Professor Nick Brindle

Dr Nick Brindle

Professor of Cell Signalling  
Departments: Cardiovascular Sciences (primary affiliation) and Biochemistry

Bsc University of Leeds 1982

PhD University of Manchester 1986

Tel: +44 (0)116 229 7170

Email: npjb1@le.ac.uk

Address: Department of Cardiovascular Sciences, University of Leicester, Room 2/03, Henry Welcome Building, Leicester

Personal details

Bsc (Hon), PhD

I attended the University of Leeds and the University of Manchester in 1982 and 1986 respectively. I know work for the University of Leicester in the Department of Cardiovascular Sciences. In the past of held a variety of positions such Associate Research Scientist Oklahoma Medical Research Foundation, USA (1987), MRC Postdoctoral Research Fellow University of Cambridge (1987-1990), Lecturer, University of Wales College of Medicine (1990-1994), Lecturer, Senior Lecturer, Reader, University of Leicester (1994-2010) and Visiting Scientist, Harvard University & Beth Israel Deaconess Medical Centre, USA (1998).

Publications

Tahir TA, Singh H, Brindle NP. 2014. The RNA binding protein hnRNP-K mediates post-transcriptional regulation of uncoupling protein-2 by angiopoietin-1. Cell Signal. 26(7): 1379-84.

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 Nov 15;288(46):33205-12

Singh H, Hansen TM, Patel N, Brindle NP. 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.

Hansen, TM, Singh, H, Tahir, TA & Brindle NPJ. Effects of Angiopoietin-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surfaceCellular Signalling. 2010 22 527-532.

Singh H, Milner CS, Aguilar Hernandez MM, Patel N, Brindle NP. Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell Signal. 2009 21 1346-50

Milner CS, Hansen TM, Singh H, Brindle NP. Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvasc Res. 2009 Mar;77(2):187-91

Moss AJ, Sharma S, Brindle NP. Rational design and protein engineering of growth factors for regenerative medicine and tissue engineering. Biochem Soc Trans. 2009 37 717-21

Marron MB, Singh H, Tahir TA, Kavumkal J, Kim HZ, Koh GY, Brindle NP. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem. 2007 282 30509-17

Tadros A, Hughes DP, Dunmore BJ, Brindle NP. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood. 2003 102 4407-9

Hughes DP, Marron MB, Brindle NP. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. Circ Res. 2003 92 630-6

Recent papers

Fischer M, Kang M, Brindle NP. 2016. Using experimental evolution to probe molecular mechanisms of protein functionProtein Sci. 25(2): 352-9.

Tahir TA, Singh H, Brindle NP. 2014. The RNA binding protein hnRNP-K mediates post-transcriptional regulation of uncoupling protein-2 by angiopoietin-1Cell Signal. 26(7): 1379-84.

Brindle, N. P., Sale, J. E., Arakawa, H., Buerstedde, J. M., Nuamchit, T., Sharma, S., and Steele, K. H. 2013. Directed evolution of an Angiopoietin-2 ligand trap by somatic hypermutation and cell surface displayJournal of Biological Chemistry 288: 33205-33212.

Singh, H., Hansen, T. M., Patel, N., & Brindle, N. P. J. 2012. The Molecular Balance between Receptor Tyrosine Kinases Tie1 and Tie2 Is Dynamically Controlled by VEGF and TNF alpha and Regulates Angiopoietin SignallingPLOS ONE, 7(1).

Singh, H., Tahir, T. A., Alawo, D. O. A., Issa, E., & Brindle, N. P. J. 2011. Molecular control of angiopoietin signallingBiochem. Soc. Trans. 39: 1592-1596.

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 talin1Eur J Cell Biol. 89(9): 661-73.

Singh H, Brindle NP, Zammit VA. 2010. High glucose and elevated fatty acids suppress signaling by the endothelium protective ligand angiopoietin-1Microvasc Res. 79(2): 121-127.

Hansen TM, Singh H, Tahir TA, Brindle NP. 2010. Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface. Cell Signal. 22(3): 527-32.

Moss AJ, Sharma S, Brindle NP. 2009. Rational design and protein engineering of growth factors for regenerative medicine and tissue engineering. Biochem Soc Trans. 37(Pt4): 717-21.

Singh H, Milner CS, Aguilar Hernandez MM, Patel N, Brindle NP. 2009. Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell Signal. 21(8): 1346-50.

Milner CS, Hansen TM, Singh H, Brindle NP. 2009. Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvasc Res. 77(2): 187-91.

Hansen TM, Moss AJ, Brindle NP. 2008. Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr Neurovasc Res. 5(4): 235-44.

Milner CS, Hansen TM, Singh H, Brindle NP. 2009. Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvasc Res. 77(2): 187-91.

Rees KA, Singh H, Brindle NP. 2007. The receptor tyrosine kinase Tie1 is expressed and activated in epithelial tumour cell lines. Int J Oncol. 31(4): 893-7.

Marron MB, Singh H, Tahir TA, Kavumkal J, Kim HZ, Koh GY, Brindle NP. 2007. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J Biol Chem. 282(42): 30509-17.

Dunmore BJ, McCarthy MJ, Naylor AR, Brindle NP. 2007. Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques. J Vasc Surg. 45(1): 155-9.

Morris PN, Dunmore BJ, Brindle NP. 2006. Mutant Tie2 causing venous malformation signals through Shc. Biochem Biophys Res Commun. 346(1): 335-8.

Brindle NP, Saharinen P, Alitalo K. 2006. Signaling and functions of angiopoietin-1 in vascular protection. Circ Res. 98(8): 1014-23.

