Role of PDK1 in the PtdIns 3-kinase-dependent protein kinase cascade that mediates actions of insulin & survival factors
Lead Research Organisation:
MRC Protein Phosphorylation Unit
Abstract
Over the last five years we have been able to demonstrate that PDK1, an enzyme we discovered in 1997, not only plays a crucial role in enabling insulin to regulate metabolism, but also controls the growth of living cells. Excitingly, we found that lowering the level of PDK1 by 80-85% protects many organs of the body from developing a variety of cancers, without compromising its ability to regulate metabolism. These findings suggest that PDK1 is a promising target for an anti-cancer target and that drugs capable of switching off PDK1 activity, should suppress the growth of some of the most prevalent forms of human cancers. We have licensed the technology and reagents that we have developed in this area to several pharmaceutical companies, which should to accelerate the development of such drugs.||We have identified several other proteins over the past five years, which like PDK1, may also control processes that are related to cancer and diabetes. We now plan to study these proteins in much greater detail and find out how they work. We anticipate that these studies will provide new insights into the molecular causes of diabetes and cancer and hence to improved treatments for combating these terrible diseases.
Technical Summary
The interaction of insulin and growth factors with their receptors on the outer surface of the cell membrane, leads to the generation of a lipid second messenger termed PtdIns(3,4,5)P3 at the inner surface of the cell membrane, which then triggers their intracellular actions. In the late 1990s we discovered a PtdIns(3,4,5)P3-binding protein kinase termed the 3-phosphoinositide-dependent kinase 1 (PDK1) and found that it activates a number of other related protein kinases, including PKB, S6K, SGK and PKC isoforms, which mediate the diverse cellular effects of insulin and growth factors. By using knock-out and knock-in technology in both embryonic stem cells and mice, we have recently been able to provide the genetic evidence needed to establish the crucial role played by PDK1 in activating other protein kinases and in regulating physiological processes such as glycogen synthesis and glucose uptake. In collaboration with Daan van Aalten at Dundee, we have crystallised and solved the structures of both the catalytic and PtdIns(3,4,5)P3-binding PH domain of PDK1, which has provided fundamental information about how PDK1 activity is regulated. We have exploited this information to generate appropriate knock-in mutations of PDK1 and used these strains of mice to show that PDK1 activates PKB in a completely different way to all of its other substrates. The uncontrolled activation of PKB and or S6K caused by elevated levels of PtdIns(3,4,5)P3 occurs in up to 50% of all cancers, and this contributes to the enhanced growth and survival of these cells. In order to investigate the role of PDK1 in mediating tumourigenesis, we therefore crossed mice, which have elevated levels of PtdIns(3,4,5)P3 with mice that only express only10-15% of the normal level of PDK1. Remarkably, this reduction in the level of PDK1 protected the mice from developing a wide variety of tumours, showing that PDK1 is a key effector in mediating neoplasia resulting from abnormally high levels of PtdIns(3,4,5)P3. These results indicate that PDK1 is a promising anti-cancer target. This has led to the patents we have filed on PDK1 being licensed by 12 pharmaceutical companies.||PtdIns(3,4,5)P3 is further metabolised to PtdIns(3,4)P2 and our recent work suggests that the latter molecule may be a second messenger in its own right. We identified a high affinity binding protein for PtdIns(3,4)P2, termed TAPP, and showed that it binds to PTPL1, a protein tyrosine phosphatase. The TAPP-PTPL1 complex translocates from the cytosol to the cell membrane when PtdIns(3,4,5)P3 is elevated in response to insulin or growth factor stimulation, and we hypothesise that the membrane-associated PTPL1 may inactivate the receptors for insulin and growth factors and thereby down-regulate the physiological processes controlled by these agonists. We will investigate this hypothesis by generating mice that do not express TAPP or express a catalytically inactive form of PTPL1, which is the strategy that has been so informative in solving other problems that we have been working on.
