MRC PPU News
MRC PPU Scientist Receives Award from the British Heart Foundation
15 December, 2009

Kei Sakamoto, Programme Leader in the MRC Protein Phosphorylation Unit and Alexandar Jovanovic, Ninewells Hospital Medical School, University of Dundee have been awarded £168,000 by the British Heart Foundation (BHF).

Heart and circulatory disease is the UK’s biggest killer, and new treatments are urgently needed to combat it. Some people develop heart disease because of genetic errors that affect the normal function of the heart and circulatory system. Kei and Alexandar will study an enzyme called AMPK, which functions to co-ordinate energy balance in our bodies. Some people inherit errors in AMPK, which can damage the heart by causing it to store too much energy in the form of glucose. This can lead to the debilitating condition called Wolff-Parkinson-White syndrome. Kei and Alexander will look at ways to restore normal energy balance, potentially leading to novel new treatments for these heart conditions.

The main grant recipient, Kei Sakamoto, used to host a fitness program on Japanese TV, but was keen to find out how exercise could help people fight obesity and metabolic disease at the molecular levels. He therefore decided to undertake research for his PhD at the Joslin Diabetes Center, Harvard Medical School, USA, where he became an expert on the molecular physiology of exercise and muscle metabolism. He then moved to Dundee to join Dario Alessi's team in the MRC Protein Phosphorylation Unit in 2003, setting up his own independent research group in the Unit in 2006. His team currently studies the molecular pathways by which nutrients, hormones, and exercise coordinately regulate energy balance in our bodies, and how deregulation of these systems causes metabolic disorders including cardiovascular disease.

Roger Hunter, who recently finished his PhD at the University of Bristol with Dr Ingeborg Hers, has been appointed as a postdoctoral research fellow to undertake this project.




 

MRC Protein Phosphorylation Unit alumni Olga Goransson, Mirela Delibegovic and Kei Sakamoto meet to initiate a new collaboration
19 November, 2009
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Group retreat at the Dalmunzie House Hotel, Perthshire (L-R: Abdelali, Carl, Emma, Kei, Olga, Christine, Alexander, Amelie, Mirela, Alicja, Daria)

Olga Göransson, an Assistant Professor at the University of Lund, Sweden, and Kei Sakamoto, Programme Leader in the MRC Protein Phosphorylation Unit, have recently been awarded an international collaboration grant from the Swedish Foundation for International Cooperation in Research and Higher Education. This grant is aimed at helping promising young researchers in Sweden to build international collaborations with prominent young scientists in other countries. In order to initiate their collaboration, Olga, Kei and the members of their research groups held a research retreat on November 10th in the Scottish Highlands, some 45 miles north of the MRC-PPU. Since Olga and Kei are both interested in the metabolic phenotyping of mouse models for insulin resistance and type 2 diabetes, they also invited Mirela Delibegovic and her team at the University of Aberdeen who are studying the function of protein-tyrosine phosphatases in regulating insulin and leptin signaling pathways and how deregulation of these pathways leads to the development of diseases such as type 2 diabetes and obesity.

Olga and Kei met during the period 2003-2006, when they were both postdoctoral fellows in Dario Alessi's laboratory in the MRC-PPU and they started to run their own independent research groups at about the same time. Mirela carried out her PhD in the MRC-PPU in Tricia Cohen’s laboratory (1999-2003), and after postdoctoral training in Benjamin Neel’s laboratory at Harvard Medical School, started her own laboratory at Aberdeen, 70 miles north-east of Dundee.

The grant is for three years and will be used to accelerate research collaborations between Olga and Kei’s groups and also to provide an opportunity for students and postdoctoral researchers in their groups to visit each other’s laboratories and learn new techniques. Emma Henriksson, a PhD student in Olga’s group, will join Kei’s team from January 2010 for 4 months.




 

MRC PPU researchers part of international teams awarded millions for research into neurodegenerative disease
10 November, 2009

Three teams of researchers – that include Dario Alessi and John Rouse – have received £16.99 million from the Wellcome Trust and the Medical Research Council (MRC) to bolster research into devastating neurodegenerative diseases in a bid to develop better approaches for early diagnosis and therapeutic interventions for these diseases. The team that Dario is part of, led by researchers at University College London, aims to study the mechanisms underlying Parkinson’s disease while John is part of a team, headed by King’s College London, that will study the role of RNA binding proteins in frontotemporal dementia, amyotrophic lateral sclerosis and motor neuron disease. The collaborations bring together leading academic research teams from around the UK, from London, Bristol, Cambridge, Dundee, Manchester and Sheffield, as well as leading international groups and pharmaceutical companies.

Neurodegenerative diseases represent a significant burden on patients and carers, as well to wider society and the economy. As the elderly population increases worldwide, this burden is set to increase further. Although treatment options are already available for some conditions, these are generally of very limited effectiveness and treat the symptoms rather than preventing onset. The development of new therapeutic approaches is therefore essential. Alongside this, identifying markers to allow for the earliest possible diagnosis will maximise the effectiveness of preventative measures and optimise the use of current treatments.




