Professor Robin Plevin

Head Of Institute

Strathclyde Institute of Pharmacy and Biomedical Sciences

Personal statement

Robin Plevin, Professor in Pharmacology (2002). BSc (Hons), University of Edinburgh (1983), PhD, University of Southampton (1987). The Plevin laboratory is hard working but friendly, housing researchers from many countries around the world. The laboratory studies aspects of signalling in relation to inflammation, vascular disease and cancer. The lab has strong collaborations both internally, nationally and internationally. A strong emphasis on career development is one of the features of this laboratory.

Research Interests

  • MAP kinase phosphatase-2 in cellular function. We have recently generated a novel MKP-2 (DUSP-4) KO mouse and are currently assessing outcomes in cancer, inflammatory disease and immunity. We have recently identified a novel role for this gene during leishmania infection and in controlling the cell cycle.
  • Protease-activated receptors- signalling and inflammation. We are investigating the role of this novel class of GPCR within the immune system and correlating this with effects upon intracellular signalling and trafficking.
  • Cell signalling responses to Leishmania. We are currently studying the intracellular signalling effects of Leishmania mexicana in relation to infection.
  • Natural products as inhibitors of NFκB signalling - implications for inflammatory disease and cancer. We are sudying the effects of defined natural products as inhibitors of intracellular signalling pathways, in particular the NFκB cascade, for use in vascular disease, arthritis and cancer.

Teaching - The Angina Monologues
In addition to teaching across the curriculum Professor Plevin has engaged in science engagement activities. The Angina Monologues was a comedy sketch play looking at obesity and was shortlisted for a THE award in 2009.

Publications

Whole genome microarray analysis of DUSP4-deletion reveals a novel role for MAP kinase phosphatase-2 (MKP-2) in macrophage gene expression and function
Neamatallah Thikryat, Jabbar Shilan, Tate Rothwelle, Schroeder Juliane, Shweash Muhannad, Alexander James, Plevin Robin
International Journal of Molecular Sciences Vol 20 (2019)
https://doi.org/10.3390/ijms20143434
Cytotoxicity of Nubein6.8 peptide isolated from the snake venom of Naja nubiae on melanoma and ovarian carcinoma cell lines
Abdel-Ghani Lougin M, Rahmy Tarek R, Tawfik Mohamed M, Kaziri Ibtisam, Al-Obaidi Ahlam, Rowan Edward G, Plevin Robin, Abdel-Rahman Mohamed A
Toxicon Vol 168, pp. 22-31 (2019)
https://doi.org/10.1016/j.toxicon.2019.06.220
Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis
Schroeder Juliane, Ross Kirsty, McIntosh Kathryn, Jabbar Shilan Khayrula Jabbar, Woods Stuart, Crowe Jenny, Patterson-Kane Janet C, Alexander James, Lawrence Catherine, Plevin Robin
RMD Open Vol 5, pp. e000711 (2019)
https://doi.org/10.1136/rmdopen-2018-000711
Inhibition of cytokine-mediated JNK signalling by purinergic P2Y11 receptors, a novel protective mechanism in endothelial cells
Ng Pei Y, McIntosh Kathryn A, Hargrave Gillian, Ho Ka H, Paul Andrew, Plevin Robin
Cellular Signalling Vol 51, pp. 59-71 (2018)
https://doi.org/10.1016/j.cellsig.2018.07.016
Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis
Chen Ming, Zhang Jiangwen, Berger Alice H, Diolombi Moussa S, Ng Christopher, Fung Jacqueline, Bronson Roderick T, Castillo-Martin Mireia, Thin Tin Htwe, Cordon-Cardo Carlos, Plevin Robin, Pandolfi Pier Paolo
Journal of Clinical Investigation (2018)
https://doi.org/10.1172/JCI99699
Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival
Choi Jason C, Wu Wei, Phillips Elizabeth, Plevin Robin, Sera Fusako, Homma Shunichi, Worman Howard J
Human Molecular Genetics (2018)
https://doi.org/10.1093/hmg/ddy134

more publications

Research interests

DETAILS OF INDIVIDUAL RESEARCH PROGRAMMES

Research Programme 1:  The regulation and function of MAP kinase phosphatase-2

We have several achievements in this area since cloning the gene (DUSP4) for this phosphatase in the late 90's.  MKP-2 plays a key role in negatively regulating the activities of the MAP kinases and is thus implicated in several different cellular functions and diseases.  In our original studies we re-defined the kinase specificity of the phosphatase in normal cells and identified for the first time, a novel site that dictated nuclear localization.  We also demonstrated that over-expression of MKP-2 could limit genotoxic induced cell death, indicating its potential as a target in different forms of cancer.  We also identified for the first time a novel variant of human MKP-2 and delineated its function again relevant to a potential role in cancer. 

My group has also generated a novel DUSP-4 KO mouse, the first time a mouse for this deletion had been developed and a first for Strathclyde.  This has enabled Strathclyde researchers to play a leading role in developing the understanding of MKP-2 function.  Using the mouse we showed for the first time a role of MKP-2 in the response to pathogens such as Leishmania mexicana, work published recently in the high impact open access journal, Plos Pathogens and also Leishamania major and Toxoplasma (see submitted 2012 papers).  Using cells from the MKP-2 KO we have also made important novel observations in relation to icell cycle progression. 

