteins and peptides. Peter also gave a fantastic overview of his quest to find new fluorescent proteins from coral reefs, in an MRCPPU seminar held on the same day. Dimitris is from the GRE division and his work is focussed on the role of the small ubiquiitn like modifier NEDD8. Emma is now working at the Paterson Institute in Manchester with Tony Whetton.
Three Medical Research Council Units in Scotland have set up an exchange seminar programme for their PhD students. The MRC Protein Phosphorylation Unit at Dundee, the MRC Human Genetics Unit at Edinburgh and the MRC Human Reproductive Sciences Unit in Edinburgh have invited a final year PhD student from each of the other Units to present a seminar. The aims are to give the students the experience of presenting their work to a completely different audience, hone their presentation skills and share experiences with their counterparts in the other Units.
The MRC Protein Phosphorylation Unit will host a lecture on February 10th by Emmanouil Stavrou from the MRC Human Reproductive Sciences Unit, Edinburgh entitled ‘Regulation of FOXO transcription factors by gonadotropin-releasing hormone (GnRH)’ and a lecture on March 2nd by Rachel Rigby from the MRC Human Genetics Unit, Edinburgh entitled ‘Ribonuclease H2, RNA:DNA hybrids and the innate immune response’. Conversely, Hilary Smith and Laura Pearce from the MRC Protein Phosphorylation Unit will give lectures at the MRC Human Genetics Unit and the MRC Human Reproductive Sciences Unit, respectively.
Professor Salvador Moncada, Director of the Wolfson Institute for Biomedical Research at University College London, has received a knighthood in the Queen's New Years Honours List published today. Sir Salvador, who gave the first Dundee Cell Signaling Lecture in 1998, has made many important contributions to science including the discovery that aspirin inhibits the synthesis of prostaglandins and the discovery of nitric oxide synthase, the enzyme that converts arginine to the "second messenger" nitric oxide. According to the Institute for Scientific Information, Sir Salvador was the UK's most cited scientist of the 1990's. When the knighthood is conferred later this year it will take place at a different Palace from the one he normally frequents; Salvador is married to Princess Maria-Esmeralda, the sister of the King of Belgium!