Organisations
- MRC Protein Phosphorylation Unit (Lead Research Organisation)
- University of Oxford, United Kingdom (Collaboration)
- University of Edinburgh, United Kingdom (Collaboration)
- Memorial Sloan Kettering Cancer Center (Collaboration)
- Redx Pharma Plc (Collaboration)
- Tokyo Medical and Dental University (Collaboration)
- Kiel University, Germany (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Merck (Collaboration)
- University of Cambridge, United Kingdom (Collaboration)
- Yale University (Collaboration)
- Medical Research Council (Collaboration)
- National Autonomous University of Mexico, Mexico (Collaboration)
- Technical University of Munich (Collaboration)
- Boehringer Ingelheim, Germany (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- Avacta Group (Collaboration)
- Johnson & Johnson Ltd, United Kingdom (Collaboration)
- Pfizer Ltd (Collaboration)
- AstraZeneca plc (Collaboration)
- University of Manitoba, Canada (Collaboration)
- Ubiquigent (Collaboration)
- University of Pittsburgh (Collaboration)
People |
ORCID iD |
| Dario Renato Alessi (Principal Investigator) |
Publications
Alessi DR
(2009)
New insights into mTOR signaling: mTORC2 and beyond.
in Science signaling
Alessi DR
(2013)
Structural biology: Security measures of a master regulator.
in Nature
Bain J
(2007)
The selectivity of protein kinase inhibitors: a further update.
in The Biochemical journal
Bayascas JR
(2008)
Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance.
in Molecular and cellular biology
Bayascas JR
(2006)
Evaluation of approaches to generation of tissue-specific knock-in mice.
in The Journal of biological chemistry
Belgardt BF
(2008)
PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response.
in Cell metabolism
Boini KM
(2009)
Proteinuria in mice expressing PKB/SGK-resistant GSK3.
in American journal of physiology. Renal physiology
Budas GR
(2006)
3'Phosphoinositide-dependent kinase-1 is essential for ischemic preconditioning of the myocardium.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Chwang WB
(2007)
The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Cuenda A
(2007)
p38 MAP-kinases pathway regulation, function and role in human diseases.
in Biochimica et biophysica acta
| Description | Assessment of LRRK2 activity in G2385R carriers |
| Amount | £57,771 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 08/2018 |
| End | 07/2019 |
| Description | CASE studentship - role of the PDK1-SGK pathway in cancer with Astra Zeneca/BBSRC |
| Amount | £97,420 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2010 |
| End | 09/2014 |
| Description | Equipment Grant for our mid career investigators |
| Amount | £54,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 03/2013 |
| End | 03/2014 |
| Description | Equipment grant |
| Amount | £260,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | |
| Description | Genome wide screens to uncover novel upstream regulators of LRRK2 |
| Amount | £305,944 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | |
| Description | Impact of Shared Crohn's disease |
| Amount | £55,444 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 11/2018 |
| End | 10/2019 |
| Description | Lanston Award |
| Amount | £17,582 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 01/2018 |
| End | 12/2019 |
| Description | QQ Renewal |
| Amount | £25,590,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | |
| Description | Rab LEAPs Renewal |
| Amount | £332,000 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 08/2018 |
| End | 07/2020 |
| Description | Renewal of Division of Signal Transduction Therapy Unit |
| Amount | £7,200,000 (GBP) |
| Organisation | Dundee Signal Transduction Therapy (DSTT) Consortium |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | |
| Description | Renewal of MRC-PPU quinquenial funding |
| Amount | £23,100,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 04/2013 |
| End | 03/2018 |
| Description | Tools Development |
| Amount | £83,244 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 10/2018 |
| End | 09/2020 |
| Description | Tools and Animal Models |
| Amount | £54,902 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 07/2018 |
| End | 12/2019 |
| Title | Development of novel state of the art phospho-specific Rabbit monoclonal antibodies to studdy LRRK2 mediated phosphorylation of Rab proteins in Parkinson's disease |
| Description | Mutations that activate the LRRK2 (leucine-rich repeat protein kinase 2) protein kinase predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Our recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector-binding switch-II motif. In the present study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against nine different LRRK2-phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43). We identify rabbit monoclonal phospho-specific antibodies (MJFF-pRAB10) that are exquisitely selective for LRRK2-phosphorylated Rab10, detecting endogenous phosphorylated Rab10 in all analysed cell lines and tissues, including human brain cingulate cortex. We demonstrate that the MJFF-pRAB10 antibodies can be deployed to assess enhanced Rab10 phosphorylation resulting from pathogenic (R1441C/G or G2019S) LRRK2 knock-in mutations as well as the impact of LRRK2 inhibitor treatment. We also identify rabbit monoclonal antibodies displaying broad specificity (MJFF-pRAB8) that can be utilised to assess LRRK2-controlled phosphorylation of a range of endogenous Rab proteins, including Rab8A, Rab10 and Rab35. The antibodies described in the present study will help with the assessment of LRRK2 activity and examination of which Rab proteins are phosphorylated in vivo These antibodies could also be used to assess the impact of LRRK2 inhibitors in future clinical trials. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | All companies and researchers investigating LRRK2 are now using our technology. A company called Denali has just launched the first clinical trials for LRRK2 inhibitors and are using our reagents for their monitoring efficacy of LRRK2 inhibitors. Many other companies are likely to follow suit |
| Title | Protor deficient mice |
| Description | Generated Protor-1 and Protor-2 deficient mice |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | No |
| Impact | These animals will enable us to define the role that Protor-1 and Protor-2 has on the acivity of the mTOR pathway |
| Description | Aaron M |
| Organisation | University of Manitoba |
| Department | Department of Immunology |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Provision of TAPP1 and TAPP2 knock-in mice |
| Collaborator Contribution | Studying impact of TAPP1 and TAPP2 mutations in B cell signalling responses |
| Impact | Jayachandran, N., Landego, I., Hou, S., Alessi, D. R. and Marshall, A. J. (2016). B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice. Eur J Immunol Landego, I., Jayachandran, N., Wullschleger, S., Zhang, T. T., Gibson, I. W., Miller, A., Alessi, D. R. and Marshall, A. J. (2012). Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)-bisphosphate regulates B-cell activation and autoantibody production. Eur J Immunol 42, pp. 2760-2770 |
| Start Year | 2011 |
| Description | Andy C |
| Organisation | Redx Pharma Plc |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Provision of reagents technolgy and advice to better study SGK biology in cancer |
| Collaborator Contribution | Use of our expertise and technology and reagents to identify improved inhibitors of the SGK protein kinase |
| Impact | . |
| Start Year | 2015 |
| Description | Christian P |
| Organisation | University of Kiel |
| Department | Department of Pharmaceutical Chemistry |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Undertaking kinase assays to assess effects of novel light sensitive kinase inhibitors |
| Collaborator Contribution | development of novel light sensitive kinase inhibitors |
| Impact | Horbert, R., Pinchuk, B., Davies, P., Alessi, D. and Peifer, C. (2015). Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib. ACS Chem Biol 10, pp. 2099-2107 |
| Start Year | 2015 |
| Description | D Saur |
| Organisation | Technical University of Munich |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | advice and reagents and techical support |
| Collaborator Contribution | analysed effect of kinase inhibitors and mutations in various models of human tumours |
| Impact | Schonhuber, N., Seidler, B., Schuck, K., Veltkamp, C., Schachtler, C., Zukowska, M., Eser, S., Feyerabend, T. B., Paul, M. C., Eser, P., Klein, S., Lowy, A. M., Banerjee, R., Yang, F., Lee, C. L., Moding, E. J., Kirsch, D. G., Scheideler, A., Alessi, D. R., Varela, I., Bradley, A., Kind, A., Schnieke, A. E., Rodewald, H. R., Rad, R., Schmid, R. M., Schneider, G. and Saur, D. (2014). A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med 20, pp. 1340-1347 Eser, S., et al including Alessi, D. R. and Saur, D. (2013). Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer. Cancer Cell 23, pp. 406-420 |
| Start Year | 2012 |
| Description | DSTT |
| Organisation | AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT |
| Organisation | Boehringer Ingelheim |
| Country | Germany |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT |
| Organisation | Johnson & Johnson |
| Department | Janssen Pharmaceutica |
| Country | Global |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT |
| Organisation | Merck |
| Department | Merck Serono |
| Country | Germany |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT |
| Organisation | Pfizer Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php |
| Collaborator Contribution | Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on. |
| Impact | During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Description | DSTT renewal 2016 |
| Organisation | Boehringer Ingelheim |
| Country | Germany |
| Sector | Private |
| PI Contribution | Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. |
| Collaborator Contribution | The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. |
| Impact | uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Start Year | 2016 |
| Description | DSTT renewal 2016 |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. |
| Collaborator Contribution | The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. |