We have also developed a number of important external collaborations one with Owen Samson (Beatson, Cancer Institute) looking at DUSP-4 in breast cancer, and with Ari Elson (Weizmann Institute), assessing the role of MKP-2 in bone development.  In addition, we are involved in making a double KO mouse (MKP-1 and 2), with Dr Rosario Perona (University of Madrid), again a first for Strathclyde.  We have also examined the potential of utilising Adv-MKP-2 as a therapy in cardiovascular disease (see also recent BHF grant award) and are investigating the role of MKP-2 in cardiac function (with Dr Susan Currie).  We are assessing the potential of over-expression MKP-2 to be linked with the development of prostate cancer in collaboration with Drs Marie Boyd and Joanne Edwards.

 

Research Programme 2: The Biology of Protease-activated Receptors

The enzyme thrombin is well recognised to activate a series of cell signaling events important in mediating the growth of cells of the vasculature. This is achieved though the activation of a specific receptor called protease-activated receptor-1 (PAR-1).  In examining signaling responses to thrombin, relevant to this action, we also recognised the potential for cells to be activated by other proteases through different members of this receptor family.  Our review on Proteinase-activated Receptors (PARs) has now become one of the top ten cited articles from Strathclyde University (see Macfarlane et al., review).  Research from two original papersresulted in substantial funding from the Japanese pharmaceutical company KOWA Company LTD and enabled a program of work to be funded via the Scottish Biomedical Foundation (SBF), the Strathclyde Institute for Drugs Research (SIDR) and the department of Chemistry at the University of Edinburgh. The funding totaled approximately £3 million.  This project generated a number of research papers and additional funding from research councils and charities and has lead to a sustained collaborative effort between the Ferrell, Lockhart and Plevin laboratories, numerous grants and publications (see above and below listings).  This work has demonstrated my ability to maintain a programme of research excellence over the longer period.

2a) Cell signalling through activation of PARs

Many years ago, my group was the first to show activation of MAP kinase signalling through the novel ‘thrombin like' receptor protease-activated receptor-2 (PAR-2). Using the cloned hPAR-2 in a model transfection system we established that PAR-2 was linked to both SAP kinase and NFκB signalling pathways, events linked to the proposed pro-inflammatory effects of PAR-2 .  We used a series of molecular approaches to identify novel intermediates that couple PAR-2 to downstream signalling events including the activation of the MAP kinases and NFκB.  Most recently we have established a novel regulatory role for PAR-2 and other GPCRs in the negative modulation of JNK as a general model for the anti-inflammatory actions of PAR-2 and other GPCRs (see recent submissions). We have established systems to examine PAR dimerisation, again a first for the University of Strathclyde and using this approach have demonstrated for the first time a novel role for PAR-2 in PAR-4 directed trafficking to the plasma membrane. In the area of pharmacology we have screened a peptide mimetic library and identified a novel peptide which mediated agonist selective signalling. Collaborations with medicinal chemists in SIPBS are developing this area further with a view to finding novel PAR-2 inhibitors and we have secured small amounts of funding (SULSA £20k and West of Scotland Cancer Consortium £8k) to develop the chemistry further.  This latter work also involved collaborators in Japan.

2b) Development and utilization of PAR-2 knockout mice - revealing a role in rheumatoid- and osteoarthritis

We successfully developed PAR-2 deletion mice in collaboration with the Centre of Genome Research (CGR) at the University of Edinburgh.  This was the first mouse designed using expertise within the University Strathclyde and is one of only two such colonies in the world.  This success allowed the development of research relating to the physiological and pathophysiological role of PAR-2.  This included Type IV allergic responses in skin but more importantly chronic arthritis.  Most recently, we have identified a novel role for PAR-2 in osteoarthritis via the involvement of the enzyme matriptase. The underlying immune consequences have also been examined.  In further collaborative work with Professors Ferrell and Lockhart, we have characterized a number of intervention strategies to block PAR-2 actions within the arthritic joint including antibody administration, siRNA and the first PAR-2 antagonist.  This work will continue to explore avenues for therapeutic intervention in humans with the development of a novel humanized antibody with the potential for clinical trials (see recent CSO funding) and novel peptide antagonists.  This work and its potential is the subject of a joint ARC programme grant proposal (result pending) and an ARC project grant.

 

Research Programme 3: NFκB sigalling in disease and infection

My group has had a long standing interest in the regulation of nuclear factor kappa B in disease particularly of the cardiovascular system and in inflammation.

3a) Regulation of NFκB signalling in the cardiovascular system

In a number of papers we have described the essential role of the inhibitory kappa B kinases (IKK) in key NFκB-dependent events within smooth muscle cells and have elucidated IKK2 as a potential target for drug therapy.  This was made possible by using adenoviral constructs encoding inhibitory components of the pathways (see previous BHF awards and references).  Using these approaches and also lentivirus we are investigating the role of individual IKK isoforms in endothelial and smooth muscle cell function and the upstream regulator of non-canonical NFkB signalling, NIK.