Gill KA, Brindle NP. 2005. Angiopoietin-2 stimulates migration of endothelial progenitors and their interaction with endothelium. Biochem Biophys Res Commun. 336(2): 392-6.

Saharinen P, Kerkelä K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. 2005. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 169(2): 239-43.

Morris PN, Dunmore BJ, Tadros A, Marchuk DA, Darland DC, D'Amore PA, Brindle NP. 2005. Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations. J Mol Med. 83(1): 58-63.

Clover AJ, McCarthy MJ, Hodgkinson K, Bell PR, Brindle NP. 2003. Noninvasive augmentation of microvessel number in patients with peripheral vascular disease. J Vasc Surg. 38(6): 1309-12.

Tadros A, Hughes DP, Dunmore BJ, Brindle NP. 2003. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood. 102(13): 4407-9.

Hughes DP, Marron MB, Brindle NP. 2003. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. Circ Res. 92(6): 630-6.

Tsiamis AC, Morris PN, Marron MB, Brindle NP. 2002. Vascular endothelial growth factor modulates the Tie-2:Tie-1 receptor complex. Microvasc Res. 63(2): 149-58.

Cotton JM, Thomas MR, Dunmore BJ, Salisbury J, Shah AM, Brindle NP. 2002. Angiogenesis in chronically ischaemic human heart following percutaneous myocardial revascularisation. Heart. 87(3): 281-3.

Book chapters

McCarthy MJ and Brindle NPJ. (2004) Molecular Approaches to Revascularization in Peripheral Vascular Disease in Mechanisms of Vascular Disease (R Fitridge and M Thompson, eds.) Greenwich Medical Media Publishers, London.

Marron MB and Brindle NPJ. (2004) Receptor tyrsosine kinase signal transduction in the microvasculature in Encyclopaedia of the Microvasculature (D Shepro, ed,) Elsevier.

Research

  • How receptors work: mechanistic, functional and structural biology of receptors
  • Directed evolution for creating new proteins and understanding protein function and structure

Tie interaction shows "localization and co-localization (yellow) of the receptor tyrosine kinases Tie1 (green) and Tie2 (red) on the surface of a single live endothelial cell"
Tie interaction shows "localization and co-localization (yellow) of the receptor tyrosine kinases Tie1 (green) and Tie2 (red) on the surface of a single live endothelial cell"

  • Cardiovascular protective signalling

Highlights

Directed protein evolution by somatic hypermutation combined with cell surface display

N Brindle - Image 1

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 in B cells 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.

The approach we described has great potential for engineering other complex proteins.

Brindle, N. P., Sale, J. E., Arakawa, H., Buerstedde, J. M., Nuamchit, T., Sharma, S., and Steele, K. H. (2013) Directed evolution of an Angiopoietin-2 ligand trap by somatic hypermutation and cell surface display. J. Biol. Chem. 288, 33205-33212.

Receptor interactions regulate angiopoietin signalling

N Brindle - Image 2

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 at the cell surface. We also found this interaction regulates the activity of Tie2 by controlling access of one of the ligands to the receptors ligand binding site. This occurs because the Tie1 extracellular domain obstructs Ang1 access to Tie2. Interestingly we found that other signals, such as VEGF and TNF-alpha, can relieve this suppression of Ang1 binding by stimulating cleavage of Tie1 ectodomain and allowing the ligand to access and activate 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.

Singh, H., Hansen, T. M., Patel, N., and Brindle, N. P. J. (2012) The molecular balance between receptor tyrosine kinases Tie1 and Tie2 is dynamically controlled by VEGF and TNFα and regulates angiopoietin signalling. PLoS One 7, e29319. 

Singh, H., Tahir, T. A., Alawo, D. O., Issa, E., and Brindle, N. P. (2011) Molecular control of angiopoietin signalling. Biochem. Soc. Trans. 39, 1592-1596

Hansen, T. M., Singh, H., Tahir, T. A., and Brindle, N. P. (2010) Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface. Cell. Signal. 22, 527-532

Singh, H., Milner, C. S., Aguilar Hernandez, M. M., Patel, N., and Brindle, N. P. (2009) Vascular endothelial growth factor activates the Tie family of receptor tyrosine kinases. Cell. Signal. 21, 1346-1350

Marron, M. B., Singh, H., Tahir, T. A., Kavumkal, J., Kim, H.-Z., Koh, G. Y., and Brindle, N. P. J. (2007) Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor tyrosine kinase Tie2. J. Biol. Chem. 282, 30509-30517

Marron, M. B., Hughes, D. P., Edge, M. D., Forder, C. L., and Brindle, N. P. J. (2000) Evidence for heterotypic interaction between the receptor tyrosine kinases TIE-1 and TIE-2. J. Biol. Chem. 275, 39741-39746

New signalling pathways

N Brindle - Image 3

 

In order to define signalling pathways by which angiopoietins 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.

Tahir, TA, Singh, H & Brindle NPJ (2014) “The RNA binding protein hnRNP-K mediates post –transcriptional regulation of Uncoupling Protein-2 by angiopoietin-1” Cell. Signal. In press DOI: 10.1016/j.cellsig.2014.03.005

Brindle, N. P. J., Saharinen, P., and Alitalo, K. (2006) Signaling and functions of Angiopoietin-1 in vascular protection. Circ. Res. 98, 1014-1023

Hughes, D. P., Marron, M. B., and Brindle, N. P. J. (2003) The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-{kappa}B inhibitor ABIN-2. Circ. Res.92, 630-636

Tadros, A., Hughes, D. P., Dunmore, B. J., and Brindle, N. P. J. (2003) ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood102, 4407-4409

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