| Impact | uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Start Year | 2016 |
| Description | DSTT renewal 2016 |
| Organisation | Merck |
| Department | Merck Serono Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. |
| Collaborator Contribution | The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. |
| Impact | uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee. |
| Start Year | 2016 |
| Description | Gerardo G |
| Organisation | National Autonomous University of Mexico |
| Country | Mexico |
| Sector | Academic/University |
| PI Contribution | Undertaking biochemical analysis of WNK signalling pathways as well as provision of advice, reagents and technology |
| Collaborator Contribution | Performing physiological measuremnts of WNK signalling pathway in mice |
| Impact | Melo, Z., de los Heros, P., Cruz-Rangel, S., Vazquez, N., Bobadilla, N. A., Pasantes-Morales, H., Alessi, D. R., Mercado, A. and Gamba, G. (2013). N-terminal serine dephosphorylation is required for KCC3 cotransporter full activation by cell swelling. J Biol Chem 288, pp. 31468-31476 Castaneda-Bueno, M., Cervantes-Perez, L. G., Vazquez, N., Uribe, N., Kantesaria, S., Morla, L., Bobadilla, N. A., Doucet, A., Alessi, D. R. and Gamba, G. (2012). Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci U S A 109, pp. 7929-7934 Rafiqi, F. H., Zuber, A. M., Glover, M., Richardson, C., Fleming, S., Jovanovic, S., Jovanovic, A., O'Shaughnessy, K. M. and Alessi, D. R. (2010). Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2, pp. 63-75 San-Cristobal, P., Pacheco-Alvarez, D., Richardson, C., Ring, A. M., Vazquez, N., Rafiqi, F. H., Chari, D., Kahle, K. T., Leng, Q., Bobadilla, N. A., Hebert, S. C., Alessi, D. R., Lifton, R. P. and Gamba, G. (2009). Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc Natl Acad Sci U S A 106, pp. 4384-9 |
| Start Year | 2008 |
| Description | J Baselga |
| Organisation | Memorial Sloan Kettering Cancer Center |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Undertaking functional studies on the SGK1 and SGK3 protein kinases in the field of cancer research |
| Collaborator Contribution | Undertaking xenograph analysis of effects of Akt and SGK inhibitors on tumour development |
| Impact | Bago, R., Sommer, E., Castel, P., Crafter, C., Bailey, F. P., Shpiro, N., Baselga, J., Cross, D., Eyers, P. A. and Alessi, D. R. (2016). The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. EMBO J 35, pp. 1902-1922 Castel, P., Ellis, H., Bago, R., Toska, E., Razavi, P., Carmona, F. J., Kannan, S., Verma, C. S., Dickler, M., Chandarlapaty, S., Brogi, E., Alessi, D. R., Baselga, J. and Scaltriti, M. (2016). PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kalpha Inhibition. Cancer Cell 30, pp. 229-242 |
| Start Year | 2015 |
| Description | Jason B |
| Organisation | Ubiquigent |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Provision of reagents technolgy and advice to help ubiquigent provide services and reagents to its customers |
| Collaborator Contribution | Ubiqigent sells our reagents to customers and also uses our advice reagents and expertise to help provide its customers with improved services |
| Impact | . |
| Start Year | 2010 |
| Description | Jon E |
| Organisation | University of Oxford |
| Department | Wellcome Trust Centre for Human Genetics |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Undertaking mutational analysis to help study crystal structures of the SGK3 protein kinase |
| Collaborator Contribution | Crystallisation of the SGK3 protein kinase |
| Impact | . |
| Start Year | 2015 |
| Description | Kevin O |
| Organisation | University of Cambridge |
| Department | Department of Anglo-Saxon, Norse and Celtic |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | provided genetically modified mice, reagents, technology and advice |
| Collaborator Contribution | Undertook blood pressure measuremnts in mice and other physiological experiments |
| Impact | Zhang, J., Siew, K., Macartney, T., O'Shaughnessy, K. M. and Alessi, D. R. (2015). Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet 24, pp. 4545-4558 Rafiqi, F. H., Zuber, A. M., Glover, M., Richardson, C., Fleming, S., Jovanovic, S., Jovanovic, A., O'Shaughnessy, K. M. and Alessi, D. R. (2010). Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2, pp. 63-75 |
| Start Year | 2009 |
| Description | Kris K |
| Organisation | Yale University |
| Department | School of Medicine |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Undertaking biochemical analysis of WNK signalling pathways as well as provision of advice, reagents and technology |
| Collaborator Contribution | Performing physiological measuremnts of WNK signalling pathway in mice |