 

Elton Zeqiraj and Beatrice Filippi publish spectacular structure of the LKB1 tumour suppressor complex
10 November, 2009
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Elton Zeqiraj and Beatrice Filippi

Much research in the MRC PPU over the last 11 years has focused on understanding the roles of the LKB1 tumour suppressor protein kinase, as loss of function mutations in this enzyme are frequently observed to promote cancer. Some progress has been made. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of other ~14 kinases comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions.

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. For the last 8 years in collaboration with Daan van Aalten’s lab we have been attempting to crystallize this complex to understand the molecular mechanism by which LKB1 is activated. Elton courageously took up the challenge to crystallize LKB1 for his PhD project. For the first 3 years Elton encountered numerous obstacles in expressing and crystallizing LKB1 and it was suggested many times that he should find another simpler project to work on. However, Elton ignored these comments and persevered defying the odds by succeeding in crystallizing and solving the structure of the heterotrimeric LKB1:STRAD:MO25 complex. Click here to see a movie of the crystal structure of the heterotrimeric LKB1. (Pink): STRAD (green): MO25 (blue). Location of LKB1 residues mutated in cancer are shown in purple.

With the help of Maria Deak, Beatrice Filippi then analysed the effect that over 100 mutations in interesting regions of the LKB1 complex had on complex assembly and activity.

Together, these data provide a stunning picture of how LKB1 is activated. The pseudokinase STRAD 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 structure of the LKB1 complex also strikingly reveals how many mutations found in Peutz-Jeghers syndrome and other cancers impair LKB1 function.

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 which 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 ~30-50 encoded by the human genome).

Click here to read the paper describing the LKB1 heterotrimeric structure.

Elton has now completed his PhD and is departing to undertake postdoctoral research in one of Canada’s pre-eminent scientists, Frank Sicheri’s laboratory at the Samuel Lunenfeld Research institute. Beatrice is now investigating the docking mechanisms by which LKB1 interacts with its substrates.




 

The MRC Protein Phosphorylation Unit at Dundee publishes Europe’s most quoted paper in the field of cell biology
27 October, 2009

A paper published by Sir Philip Cohen and members of his research team in 2000 has been named as Europe’s most influential publication over the period 1996-2007 in an article published in the September 2009 issue of Lab Times using information in Thomson Scientific’s Web of Science. The influence of the paper was judged by the number of times it had been quoted subsequently by other scientists in their own publications (termed citations). The paper, entitled “Specificity and mechanism of action of some commonly used protein kinase inhibitors” was published in volume 351, pages 95-105 of the Biochemical Journal and had garnered 2,199 citations by the end of May 2009, 340 more than its nearest rival.

The article also confirms Sir Philip as the UK’s most cited cell biologist, his 150 publications over the period 1996-2007 being quoted 20,171 times by other scientists. Professor Dario Alessi, another research scientist in the Medical Research Council (MRC) Protein Phosphorylation Unit at the University of Dundee, Scotland, whose papers were quoted 15, 599 times, was the UK’s 3rd most cited cell biologist. Splitting Philip and Dario was Professor Alan Hall, the Director of the MRC Molecular and Cellular Biology Unit at University College London until 2007, whose 19, 961 citations placed him in 2nd in the UK. Scientists working in MRC Units therefore occupied all the top three places in the UK rankings.

Commenting on his most quoted paper Sir Philip said:- “protein kinases are a class of enzyme that controls many of the functions of the human body but they can become deregulated in many diseases. For this reason, protein kinases have become the pharmaceutical industry’s most important class of drug target, especially in the field of cancer. To help accelerate the development of these novel drugs we introduced a technology called “Protein Kinase Profiling” in the late 1990’s. I thought that the information we were obtaining in this way would be useful to other cell biologists but was taken aback by the deluge of e.mails that followed the publication of our paper on this topic, which by far exceeded the reaction to any other paper that I have published before or since. The Biochemical Journal told me a few years ago that the article had been downloaded from their website 7,600 times in 2004 alone. “Protein Kinase Profiling” was first marketed by the European division of Upstate Incorporated, a biotechnology company set up in Dundee in 1999. It became a huge commercial success leading to its acquisition for over US$200 million by Serologicals in 2004.

The article published in the September issue of Lab Times contains other intriguing information. It reveals that, with an average of 30.1 citations per paper, Scotland is the 2nd most influential country in the world in the field of cell biology, just behind Switzerland. England is third in the list, with Israel 4th and the Netherlands 5th. Surprisingly, the USA with 18.7 citations per paper only comes 13th in the world list.




