Stephen Yarwood

PhD

Associate Professor

Telephone
+44 (0)131 451 3148
Email
s.yarwood@hw.ac.uk
Address
Room 3.07
William Perkin Building
Heriot-Watt University
Roles and responsibilities

 

Research in the Yarwood lab is centered on the field of cyclic AMP signalling, particularly the role of exchange protein activated by cyclic AMP (EPAC) sensor proteins in the control of health and disease.

Our most recent objective has been to understand the fundamental molecular mechanisms underlying the attenuation of inflammatory signalling mediated by the EPAC1 isoform in vascular endothelial cells (VECs). From this work we have defined SOCS3 induction as a new paradigm for cyclic AMP-mediated transcriptional control and suppression of pro-inflammatory interleukin 6 (IL-6) signalling (eg Wiejak et al, 2014; Wiejak et al, 2013; Wiejak et al, 2012; Borland et al, 2009; Yarwood et al, 2008). Our current work is aimed at understanding how tethering of EPAC1 to the nuclear pore complex in VECs underlies the induction of multiple regulatory genes, including the SOCS3 gene, which are involved in the suppression of pro-inflammatory cytokine signalling.

Given the importance of EPAC1 in the control of disease processes, a number of drug discovery programmes have now been initiated to identify small molecule regulators of EPAC activity in cells. This approach displays a reduced risk of side-effects compared with general cyclic AMP-elevating agents, such as type 4 cyclic AMP phosphodiesterase (PDE) inhibitors, which activate multiple response pathways. We have also initiated ultra high throughput-screening (uHTS) protocols to identify EPAC regulators in collaboration with the European Screening Centre at Newhouse, Scotland and the European Lead Factory. We have already identified a number of hits in primary HTS that are effective EPAC agonists. We have generated preliminary data demonstrating that these novel compounds can regulate the differentiation of mesenchymal stem cells (MSCs) from fat- to bone-forming cells and may therefore be effective in helping to maintain bone health in diseases, such as diabetes, where there is impairment in bone density. This work complements ongoing work in my laboratory, funded by Tenovus Scotland, which is aimed at discovering the mechanisms of actions of anti-diabetic drugs, such as metformin and regulators of free fatty acid (FFA) G-protein coupled receptors, in the control of MSC differentiation.

Professional and Learned Societies:

2018 - ongoing Cellular Signalling – Editorial Board

2018 – ongoing Cells – Editorial Board

2016 - present Local Ambassador for the Biochemical Society at Heriot-Watt University

2015 - present Journal of Cell Signalling – Editorial Board

2013 - present Fellow of the Higher Education Academy

2012 - 2014 Biochemical Society - Member of Council

2011 - present Biochemical Journal – Editorial Advisor

2011 - 2013 Biochemical Society - Chair of the Signal Transduction Theme Panel

 

2008 - 2011 Biochemical Society - "Theme Panel V: Signal Transduction" committee member

1999 - 2001 Human Frontiers Science Program Fellow

1993 - present Biochemical Society – Member

Research

Recent Grants:

Use of Affimer Technology to discriminate between Agonist- and Antagonist-induced Conformational Changes in the Cyclic-nucleotide Binding Domain (CNBD) Protein, EPAC1, Medical Research Scotland PhD Studentship (2015-2019), £109,784, Principal Investigator

Identification of Small Molecule Agonists – European Lead Factory (2015-2018), contract worth £300,000, Program Owner

Regulation of anti-inflammatory gene expression in vascular endothelial cells by EPAC1 – British Heart Foundation (2015-2018), £220,852, Principal Investigator

The role of insulin-dependent signalling pathways in the control of Mesenchymal stem cell differentiation towards bone and fat - Tenovus-Scotland (2014 – 2016), £10,000, Principal Investigator

The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetes Diabetes UK (2011 – 2014), £94,941, Co-Investigator