| Impact | Zhang, J., Gao, G., Begum, G., Wang, J., Khanna, A. R., Shmukler, B. E., Daubner, G. M., de Los Heros, P., Davies, P., Varghese, J., Bhuiyan, M. I., Duan, J., Zhang, J., Duran, D., Alper, S. L., Sun, D., Elledge, S. J., Alessi, D. R. and Kahle, K. T. (2016). Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain. Sci Rep 6, pp. 35986 Alessi, D. R., Zhang, J., Khanna, A., Hochdorfer, T., Shang, Y. and Kahle, K. T. (2014). The WNK-SPAK/OSR1 pathway: Master regulator of cation-chloride cotransporters. Sci Signal 7, pp. re3 de Los Heros, P., Alessi, D. R., Gourlay, R., Campbell, D. G., Deak, M., Macartney, T. J., Kahle, K. T. and Zhang, J. (2014). The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J 458, pp. 559-573 San-Cristobal, P., Pacheco-Alvarez, D., Richardson, C., Ring, A. M., Vazquez, N., Rafiqi, F. H., Chari, D., Kahle, K. T., Leng, Q., Bobadilla, N. A., Hebert, S. C., Alessi, D. R., Lifton, R. P. and Gamba, G. (2009). Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc Natl Acad Sci U S A 106, pp. 4384-9 |
| Start Year | 2011 |
| Description | MRC HGU |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | advice and reagents and techical support |
| Collaborator Contribution | They undertook the bulk of the experimentation |
| Impact | . |
| Start Year | 2010 |
| Description | Mike C |
| Organisation | University of Edinburgh |
| Department | MRC Centre for Inflammation Research |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Undertook key experiments on TTBK2 kinase and advice and reagents and techical support |
| Collaborator Contribution | Undertook detailed synapse function studies and generation of primary neurons |
| Impact | Zhang, N., Gordon, S. L., Fritsch, M. J., Esoof, N., Campbell, D. G., Gourlay, R., Velupillai, S., Macartney, T., Peggie, M., van Aalten, D. M., Cousin, M. A. and Alessi, D. R. (2015). Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family Kinases Controls the Specific Retrieval of Synaptotagmin-1. J Neurosci 35, pp. 2492-2507 |
| Start Year | 2013 |
| Description | Neil B |
| Organisation | University of Oxford |
| Department | Nuffield Department of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Undertaking mutational analysis to help study crystal structures of the WNK protein kinase |
| Collaborator Contribution | Crystallisation of the WNK protein kinase |
| Impact | Schumacher, F. R., Sorrell, F. J., Alessi, D. R., Bullock, A. N. and Kurz, T. (2014). Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation. Biochem J 460, pp. 237-246 |
| Start Year | 2013 |
| Description | Paul K F |
| Organisation | Avacta Group |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Provision of reagents technolgy and advice to generate new affimers to better study protein phosphorylation |
| Collaborator Contribution | Use of our expertise and technology and reagents to develop novel affimers |
| Impact | . |
| Start Year | 2016 |
| Description | Shinichi U |
| Organisation | Tokyo Medical and Dental University |
| Department | Department of Neurology and Neurological Science |
| Country | Japan |
| Sector | Academic/University |
| PI Contribution | Undertaking biochemical analysis of WNK signalling pathways as well as provision of advice, reagents and technology |
| Collaborator Contribution | Performing physiological measuremnts of WNK signalling pathway in mice |
| Impact | Nishida, H., Sohara, E., Nomura, N., Chiga, M., Alessi, D. R., Rai, T., Sasaki, S. and Uchida, S. (2012). Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice. Hypertension 60, pp. 981-990 Oi, K., Sohara, E., Rai, T., Misawa, M., Chiga, M., Alessi, D. R., Sasaki, S. and Uchida, S. (2012). A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo. Biol Open 1, pp. 120-127 Susa, K., Kita, S., Iwamoto, T., Yang, S. S., Lin, S. H., Ohta, A., Sohara, E., Rai, T., Sasaki, S., Alessi, D. R. and Uchida, S. (2012). Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clin Exp Nephrol 16, pp. 530-538 Chiga, M., Rafiqi, F. H., Alessi, D. R., Sohara, E., Ohta, A., Rai, T., Sasaki, S. and Uchida, S. (2011). Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. J Cell Sci 124, pp. 1391-1395 |
| Start Year | 2011 |
| Description | Timothy G |
| Organisation | University of Pittsburgh |
| Department | Pittsburgh Institute for Neurodegenerative Diseases |
| Country | United States |
| Sector | Hospitals |
| PI Contribution | Provisions of Regeants, technology and experimental support to measure the impact that rotenone has on LRRK2 protein kinase activity |
| Collaborator Contribution | Undertaking assays to measure LRRK2 and Rab phosphorylation using reagents provided by us |
| Impact | , |
| Start Year | 2016 |
| Description | Youcef M |
| Organisation | Cardiff University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Undertaking assays to study inhibitors of the WNK signalling pathway as well as advice, reagents and technology |
| Collaborator Contribution | Generation of novel kinase inhibitors that tartget components of the WNK signalling pathway |
| Impact | . |
| Start Year | 2015 |
| Title | PDK1 (the kinase that phosphorylates and activates PKB) nucleotide and peptide sequence; methods of purifying and expressing PDK1 and screens to identify PDK1 modulators. |
| Description | Assay and use of PDK1 inhibitors |
| IP Reference | US2007196883 |
| Protection | Patent granted |
| Year Protection Granted | 2007 |
| Licensed | Yes |
| Impact | Patent granted, Consortium licence (to Pharma companies in Dundee Collaboration) |
| Title | PDK1 crystal structure |
| Description | Assay of PDK1. |
| IP Reference | JP2005323611 |
| Protection | Patent granted |
| Year Protection Granted | |