 

Elton Zeqiraj awarded PhD!
20 October, 2009
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L-R: Steve Gamblin, Elton Zeqiraj, Grahame Hardie

Elton Zeqiraj, who has been working jointly in the labs of Daan van Aalten and Dario Alessi for nearly the last 4 years on structural analysis of the LKB1 complex, has been awarded his PhD. Pictured is Elton celebrating his success with his two examiners, Grahame Hardie a grandfather and pioneer of the AMPK field, and Steve Gamblin the world authority on structural analysis of the AMP kinase complex. Elton has secured a postdoc position to work in the laboratory of Frank Sicheri at the Samuel Lunenfeld Researh Institute in Toronto. This is the same Institute where a growing list of other previous PhD students in the unit have in recent times gone to undertake a postdoc research including Abdallah Al-Hakim (Dan Durocher), Giselle Wiggin (Tony Pawson) and Satish Patel (Jim Woodgett). Elton’s last paper has recently been accepted and Elton plans to depart for his postdoc on the 7th November.




 

Congratulations, Dr Green!
12 October, 2009
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Left to Right:- Mike Ashford, Bente Pedersen, Charlotte Green, Harinder Hundal and Kei Sakamoto

Charlotte Green, a graduate student co-supervised by Harinder Hundal (Division of Molecular Physiology, College of Life Sciences, University of Dundee) and Kei Sakamoto (MRC Protein Phosphorylation Unit), successfully defended her PhD thesis entitled "Insulin sensitivity and fatty acid induced lipotoxicity: the role of PKB and AMPK signaling" on October 7th 2009. Charlotte gave an excellent lecture on her research, which was followed by a two hour “viva”, this oral examination being conducted by external examiner Professor Bente Pedersen, Director of the Centre of Inflammation and Metabolism at the University of Copenhagen, Denmark, and internal examiner Professor Mike Ashford of the Biomedical Research Institute, University of Dundee Medical School. After this comprehensive and exhausting examination, Charlotte emerged from the room with a smile and the party started.

Charlotte, Harinder and Kei are grateful to Diabetes UK for providing the PhD studentship and research consumables that made this project possible.




 

Congratulations to Dr Thastrup
25 September, 2009

Jacob Thastrup, working in Dario Alessi’s lab, has been awarded a PhD for work carried out on analysis of the function and regulation of WNK isoforms. Pictured is Jacob next to his parents, Ole and Lise Birgitte, and his examiners Dr Pat Eyers, YCR Institute for Cancer Studies, University of Sheffield and Stuart Wilson, maternal and Child Health Sciences, Ninewells Hospital and Medical School.

To our knowledge this is the first time that the parents of the candidate have attended a PhD viva seminar. Jacob’s father is a well-known Danish entrepreneur having founded several biotech companies and was also one of the first people to realise the potential of the green fluorescent protein as a tool to study protein cellular localisation. Most impressively Jacob’s dad asked Jacob the hardest and most probing question at the end of the viva seminar. By all accounts after the seminar Jacob was given quite a grilling by his examiners, who asked him a very wide-ranging series of questions on the nuts and bolts of protein kinases and physiology of salt transport. After nearly 4 hours he eventually passed and celebrations commenced.




 

MRC Unit postdocs Jeremy Nichols and Nic Dzamko publish important new paper
11 September, 2009
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Jeremy Nichols and Nic Dzamko

There has been much interest in studying the function and regulation of the Leucine Rich Repeat Protein Kinase-2 (LRRK2) which is mutated in a significant number of Parkinson’s disease patients. Progress in this area has been slow and hampered by a lack of tools to investigate the intrinsic properties, activity and function of the endogenously expressed LRRK2 enzyme.

To address these concerns, Jeremy Nichols undertook a detailed analysis of substrate preferences of LRRK2 and used this information to elaborate a new peptide substrate termed Nictide (reflecting the names of the first two authors of the paper, pictured above). Jeremy demonstrated that Nictide is vastly superior to the original LRRKtide substrate that is widely deployed to assay LRRK2. Nic Dzamko also developed the first ever antibody reagents that enable the detection of endogenous LRRK2. Employing Nictide as substrate Nic was able to develop an immunoprecipitation based assay that permits measurement of endogenous LRRK2 kinase activity. In addition, Jeremy also discovered that relatively specific Rho kinase (ROCK) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In collaboration with Alastair Reith’s group at GlaxoSmithKline we identified GSK429286A a selective ROCK inhibitor that did not inhibit LRRK2. Using these reagents Jeremy developed a strategy to validate whether substrates are phosphorylated by LRRK2 and used this to show that LRRK2 is probably not rate-limiting for the phosphorylation of the proposed substrate moesin.

We hope that these new results will aid with dissecting the functional roles of the LRRK2 kinase and how mutations in this enzyme lead to Parkinson’s disease. To read the paper describing this work please click here




 

PhD Projects now available for 2010
7 September, 2009

We are now recruiting for PhD studentships to start in 2010. Information on the available projects can be found here . Please click here for how to apply. The closing date is October 30 2009




 

Edinburgh Science and Ferryport Summer Festivals
24 July, 2009

At this year’s Edinburgh Science festival, MRC PPU students Laura Pearce, Laura Brown, Hilary Smith, Eris Duro and Hosea Handoyo ran an activity showing how a blood cancer can be cured by blocking the 'Bcr-Abl' kinase with the medicine Gleevec. The model attracted attention from many children and parents, who posed challenging questions about proteins, kinases, cell signalling, and drug discovery. Thanks to Professor Carol MacKintosh for working with her husband Bob and FifeX, a company in her home village of Tayport, to make the exhibit.