3b) Screening natural products as NFκB inhibitor drugs for use in cancer

Historically, phytochemists in SIPBS produced a large number of compounds however, there was no proper rapid drug screening approaches to compliment this.  As part of the KOWA award, my group was able to generate reporter cell lines for this purpose.  Using this approach we produced one of the first papers in Strathclyde systematically pinpointing the site and mechanism of action of a natural product. 

Screening of a number of natural compounds provided elucidated their mode of action as selective IKK inhibitors.  This work provided the basis for a successful CRUK programme grant award. 

3c) Regulation of NFκB signaling during Leishmania infection  

This work is a component of a long standing collaboration with Professor James Alexander.  Initially we identified that amastigoes from Leishmania Mexicana were able to degrade NFκB intermediates and this is viewed as an important observation in the field and often cited.  This work was a component of The Wellcome Trust Programme grant awarded to James Alexander.  We have more recently also demonstrated, using again specific KO mice, a role for TLR-4 in the effects of promastigotes on macrophage function and a potentially novel affect of these pathogens on NFκB signaling.  This work significantly augments the work ongoing with the MKP-2 deletion mouse in immunology.

 

 

Professional activities

Life Sciences , UK
Chair
1/2008
European Respiratory Society , UK
Keynote/plenary speaker
1/2008
British Journal of Pharmacology
Editorial board member
1/2008

more professional activities

Projects

Preventing the damaging effects of cancer chemotherapy and radiation treatment on human endothelial cells targeting the JNK pathway
Plevin, Robin (Principal Investigator) Boyd, Marie (Co-investigator) McIntosh, Kathryn (Co-investigator)
01-Jan-2019 - 31-Jan-2022
Prevention of CXCL12 production in cells of the cardiovascular system by IKK alpha inhibition (BHF PhD Studentship)
Plevin, Robin (Principal Investigator) Coats, Paul (Co-investigator) MacKay, Simon (Co-investigator) Paul, Andrew (Co-investigator)
01-Jan-2018 - 30-Jan-2021
CXCL12 as a assay system for IKKapha inhibitor drugs
Plevin, Robin (Principal Investigator) Paul, Andrew (Co-investigator)
01-Jan-2015 - 31-Jan-2017
Investigating novel roles for MAP kinase phosphatase-2 and Vaccinia Related Kinase 1 in vascular smooth muscle cell cytokinesis
Plevin, Robin (Principal Investigator)
01-Jan-2014 - 31-Jan-2016
Preclinical validation of novel PAR-2 inhibitors for the treatment of Osteoarthritis and Cancer
McIntosh, Kathryn (Research Co-investigator) Plevin, Robin (Principal Investigator)
Preclinical validation of novel PAR-2 inhibitors for the treatment of Osteoarthritis and Cancer.

Protease-activated Receptor 2 (PAR-2) is a member of a unique family of G-protein coupled receptors activated by serine protease cleavage of the N-terminus to generate a new tethered ligand. The distribution of this receptor, up-regulation by cytokines and activation by proteases, strongly suggests a role in inflammation. Indeed, we have established a key role for PAR-2 in chronic joint disease and the group are world leaders (Crilly et al., 2012; Ferrell et al., 2010; Ferrell et al., 2003; Kelso et al., 2006). Recently, we established for the first time a role for PAR-2 in osteoarthritis a condition affecting more than 4.4 million sufferers in the UK and a cost to society estimated at over £1B annually. Our current studies show that mice lacking the PAR-2 gene are protected from arthritis for up to a year, a breakthrough finding. Given the paucity of drugs for this disease our data highlights the clinical potential of PAR-2 antagonism. PAR-2 inhibition may also be of benefit in other conditions, for example in cancer, where recent studies have linked cancer progression to the inflammatory environment.
To date the translational aspect of PAR-2 biology has developed slowly due to the lack of potent and selective antagonists, although recently a number of moderately potent putative PAR-2 inhibitors have been identified. One of these, GB88, has also good oral availability. In our hands we find that GB88 functions as a partial agonist, making predictions as to its clinical value difficult. Therefore new and better prototype compounds are required to validate PAR-2 as a bonafide target in disease pathology. We have now identified two new lead compounds (141/2 and 143/1) which have a better antagonist profile (see figure 1 for 141/2), lacking the partial agonist activity of GB88. Our project is to determine if these drugs are effective in disease models, providing critical proof of concept data.


pFact ID (Internal Reference): 9932
RKES Reference (Internal Reference): 130814

SULSA (University Administered): £49,073.00, fEC% 49.00%

1/02/14 → 30/09/15

01-Jan-2014 - 30-Jan-2015
Preclinical validation of novel PAR-2 inhibitors for the treatment of Osteoarthritis and Cancer
Plevin, Robin (Principal Investigator)
01-Jan-2014 - 30-Jan-2015

more projects

Address

Strathclyde Institute of Pharmacy and Biomedical Sciences
Robertson Wing

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