Nicholas PJ Brindle

Personal Details

Nick Brindle
Nick Brindle

DepartmentMolecular and Cell Biology
Telephone: 0116 229 7170
Emailnpjb1@le.ac.uk
Web Linkshttps://www2.le.ac.uk/departments/molcellbiol

Biography

I am Professor of Cell Signalling. My first degree was from the University of Leeds and PhD from the University of Manchester. After a short period in the US, I began studying cell surface receptors during my postdoctoral work on the insulin receptor at the University of Cambridge, and a short period studying insect glutamate receptors at the Molecular Neurobiology Unit in the MRC Laboratory of Molecular Biology. Following this I held a British Heart Foundation Lectureship at Cardiff University where I started working on receptor tyrosine kinases in cardiovascular disease. At the University of Leicester I have continued to develop my interests in the molecular mechanisms by which receptors work. In recent years I have become interested in applying evolutionary approaches to understanding receptor structure, function and mechanism. This resulted in me spending a period at the MRC Laboratory of Molecular Biology where I developed a powerful directed evolution approach for understanding and engineering receptors. This approach is providing us with fundamental insights into how receptors work, as well as helping us create new potential drugs.

Qualifications

  • BSc (Hons) University of Leeds
  • PhD University of Manchester
  • FHEA

Publications

  1. Alawo, DOA, Tahir, TA, Fischer,M, Bates, D, Amirova, SR & Brindle, NPJ (2017). "Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap." Sci Reports 7(1): 3658
  2. Fischer, M., M. Kang and N. P. Brindle (2016). "Using experimental evolution to probe molecular mechanisms of protein function." Protein Sci 25(2): 352-359.
  3. Tahir, TA, Singh, H & Brindle NPJ. The RNA binding protein hnRNP-K mediates post – transcriptional regulation of Uncoupling Protein-2 by angiopoietin-1. Cell Signal (2014) 26 1379- 1384.
  4. Brindle, NP, Sale, JE, Arakawa, H, Buerstedde, JM, Nuamchit, T, Sharma, S, Steele, KH. Directed evolution of an Angiopoietin-2 ligand trap by somatic hypermutation and cell surface display. J Biol Chem (2013) 288, 33205-33212.
  5. Singh H, Hansen TM, Patel N, Brindle NPJ. The molecular balance between receptor tyrosine kinases Tie1 and Tie2 is dynamically controlled by VEGF and TNFα and regulates angiopoietin signalling. PLoS ONE (2012) 7(1): e29319.
  6. Singh, H, Tahir, TA, Alawo, DOA, Issa, E & Brindle NPJ. Molecular control of angiopoietin signaling. Biochem Soc Trans (2011) 39 1592-1596.
  7. Hansen, TM, Singh, H, Tahir, TA & Brindle NPJ (2010) “Effects of Angiopoietin-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface” Cellular Signalling 22 527-532.
  8. Kopp, PM, Bate, N, Hansen, TM, Brindle, NP, Praekelt, U, Debrand, E, Coleman, S, Mazzeo, D, Goult, BT, Gingras, AR, Pritchard, CA, Critchley, DR, Monkley, SJ (2010) “Studies on the morphology and spreading of human endothelial cells define key inter- and intramolecular interactions for talin1” European Journal of Cell Biology 89 661-673.
  9. Singh, H, Brindle NPJ & Zammit, VA (2010) “High glucose and elevated fatty acids suppress signaling by the endothelium protective ligand angiopoietin-1” Microvascular Research 79 121-127.
  10. Moss, AJ, Sharma S & Brindle, NPJ (2009) “Rational design and protein engineering of growth factors for regenerative medicine and tissue engineering” Biochemical Society Transactions 37 717-721.
  11. Singh, H, Milner, CS, Aguilar Hernandez, MM, Patel, N & Brindle NPJ (2009) “Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases” Cellular Signalling 21 1346-1350.
  12. Milner, CS, Hansen, TM, Singh H & Brindle, NPJ (2009) “Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of Angiopoietin1 on endothelial permeability and apoptosis” Microvascular Research 77 187-191.
  13. Hansen, TM, Moss, AJ & Brindle, NPJ (2008) “Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke” Current Neurovascular Research 5 235-244.
  14. Marron, MB., Singh, H, Tahir, TA., Kavumkal, J, Kim, H-Z, Koh, GY & Brindle, NPJ (2007) “Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor tyrosine kinase Tie2” Journal of Biological Chemistry 282 30509-30517.
  15. Rees, KA, Singh, H & Brindle, NPJ (2007) “The receptor tyrosine kinase Tie1 is expressed and activated in epithelial tumour cell lines” International Journal of Oncology 31 893-897.
  16. Dunmore BJ, McCarthy MJ, Naylor AR & Brindle NPJ (2007) “Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques” Journal of Vascular Surgery 45 155-159.
  17. Brindle, NPJ, Saharinen, P & Alitalo, K (2006) “Signalling and functions of Angiopoietin-1 in vascular Protection” Circulation Research 98 1014-1023.
  18. Morris, PN, Dunmore BJ & Brindle NPJ (2006) “Mutant Tie2 causing venous malformations signals through Shc” Biochemical and Biophysical Research Communications 346 335-338.
  19. Saharinen, P., Kerkela, K., Ekman, N., Marron, M., Brindle, N., Lee, G.M., Augustin, H., Koh, G.Y. and Alitalo, K. (2005). Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2 Journal of Cell Biology 169 239-243.
  20. Gill, KA & Brindle, NPJ (2005) Angiopoietin-2 stimulates migration of endothelial progenitors and their interaction with endothelium Biochemical and Biophysical Research Communications 336 392-396.
  21. Morris, P.N., Dunmore, B.J., Tadros, A., Marchuk, D.A., Darland, D.C., D'Amore, P.A. & Brindle, NPJ (2005). Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations Journal of Molecular Medicine 83 58-63.
  22. Tadros, A, Hughes, DP, Dunmore, BJ & Brindle NPJ (2003) "ABIN-2 protects endothelial cells from death and has a role in the anti-apoptotic effect of angiopoietin-1" Blood 102 4407-4409
  23. Hughes, DP, Marron, MB & Brindle, NPJ (2003) “The Antiinflammatory Endothelial Tyrosine Kinase Tie2 Interacts With a Novel Nuclear Factor-κB Inhibitor ABIN-2” Circulation Research 92 630-636.