Tayport has its own summer festival, and Carol felt that science should join the usual mix of music, arts and dance this year. The resulting ‘Made of Molecules’ tent was a great success, led by Dr Linda Morris of the College of Life Sciences on the day, with enthusiastic support from others in the college, including postdocs Richard Ward and Sapan Gandhi, and undergraduate student Erman Sozudogrui who took the photo. Pictured are Linda, Angie Nicoll (SCILLs administrator), with Dr Will Whitfield supervising a DNA extraction experiment.




 

New postdoc position available in Alessi group
22 July, 2009

New postdoc position in Dario Alessi's group currently being advertised, closing date 31st August 2009. For more info please click here




 

DNA `SWISS ARMY KNIFE’ DISCOVERED BY MRC-PPU SCIENTISTS
14 July, 2009

John Rouse’s research group in the Medical Research Council (MRC) Protein Phosphorylation Unit at the University of Dundee have discovered a group of proteins acting like a `Swiss Army Knife’ to repair damaged DNA in our cells, a finding which could have future implications for the treatment of cancers.

The team discovered a set of proteins, known as “SLX” proteins, which are present in each cell and play a vital role in maintaining healthy DNA and thus preventing mutations which can lead to cancers.

“The DNA in every cell of the human body encodes the instructions for the correct working of the each cell,” said John Rouse. “A major problem is that DNA becomes damaged regularly. If DNA damage is not fixed quickly then the instructions for the proper functioning of the cell are altered and the result is mutations 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 start to repair the damage. 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 set of proteins - the “SLX” proteins - that are essential for the repair of DNA breaks.

Together these proteins act like a Swiss Army knife or a `molecular toolkit’ for DNA repair. During repair of DNA breaks, DNA `branchpoints’ (known as Holliday junctions) and DNA `flaps’ are produced that must be cut for repair to be completed. Scientists have been hunting for the factors that can cut Holliday junctions in human cells for more than two decades - our study shows that these DNA branchpoints are cut by the SLX proteins. Cells that do not have the SLX proteins are unable to repair DNA breaks and their DNA becomes irreversibly damaged and die. This underlines the fundamental importance of the SLX proteins.

Now that we have identified these proteins and the role they play in repairing DNA we can start to develop drugs that target these processes. This could have a significant effect in cancer, primarily in helping to greatly enhance the efficacy of drugs used in chemotherapeutic treatments.“

Dr Rouse’s team, in particular Ivan Muñoz and Karolina Hain, worked closely on the research with Anne-Cécile Déclais in the laboratory of Professor David Lilley, based in the College of Life Sciences at the University of Dundee. David Lilley is a world-renowned expert in Holliday junctions.

The research is published in the July 10th issue of the journal Molecular Cell (Vol. 35, pp. 116-27).

The work was funded by the Medical Research Council and St Andrews-based charity AICR (Association of International Cancer Research).

Dr Mark Matfield, from AICR, said, “This is an important step forward in our basic understanding of DNA repair. Since damage to DNA is, ultimately, the cause of all cancers, we really want to understand how cells can repair it. These findings could have implications for future developments in both cancer prevention and treatment.”




 

Diabetes Research in Dundee boosted by donation of £12,500 from Dundee and District Diabetes UK Volunteer Group
29 May, 2009
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Kei Sakamoto receiving the cheque from the Dundee and District Diabetes UK Volunteer Group (photo courtesy D. C. Thomson & Co. Ltd)

Diabetes Research in Dundee was boosted by a donation of £12,500 from the Dundee and District Diabetes UK Volunteer Group, who handed over the cheque at the Wellcome Trust building on the 26th May. The funds will be used by Dr Kei Sakamoto's independent research team, studying the molecular pathways by which nutrients, hormones and exercise regulate blood sugar levels and how deregulation of these systems causes type 2 diabetes.

Volunteer group secretary Alison McIntosh said the money was raised through a bequest of £9500, with the balance accumulated by a year of fund-raising activities. "We're delighted to be able to keep this money locally as Dundee is growing in importance as a diabetes research centre of excellence. Diabetes is a terribly debilitating condition, which is unfortunately affecting a growing number of people and this is reflected in the number who help raise money for research."

Dr Sakamoto said it was a massive boost to receive such support from the community.