| Licensed | Yes |
| Impact | Application includes the co-ordinates, X-ray data, crystallisation conditions and the cDNA construct., Patent granted, |
| Title | TAPP1 Clinical Function |
| Description | Discovery and use of TAPP1 and TAPP2. |
| IP Reference | US2007054328 |
| Protection | Patent granted |
| Year Protection Granted | 2007 |
| Licensed | No |
| Impact | "TAPP1- PTPL1 interaction is therefore identified as a target to find therapeutics for disorders such as diabetes that are associated with deregulated tyrosine kinase signalling., National phase" |
| Description | 20 Year Celebration of the DSTT |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | During an event at Dundee's recently opened V&A museum to celebrate the 20 year anniversary of the DSTT I gave an interview with STV news. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Attendance at the Scottish Parliament - MRC |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Myself, Professor John Rouse and Dr Paul Davies attended an event in the Scottish Parliament on 6th February to support the Medical Research Council's investment in science in Scotland and to present the work that we are doing in the MRC-PPU to MSPs. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Dolly scientist backs research drive to tackle Parkinson's disease - University of Dundee Press release |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Professor Sir Ian Wilmut - who led the team that created Dolly the sheep - has backed an initiative to tackle Parkinson's disease, after being diagnosed with the condition. The eminent scientist announced his diagnosis today - World Parkinson's Day - ahead of the launch of a major research programme that will see experts at the Universities of Edinburgh and Dundee join forces in the quest to better understand the disease. They will set up infrastructure to enable the first trials in Scotland in a generation for therapies that aim to slow down Parkinson's disease progression. The new Dundee-Edinburgh Parkinson's Research Initiative aims to probe the causes of disease and translate scientific discoveries into new therapies. The ultimate goal is to find new approaches to predict and prevent Parkinson's, and to facilitate clinical testing of therapies aimed at slowing or reversing disease progression. Professor Dario Alessi, of the University of Dundee, said, "All attempts to slow the progression of Parkinson's have thus far failed. Surprisingly today's most widely utilised Parkinson's drug levodopa was first used in the clinic in 1967. "In recent years, our knowledge of the genetics and biology underlining Parkinson's disease has exploded. I feel optimistic and it is not unrealistic that with a coordinated research effort, major strides towards better treating Parkinson's disease can be made." Parkinson's disease is a progressive condition caused by damage to specific cells in the brain. It affects movement and is often associated with involuntary shaking. Therapies that reduce symptoms can help to prolong quality of life, but currently there are no treatments to slow or halt the progression of the disease. At present, Scottish patients seeking to take part in clinical trials of treatments that could delay disease progression are required to travel to centres in England or Wales, or even abroad. Professor Wilmut said, "Initiatives of this kind are very effective not only because they bring more people together, but because they will include people with different experience and expertise. It was from such a rich seedbed that Dolly developed and we can hope for similar benefits in this project." Dolly the sheep was created at The Roslin Institute in 1996 by a multidisciplinary research team led by Professor Wilmut. She was the first clone of an animal from an adult cell and her birth turned scientific thinking on its head. It showed that cells from anywhere in the body could be made to behave like a newly fertilised egg - something that scientists had thought was impossible. This breakthrough paved the way for others to develop a method of using adult cells to produce reprogrammable cells that could develop into any kind of tissue in the body - so called induced pluripotent stem cells, or iPSCs. These cells hold great promise as therapies because of their potential to repair damaged tissues. The first clinical trials of iPSCs for Parkinson's disease are to begin in Japan later this year. Dr Tilo Kunath, of Edinburgh's Medical Research Council Centre for Regenerative Medicine, said, "People with Parkinson's urgently require access to earlier and more accurate diagnosis, better prediction of how their disease will progress, and most importantly, the opportunity to participate in clinical trials of new treatments. This new research partnership aims to make these hopes a reality for people in Scotland." There are more than 12,000 people living with Parkinson's disease in Scotland. Across the UK, the number is expect to double in the next 50 years as the population grows and people live longer. The Dundee-Edinburgh Parkinson's Research Initiative will be formally launched at a public event at the Royal College of Physicians of Edinburgh on Friday 13 April. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Dundee Research Interest Group (DRIG) |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Myself and several members of my lab, including Dr Esther Sammler and Dr Paul Davies participated in a Parkinson's patients event organised by the Dundee Research Interest Group (DRIG) within the SLS on 18th January 2019. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Edinburgh Parkinson's seminar that was delivered by Giovanni Mallucci |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | PRC PPU Unit co-sponsored the Edinburgh Parkinson's seminar that was delivered by Giovanni Mallucci in which 300 patients and family members attended. Professor Dario Alessi gave the vote of thanks at the end of the seminar. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Forthill Primary School Visit - June, 2014 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Scientists and support staff from the MRC PPU recently enjoyed a visit with a P3 class at Forthill Primary for a fun morning of hands on experiments. Overall, the morning proved to be a big hit and provided a fun introduction to hands-on general science experiments for the P3 children. There was plenty of loud vocal appreciation from the children and assurances from many that scientist is now their primary career choice. |
| Year(s) Of Engagement Activity | 2014 |
| Description | Interview to discuss LRRK2 and Parkinson's Disease |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Interview with "Tomorrow Edition" to discuss Parkinson's disease and LRRK2. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://tmrwedition.com/2018/09/18/interview-with-biochemist-and-lrrk2-expert-prof-dario-alessi/ |
| Description | Interviews to mark the 50th PMC DSTT meeting with our pahramceutical company collaborators |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | Local |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | helped publicize our DSTT pharmaceutical company collaboration |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.ppu.mrc.ac.uk/news_and_seminars/mrc_unit_news.php |
| Description | MRC Festical of Medical Research Inside Out Science Open Day 2018 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | MRC Festival of Medical Research Inside Out Science Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students (from the Schools of Life Sciences and Medicine at the University of Dundee). The MRC Festival aimed to inform, inspire and stimulate thinking about medical research. Our event was held within the School of Life Sciences and involved seven table top engagement activities, five ten-minute accessible science talks given by PhD students and early career researchers, three lab tours and three videos about the scientific work of the Unit on loop with visitors. There were two new activities called Chromatography and Stem Cell Game trialled that were developed by MRC PPU staff and students plus previously developed activities. Prior to the open day event, a primary six class at Glebelands Primary School attended a 90 minute session to give valuable feedback on talks and new activities. Members from my lab who participated were; Elena Purlyte - PhD Student Alexia Kalogeropoulou - PhD Student Jordana Freemantle - PhD Student Overall, 129 members of public (generally family groups) were reached with 103 people visiting on the day, a further 24 Primary Six pupils and their two teachers who gave feedback on the new talks and activities ahead of the event. The event met a number of the objectives and key messages from the 2018 - 2023 MRC Protein phosphorylation and ubiquitination Public Engagement and Communications Plan which were: Communications Objectives 1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible. 2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease. Key Messages 1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease. 2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research. 3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it. Feedback The visitors to the event were a mixture of ages which included family groups (children under 16 years) and adults up to 70 years of age. Feedback indicated that they enjoyed themselves overall and said they would come to a similar event again. Highlights included a game developed on the topic of Stem Cells and the laboratory tours. Around a third of visitors polled had not attended a University of Dundee event before indicating we were reaching new audiences. The talks in particular stimulated a number of questions from the audience such as: • How long does it take for a cell to divide? • What would happen if you lost all your amino acids? • Is it only older people who get Parkinson's? • What is it about not being obese that helps protect you from Alzheimer's? • What does wildtype mean? Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too. |
| Year(s) Of Engagement Activity | 2016,2018 |