Identification of small molecule activators of EPAC1 to serve as novel anti-inflammatory agents in vascular endothelial cells - Scottish Universities Life Sciences Alliance (2011 – 2012), contract worth £20,000, Programme Owner

The Role of EPAC1-regulated Protein Kinase C Isoforms in Mediating C/EBPdelta -dependent, Anti-inflammatory Actions of Cyclic AMP in Vascular Endothelial Cells - British Heart Foundation (2010 – 2013), £220,852, Principal Investigator

EPAC1 and ERK-dependent activation of C/EBP transcription factors: a new cyclic AMP-activated anti-inflammatory gene expression module in vascular endothelial cells - British Heart Foundation (2009 – 2012), £245,576, Co-Investigator

Selected publications

Barker, G, Parnell, E, Van Basten, B, Buist, H, Adams, DR & Yarwood, SJ 2017, 'The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation' Journal of Cardiovascular Disease and Development, vol. 4, no. 4, pp. 22-37. DOI: 10.3390/jcdd4040022

Parnell, E, McElroy, SP, Wiejak, J, Baillie, GL, Porter, A, Adams, DR, Rehmann, H, Smith, BO & Yarwood, SJ 2017, 'Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1' Scientific Reports, vol. 7, 294. DOI: 10.1038/s41598-017-00455-7

https://researchportal.hw.ac.uk/en/publications/identification-of-a-novel-small-molecule-partial-agonist-for-the-

Parnell, E, Koschinski, A, Zaccolo, M, Cameron, RT, Baillie, GS, Baillie, GL, Porter, A, McElroy, SP & Yarwood, SJ 2015, 'Phosphorylation of ezrin on Thr567 is required for the synergistic activation of cell spreading by EPAC1 and protein kinase A in HEK293T cells' Biochimica et Biophysica Acta, vol. 1853, no. 7, pp. 1749-1758. DOI: 10.1016/j.bbamcr.2015.04.009

ttps://researchportal.hw.ac.uk/en/publications/phosphorylation-of-ezrin-on-thr567-is-required-for-the-synergisti

Parnell, E, Smith, BO & Yarwood, SJ 2015, 'The cAMP sensors, EPAC1 and EPAC2, display distinct subcellular distributions despite sharing a common nuclear pore localisation signal' Cellular Signalling, vol. 27, no. 5, pp. 989-996. DOI: 10.1016/j.cellsig.2015.02.009.

https://researchportal.hw.ac.uk/en/publications/the-camp-sensors-epac1-and-epac2-display-distinct-subcellular-dis

Parnell, E, Palmer, TM & Yarwood, SJ 2015, 'The future of EPAC-targeted therapies: agonism versus antagonism' Trends in Pharmacological Sciences, vol. 36, no. 4, pp. 203-214. DOI: 10.1016/j.tips.2015.02.003.

https://researchportal.hw.ac.uk/en/publications/the-future-of-epac-targeted-therapies-agonism-versus-antagonism

Wiejak, J, Dunlop, J, Mackay, SP & Yarwood, SJ 2013, 'Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells' Biochemical Journal, vol. 454, no. 2, pp. 283-293. DOI: 10.1042/BJ20130481.

https://researchportal.hw.ac.uk/en/publications/flavanoids-induce-expression-of-the-suppressor-of-cytokine-signa

Wiejak, J, Tsimbouri, PM, Herzyk, P, Dalby, MJ, Hamilton, G & Yarwood, SJ 2013, 'Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves' Biomaterials, vol. 34, no. 8, pp. 1967-1979. DOI: 10.1016/j.biomaterials.2012.11.036.

https://researchportal.hw.ac.uk/en/publications/genomic-analysis-of-the-role-of-transcription-factor-cebpδ-in-the