 

Former Postdoctoral Fellow in the MRC Protein Phosphorylation Unit is elected a Fellow of the Royal Society
18 May, 2009
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Brian Hemmings

Brian Hemmings, a postdoctoral fellow in the MRC Protein Phosphorylation Unit for three years from 1980-1982, has been elected a Fellow of The Royal Society, the highest accolade that a UK scientist can receive. 
Brian’s election to the UK’s “Scientific Hall of Fame” recognizes his important and wide-ranging contributions to our understanding of protein kinases and protein phosphatases. His work solved the molecular complexity of the multiple regulatory components of protein phosphatase 2A. He was also the first to identify Protein Kinase B (PKB, also called Akt) and made important contributions to our understanding of its physiological roles. PKB has subsequently become an important target for the development of anti-cancer drugs, and inhibitors of this enzyme are undergoing clinical trials. More recently, Brian has made major advances to our understanding of the function and regulation of the NDR kinase

Commenting on Brian’s election, MRC Unit Director Philip Cohen said: “I congratulate Brian on this outstanding achievement. This is the fifth time in the past eight years that a scientist trained in our Unit has been elected to the Royal Society Fellowship. It means that 5% of all the Biochemists and Molecular Biologists that are currently Fellows of the Royal Society were trained in or are working in our Unit. This is truly remarkable bearing in mind the modest size of our Unit. It is a testament to the calibre of the people that we recruit and the training that they receive here".

About the Royal Society: 
Each year, just over 40 people across the UK, the British Commonwealth and the Republic of Ireland, working in all branches of science ranging from mathematics, astronomy, physics, chemistry, genetics, botany and medicine, are elected to The Royal Society. It is the world’s oldest National Academy of Sciences being founded in 1660 by King Charles II.



About Brian Hemmings: 
Brian, who is 58, obtained his B.Sc from the University of Nottingham in 1972 and Ph.D. from the University of East Anglia in 1975. Following postdoctoral work with Helmut Holzer in Freiberg, Germany and then Earl Stadtman at the National Institutes of Health Bethesda, USA, he spent nearly three years in Philip Cohen’s lab in the MRC Protein Phosphorylation Unit in Dundee from 1980-1982. He then set up his own research group at the Friedrich Miescher Institute, Basel, Switzerland, where he has worked ever since, being promoted to Senior Scientist in 1990. Brian’s achievements have been recognized previously by election to membership of the European Molecular Biology Organisation in 1996. He also received the Cioetta Foundation (Zurich) Prize for 2000, a Japanese Biochemical Society (JB) Award in 2000, the Novartis Corporate Research Award for Scientific Excellence in 2004 and the Swiss Bridge Award for 2004. According to the Institute for Scientific Information in Philadelphia, Brian is one of the world’s 100 most cited scientists working in the field of Biology and Biochemistry.




 

Monikie 10k - Sponsorship raised for Dundee Diabetes Research
13 May, 2009
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Maisie Harkins, top fundraiser

This year’s Monikie 10k run took place on Sunday 10th May. A number of people from the MRC Unit were brave enough to take part, including Maisie Harkins who raised a spectacular £625 in sponsorship for Dundee Diabetes Research. Maisie also managed to beat her previous year’s time by 2 whole minutes, completing the race in 1 hour, 11 minutes and 18 seconds.

We are also very proud of Kalina Szteyn, a visiting student in Kei Sakamoto's lab, who completed the run in a remarkable 39 minute and 49 seconds, finishing in 7th place, and being the second woman runner overall to finish! Kalina however says she was disappointed with her time as she used to run much faster!

Also taking part were:

Dario Alessi (0:48:36)
Paola de los Heros (1:12:22)
Beatrice Filippi (1:00:28)
Antje Grotemeier (1:11:16)
Ivan Munoz (0:46:38)
Sam van Beuningen (0:55:52)
Stephan Wullschleger (0:56:44)
Anna Zagorska (0:56:00)




 

Juan M. García-Martínez publishes important article describing a novel, highly specific mTOR inhibitor
1 May, 2009
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Juan M. García-Martínez

A major mission of the MRC Protein Phosphorylation Unit is to exploit the advances we and others have made in understanding signal transduction networks to help pharmaceutical companies develop the next generation signal transduction inhibitors to treat human disease.

The mTOR protein kinase is a master regulator of cell growth and proliferation. It controls the activity of many AGC protein kinases that we have been investigating over the last 15 years in our Unit such as Akt, S6K and SGK. Many mutations that cause cancer in humans lead to inappropriate over-activation of the mTOR protein kinase and hence AGC kinases. This has lead to the notion that inhibitors of the mTOR protein kinase could suppress the proliferation of a large number of common human cancers.

Using technologies that have been developed in the MRC Protein Phosphorylation Unit over many years, Juanma (Juan M. García-Martínez), has helped Astrazeneca characterise a novel and highly specific mTOR protein kinase inhibitor termed Ku-0063794. This compound inhibits mTOR complexes with an IC50 of 10 nM and is one of the most specific protein kinase inhibitors that we have ever characterised, as it does not inhibit the activity of over 80 other protein kinases tested even at very high concentrations. Juanma has established that Ku-0063794 is cell permeant, and suppresses mTOR signalling pathways in cells leading to the inhibition of Akt, S6K, and SGK1 protein kinases and downstream networks controlled by these enzymes.