| Description | MRC-PPU Collaboration with Baldragon Academy 2014 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | The Medical Research Council's Protein Phosphorylation Ubiquitylation Unit (MRCPPU), part of The University of Dundee, has prioritized public engagement in an effort to engage the general public and ensure that the research activities and breakthroughs are communicated to the community. Of equal importance in these communication efforts is educational outreach to students within the Dundee community. Thus, during session 2014 -2015 and 2015-2016 school year, the MRC-PPU will partner with a local secondary school -- Baldragon Academy (BA). Teachers in BA's Science Department will collaborate with scientists at the MRC-PPU in an educational outreach effort (see Appendix 1). The purpose of this project is to increase interest and engagement in science and related careers. It will be starting in August 2014 with the S1 pupils. Scientists from the unit will be working with the pupils on a monthly basis at the school during their science classes and will be providing them with opportunities to take part in various science experiments and demonstrations (aligned with Scotland's Curriculum for Excellence). The scientists are leaders in their field of research and as such come from all over the world. They are currently based in Dundee." Thus far, student have been very enthusiastic about the labs and very receptive to the volunteers. They have asked a multitude of quesitons and have even asked volunteers back to visit. |
| Year(s) Of Engagement Activity | 2014 |
| Description | MRC-PPU Collaboration with Baldragon Academy 2015 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | The Medical Research Council's Protein Phosphorylation Ubiquitylation Unit (MRCPPU), part of The University of Dundee, has prioritized public engagement in an effort to engage the general public and ensure that the research activities and breakthroughs are communicated to the community. Of equal importance in these communication efforts is educational outreach to students within the Dundee community. Thus, during session 2014 -2015 and 2015-2016 school year, the MRC-PPU will partner with a local secondary school -- Baldragon Academy (BA). Teachers in BA's Science Department will collaborate with scientists at the MRC-PPU in an educational outreach effort (see Appendix 1). The purpose of this project is to increase interest and engagement in science and related careers. It will be starting in August 2014 with the S1 pupils. Scientists from the unit will be working with the pupils on a monthly basis at the school during their science classes and will be providing them with opportunities to take part in various science experiments and demonstrations (aligned with Scotland's Curriculum for Excellence). The scientists are leaders in their field of research and as such come from all over the world. They are currently based in Dundee. Thus far, student have been very enthusiastic about the labs and very receptive to the volunteers. They have asked a multitude of questions and have even asked volunteers back to visit. We have also had numerous students of different ages from the school ask to participate in work experience activities to learn more about the Unit and science in general. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Parkinson's Patient/Parkinson's Uk organised event |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Professional Practitioners |
| Results and Impact | Gave a talk on LRRK2 in Parkinson's at a Parkinson's Patient/Parkinson's Uk organised event. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Parkinson's UK Supporters Event |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Discussing mine and the units research and projects to Parkinson's supporters at the Parkinson's UK Supporters Event on 2nd July 2018 |
| Year(s) Of Engagement Activity | 2018 |
| Description | Presented the Betsy Sinclair Memorial Lecture of Diabetes UK, Edinburgh |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | This is a special lecture held annually in Edinburgh that is organised by Diabetes UK Had a lot of positive feedback from audience |
| Year(s) Of Engagement Activity | 2009 |
| Description | Radio interview with Tay fm |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Conducted a Radio interview with local station Tay FM to discuss the recent press release by University of Dundee, titled "Dolly scientist backs research drive to tackle Parkinson's disease" |
| Year(s) Of Engagement Activity | 2018 |
| Description | TV and Radio Interviews publicising renewal of our MRC core funding of 24 M |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Interviews This helped publicize our Units activities |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.ppu.mrc.ac.uk/news_and_seminars/mrc_unit_news.php |
| Description | Visit from Annie MacLeod, Scotland Director for Parkinson's UKs |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Industry/Business |
| Results and Impact | Annie MacLeod, Scotland Director for Parkinson's UK visit our lab on Thursday 7th March. The purpose of Annie's visit was to find out more about our research. Annie also had a tour of our labs as well as meeting with myself, Miratul Muqit and Esther Sammler. |
| Year(s) Of Engagement Activity | 2019 |