Wiejak, J, Dunlop, J, Stoyle, C, Lappin, G, McIlroy, A, Pediani, JD, Gao, S & Yarwood, SJ 2012, 'The protein kinase C inhibitor, Ro-31-7459, is a potent activator of ERK and JNK MAP kinases in HUVECs and yet inhibits cyclic AMP-stimulated SOCS-3 gene induction through inactivation of the transcription factor c-Jun' Cellular Signalling, vol. 24, no. 8, pp. 1690-1699. DOI: 10.1016/j.cellsig.2012.04.016.

https://researchportal.hw.ac.uk/en/publications/the-protein-kinase-c-inhibitor-ro-31-7459-is-a-potent-activator-o

Wiejak, J, Dunlop, J, Gao, S, Borland, G & Yarwood, SJ 2012, 'Extracellular signal-regulated kinase mitogen-activated protein kinase-dependent SOCS-3 gene induction requires c-Jun, signal transducer and activator of transcription 3, and specificity protein 3 transcription factors' Molecular Pharmacology, vol. 81, no. 5, pp. 657-668. DOI: 10.1124/mol.111.076976.

https://researchportal.hw.ac.uk/en/publications/extracellular-signal-regulated-kinase-mitogen-activated-protein-k

Parnell, E, Smith, BO, Palmer, TM, Terrin, A, Zaccolo, M & Yarwood, SJ 2012, 'Regulation of the inflammatory response of vascular endothelial cells by EPAC1' British Journal of Pharmacology, vol. 166, no. 2, pp. 434-446. DOI: 10.1111/j.1476-5381.2011.01808.x.

https://researchportal.hw.ac.uk/en/publications/regulation-of-the-inflammatory-response-of-vascular-endothelial-c

Biography

2016 - present Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh Campus

Previous Roles:

2008 - 2015 Senior Lecturer, Institute of Molecular, Cell and Systems Biology

Faculty of Medical, Veterinary and Life Sciences University of Glasgow, Scotland

1999 - 2008 Lecturer, Division of Biochemistry & Molecular Biology, Institute of Biomedical and Life Sciences (IBLS), University of Glasgow, Scotland.

1999 - 2001 Research Leave, Human Frontiers Science Program Research Fellow, Ontario Cancer Institute, Toronto, Canada.

1996 - 1999 Post-Doctoral Fellow, Laboratory of Professor Miles D. Houslay, University of Glasgow, Scotland.

Higher Education:

2004 - 2005 University of Glasgow, U.K., Postgraduate Certificate in Academic Practice

1993 - 1996 Hannah Research Institute, Ayr, Scotland, U.K., Ph.D. in Biochemistry.

1988 - 1992 University of Strathclyde, U.K., B.Sc. (Hons) Upper Second in Biochemistry

Awards:

1999 - 2001 Human Frontiers Science Program Fellowship

Further information

Recent Invited Talks:

School of Medicine, University of Dundee 2016 (Stephen Yarwood)

Yorkhill Research Day, Glasgow 2015 (Stephen Yarwood)

Bone Marrow Adiposity meeting, Lille, France 2015 (Suet Ching Chen)

British Society for Paediatric Endocrinology and Diabetes (BSPED), Winchester 2014 (Suet Ching Chen)

Gordon Research Conference, New England, USA 2014 (Euan Parnell)

British Endocrinology Society, Liverpool 2014 (Stephen Yarwood)

Physiology Society Sponsored Lecture, Department of Physiology, University of Liverpool 2013 (Stephen Yarwood)

Targeting Cyclic AMP Signalling to Combat Cardiovascular Diseases, London 2013 (Euan Parnell)

Signalling 2013: From Structure to Function, York 2013 (Stephen Yarwood)

British Pharmacological Society, 4th Meeting on Cell Signalling, University of Leicester 2012 (Euan Parnell)
British Pharmacology Society, Cyclic AMP meeting, London 2011 (Stephen Yarwood)

Signalling 2011: A Biochemical Society Centenary Celebration, Edinburgh 2011 (Stephen Yarwood)

Signalling 2011: A Biochemical Society Centenary Celebration, Edinburgh 2011