This work establishes that Ku-0063794 will be a useful reagent to probe the physiological roles of the mTOR protein kinase. It will also help in defining whether inhibiting the mTOR protein kinase is indeed an effective anti-cancer therapeutic strategy.

The paper describing this work has been published in the Biochemical Journal.




 

Sir Philip Cohen to receive the SBS Achievement Award
29 April, 2009
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Philip Cohen with Ralph Cicerone (President of the US National Academy of Sciences) after being inducted into the US National Academy of Sciences

Professor Sir Philip Cohen, Director of the Medical Research Council Protein Phosphorylation Unit at the University of Dundee, will today (April 29th) be presented with the Society for Biomolecular Sciences (SBS) Achievement award.

Sir Philip will receive the honour at the 15th annual conference of the Society, which is being held at the Lille Grand Palais in Lille, France.

The SBS award is presented at least every three years “to recognize outstanding achievements in research, innovation, ground-breaking foundation or seminal contributions that have proven to be broadly applicable to biomolecular sciences or pharmaceutical/agricultural lead discovery.”

Last year's awardee was Takatada Yamada, the Director of the Gates Foundation and previously the Chairman of Research and Development at GlaxoSmithKline. Among other former winners is the Nobel Laureate Sir John Sulston.

Sir Philip will receive a commemorative plaque and an honorarium of $US 5000 before delivering a lecture entitled “Protein Phosphorylation; my first 40 years”. He will give a second lecture at the SBS conference tomorrow on “Targeting protein kinases for the treatment of chronic inflammatory diseases.”

Commenting on the award Philip said, “It is a great honour to receive the really prestigious SBS Achievement Award. I am particularly pleased that it has taken place at the Lille Grand Palais, which I first visited 10 years ago when I came to watch my daughter Suzanne play for Scotland in the World Bridge Olympiad that was held at this venue.”

Philip flew to attend the SBS Symposium directly from Washington DC where he was inducted as a Foreign Associate of the US National Academy of Sciences on the evening of April 25th. The 146th NAS annual meeting also included an address from President Barack Obama.




 

Hosea Handoyo wins the Golden Spatula Award
20 April, 2009

Hosea Handoyo, a graduate student in Philip Cohen’s research group in the MRC Protein Phosphorylation Unit has received the ”Golden Spatula Award” for 2008. from the Royal Dutch Chemistry Society. This prize is awarded annually to the undergraduate in Holland deemed to have carried out the best research project during the year.

Hosea was an undergraduate student at Han University, the Netherlands, but carried out his undergraduate research project in Philip Cohen’s laboratory during the academic year 2007-2008. The project provided new insights into the mechanism by which the protein kinase Tpl2 is activated by the pro-inflammatory cytokine interleukin-1, and these studies are currently being prepared for publication. After graduating from Han University with a B.Sc Cum Laude, Hosea rejoined Philip Cohen’s lab in October 2008 as a graduate student.

This is the first time that an international student (Hosea is Indonesian) has received the award since it was established in 1982. It comes with a Trophy and cash prize of 1000 Euro.

The press-release from the Royal Dutch Chemistry Society said:-
Hosea Saputro Handoyo (Hogeschool Arnhem Nijmegen).
“Hij voerde dit onderzoek uit aan de wereldwijd bekendstaande MRC ProteinPhosphorylation Unit van de University of Dundee, Schotland, onder begeleiding van Sir Philip Cohen.”

“He did his research in the world-famous MRC Protein Phosphorylation Unit of University of Dundee, Scotland under the supervision of Sir Philip Cohen.”




 

Xu Huang awarded the 2008 Howard Elder Prize for Cancer Research
14 April, 2009
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Another Success for Xu

Xu Huang who was a postdoc in Dario Alessi’s laboratory (2004-2008) has been awarded the 2008 Howard Elder Prize for his work that established the important role that the LKB1-AMPK pathway plays in suppressing tumourigenesis.

Xu undertook 4 years of painstaking work to define the importance of the LKB1‑AMPK signalling on tumourigenesis resulting from the loss of the PTEN tumour suppressor. He used a combined genetic and pharmacological approach to establish the importance of the LKB1-AMPK signalling pathway in controlling tumourigenesis in mice resulting from the loss of the PTEN tumour suppressor. Xu demonstrated that LKB1 hypomorphic mice expressing only 10% of the normal levels of LKB1 in which AMPK signalling is suppressed, tumour formation was markedly accelerated. Conversely, Xu established that administration of PTEN deficient mice with various AMPK stimulating agents, including the clinically approved drug metformin, which is used for the treatment of Type II diabetes, delayed the onset of tumourigenesis.

Xu’s findings are of particular importance as they suggest that activating AMPK through the use of already clinically approved drugs such as metformin or potentially phenformin, could be a simple strategy to exploit a cells natural growth suppressing pathway to halt proliferation of tumours. Activating the AMPK pathway in cancer cells through the use of metformin or phenformin would effectively suppress proliferation by "tricking" cells into believing that they do not have sufficient energy to grow and proliferate. Metformin or other AMPK activators could be used as an adjuvant to current cancer treatments and render these treatments more effective.