Research

We study how cell surface receptors work. We seek to understand the molecular and structural events that occur when a ligand interacts with a receptor and how this results in changes in cellular activity. Much of our work is focussed on signalling by receptor tyrosine kinases.

By better understanding these mechanisms we aim to develop interventions to correct signalling defects that contribute to cardiovascular and other diseases.

We use a range of techniques in protein engineering, biochemistry, cell biology and evolutionary approaches to understand and manipulate proteins

Directed evolution for creating new proteins and understanding protein function and structure

Directed protein evolution is a powerful approach to modify protein function, create new protein functionality and probe structure-function relationships. However, directed evolution of complex proteins, particularly mammalian proteins requiring post-translational modifications, is difficult. We have combined cell surface display with somatic hypermutation to perform directed evolution on a complex mammalian glycoprotein. This approach allowed us to evolve a new form of receptor ectodomain with a dramatic shift in its binding ability. The target protein in this evolution was the extracellular domain of the Tie2 receptor and we evolved this to a form showing specific binding to only one of its ligands, Ang2. We also showed the evolved ectodomain can be used as a ligand trap to block the action of Ang2, a ligand whose increased expression plays a key role in a number of diseases. We are now exploring the potential therapeutic applications of this evolved protein as well as using this approach to evolve other new protein functions.

How receptors work: mechanistic, functional, and structural biology of receptors

The Tie family of receptor tyrosine kinases comprises of two members Tie1 and Tie2. While Tie2 is known to be a receptor for a family of ligands known as the angiopoietins, the role of Tie1 has long been a mystery. In a series of papers, we showed that Tie1 physically interacts with Tie2 in a multiprotein signalling complex at the cell surface. We also found this interaction regulates the activity of Tie2. This receptor interaction provides an important mechanism that regulates angiopoietin signalling and enables this signalling to be co-ordinated with other signalling inputs that the cell is receiving.

In order to define signalling pathways by which ligands regulate cellular function we use a variety of approaches including proteomics and yeast two-hybrid screens. This has led us to identify a new signalling pathway for post-transcriptional regulation of the anti-oxidant protein UCP2 by Ang1. This pathway involves the RNA-binding protein, hnRNP-K, and is important for trafficking specific mRNA species to intracellular compartments for local translation in response to ligand activation. In addition, we have identified another novel signalling intermediate, A20 binding inhibitor of NFkB-2 (ABIN2), as a Tie2 binding protein. We found that following activation of cells ABIN2 is recruited from the cytoplasm to the activated receptor. ABIN2 has been shown to inhibit the inflammatory transcription factor NFkB. Suppression of ABIN2 expression blocks the ability of Ang1 to dampen NFkB activity in endothelial cells implicating ABIN2 in the anti-inflammatory and protective actions of Ang1.

Supervision

  • Receptor mechanisms, structure and function
  • Signalling in cardiovascular health and disease
  • Directed protein evolution

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Contact Details

Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

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