Xu’s study has stimulated a lot of interest. Work is in progress now to establish whether metformin or phenformin might be used to treat patients with cancer. Xu’s paper describing this work was published in June 2008 in the Biochemical Journal and has already been cited 14 times.

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. Xu is now a Postdoctoral Researcher in the Leukaemia Biology Group of Dr Tim Somervaille, at the Paterson Institute for Cancer Research in Manchester.




 

Babies take over Alessi lab
3 April, 2009
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L-R: Jeremy and Ainsley, Ciaran and Úna, Nic and Ashton, Miratul and Marwan

Four postdoctoral researchers in Dario Alessi's lab have between them managed to produce four babies in recent months. Jeremy Nichols started the trend when his wife Jenny gave birth to Ainsley Ellen on the 31st October (Halloween) last year. Ainsley was swiftly followed by Ciaran Richardson's daughter Úna on the 25th November, Miratul Muqit's son Marwan on Christmas Day and finally (so far) Nic Dzamko's son Ashton Tay who made his appearance on the 27th of January, missing his daddy's native Australia Day (26 Jan) celebrations by only one day.




 

David Komander receives Biochemical Society Early Career Research Award
2 April, 2009
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A content-looking David with his medal

David Komander, who was a joint PhD student in the laboratories of Daan van Aalten and Dario Alessi, received the Early Career Research Award from the Biochemical Society on 2-April 2009. David is the first recipient of this prestigious and highly sought-after award. After receiving his Medal he gave a stunning talk on the specificity of ubiquitination signalling to a packed lecture theatre at The Dynamic Cell, the Joint Meeting of the Biochemical Society and the British Society for Cell Biology, at the University of Edinburgh. David talked about his recent findings on the three-dimensional structure of linear polyubiquitin chains, how these interact specifically with NEMO (rather than Lys63 linked chains). He also talked about the importance of deubiquitinating enzymes and how A20 might function as a dual Lys63 and Lys48 deubiquitinating enzyme through the use of specific as yet to be identified targeting subunits.




 

MRC Unit Director publishes 500th research paper
31 March, 2009

Philip Cohen, the Director of the MRC Protein Phosphorylation Unit, has reached a scientific milestone with the publication of his 500th paper. Last year, Philip was elected a Foreign Associate of the United States National Academy of Sciences, which allows him to contribute up to four papers a year to Proceedings of the National Academy of Sciences (PNAS). By a happy coincidence, his 500th research paper was his inaugural article for this journal, a paper in which his Ph.D. student Hilary Smith identified the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for its activation by the protein kinases IRAK1 and IRAK4 (Smith et al (2009) Proc Natl Acad.Sci. USA 106, 4584-4590). Philip's first paper was published in 1968 when he was a graduate student at University College London and appeared in the first issue of the Volume 1 of FEBS Letters. Philip's "H index' is 124, which means that 124 of his papers have been cited over 124 times. According to the Institute for Scientific Information, Philadelphia, he was the world's second most cited scientist in the field of Biology and Biochemistry over the period 1992-2002.




 

International Collaboration Grant Awarded to MRC Protein Phosphorylation Unit Alumnus and Programme Leader
27 March, 2009
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Olga and Kei have kicked-off new research collaboration funded by the Swedish Foundation for International Cooperation in Research and Higher Education.

Olga Göransson, an Assistant Professor at the University of Lund, Sweden, and Kei Sakamoto, Programme Leader in the MRC Protein Phosphorylation Unit, have been awarded an international collaboration grant (1050,000 Swedish Krona; approximately £90,000 sterling) from the Swedish Foundation for International Cooperation in Research and Higher Education. This grant is aimed at helping younger researchers in Sweden to build up international collaborations with scientists in other countries who are in a similar position to themselves. Olga and Kei met during the period 2003-2006, when they were both postdoctoral fellows in Dario Alessi 's laboratory in the MRC-PPU and they started to run their own independent research groups at about the same time. Olga and Kei are both interested in understanding the physiological roles of the protein kinase LKB1 and how the signaling pathways it activates are regulated. Their collaboration has already led to the publication of several joint papers. The grant that has just been awarded will accelerate their research projects and also provide an opportunity for students and postdoctoral fellows in their groups to visit each other’s laboratories and learn new techniques.

Olga Göransson commented:
"I’m really thrilled about having received this grant, which will enable me to develop my collaboration with Kei. I’m very much looking forward to seeing what we can achieve together, and I think that interacting with a top international institute like the MRC Protein Phosphorylation Unit is going to be a great experience for me and my co-workers. "




 

MRC Protein Phosphorylation Unit student wins Poster Competition.
16 March, 2009
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Elton Zeqiraj, winner of the poster session at this year's CLS symposium

Elton Zeqiraj, who holds a Tenovus Studentship and is jointly supervised by Daan van Aalten, a structural biologist in the College of Life Sciences (CLS) at the University of Dundee and Dario Alessi in the MRC-PPU, was awarded first prize at the Scientific Poster competition held during the annual CLS Retreat at the Crieff Hydro Hotel, Crieff, Perthshire, Scotland during the weekend of March 13th-15th.

Elton's poster presented the work that he has been undertaking characterising the mechanism by which the LKB1 tumour suppressor is activated by binding to its regulatory subunits STRAD and MO25. Work by other members of Dario’s Research Group has shown that LKB1 acts as a tumour suppressor by switching on the AMP-activated protein kinase and other protein kinases in the same subfamily. The judges placed Elton's poster ahead of the other 54 entries for the quality of the poster itself, but also for the tremendous achievement in defining how the STRAD pseudokinase activates LKB1.

John Rouse, the Head of the judging panel said:
"The work that Elton has undertaken to address how the LKB1 tumour suppressor may be activated is a major achievement, not only in technical terms but also because it represents such a big step forward in our understanding of how this important molecule works at the molecular level. Elton's poster was beautifully designed and his findings were presented in a way that made them easily accessible to non–specialists. These factors, made Elton a clear winner."




 

Philip Cohen's lab retreat
18 February, 2009

Philip Cohen's Group relaxing after their lab retreat at the Ballathie House Hotel, Perthsire. The 45lb (20kg) salmon in the glass case was caught in the River Tay which flows through the garden of the hotel.




 

MRC Protein Phosphorylation Unit wins two more grants from the MRC's Translational Medicine initiative
10 February, 2009

Following, a major award to set up the National Kinase Profiling Centre in 2008, The MRC-PPU has now received two further awards to enhance its major collaboration with the pharmaceutical industry.

Carol MacKintosh and Nick Morrice have been awarded a 3-year grant of £327,000 from the MRC-National Health Service Developmental Pathway Funding Scheme, which will enhance the Unit's capability to generate and mine larger data sets of cellular phosphoproteins to identify new mechanisms underlying diseases and drug actions. Based on the initial results that Carol and Nick have generated, the five major pharmaceutical companies with whom we collaborate in the Division of Signal Transduction Therapy (DSTT) are excited by the potential of these methods to help in the prioritisation of drug candidates for human clinical trials.

The MRC-National Health Service Developmental Pathway Funding Scheme have also awarded Dario Alessi, Simon Arthur, Philip Cohen and Kei Sakamoto a three year grant of £386,000 to further exploit in vivo models for the validation of protein kinases as drug targets. The award recognises the exciting results obtained recently by Dario Alessi's research team in particular, who exploited several in vivo models to demonstrate that inhibitors of the protein kinase PDK1 and activators of the AMP-activated protein kinase are likely to have therapeutic benefit for the treatment of cancers caused by mutations in the tumour suppressor PTEN. Dario's Group have also used a further in vivo model to validate the protein kinase SPAK/STK39 as a novel target for the treatment of hypertension. The new award will allow the Unit to expand its research in this area and to validate other protein kinases for the treatment of chronic inflammatory diseases and diabetes, as well as cancer and hypertension.

These two new grants, together with the previous one to set up the National Kinase Profiling Centre, brings the total sum awarded to expand the Unit's work in Translational Medicine to £1.7 million over the past eight months. The awards will reinforce the Unit's major collaboration with the pharmaceutical industry, which is aimed at accelerating the development of drugs that modulate the activities of protein kinases and protein phosphatases.




 

MRC Unit Director receives his award from Scottish Enterprise
9 February, 2009
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Philip holding the award with John Swinney (left), Jack Perry, CEO Scottish Enterprise (right) and Rhona Allison (far right)

On Thursday February 5th, at the Annual Scottish Enterprise Life Sciences Award dinner at the Edinburgh International Conference Centre, Philip Cohen was the winner in the “leading individual contribution to the Life Sciences in Scotland” award. The trophy was presented by Cabinet Secretary John Swinney MSP, the Minister of Finance in the Scottish Government.




 

The history of Life Sciences and Biotechnology in Dundee
23 January, 2009

A book entitled "The New Scottish Enlightenment" has just been published by The Times Group to celebrate the 250th anniversary of the birth of Robert Burns and sponsored by Event Scotland and Scottish Development International. One of the invited articles entitled "Dundee: from Jute, Jam and Journalism to Biochemistry, Biomedicine and Biotechnology" (pages 123-128) which charts the rise of Life Sciences and biotech in Tayside was written by the MRC Protein Phosphorylation Unit’s Director, Philip Cohen. If you want to read the whole book, please click here




 

Miratul Muqit and Dario Alessi awarded new Parkinson's Disease Society PhD studentship
16 January, 2009

Miratul Muqit and Dario Alessi have been awarded a new Parkinson's Disease Society PhD studentship to identify substrates and regulation of the Parkinson's disease associated protein kinase PINK1.

For further details and how to apply please click here