Dr Briony Forbes
Dr Briony Forbes is the Head of the Protein Signalling and IGF structure/function group.
Research in the IGF structure/function group mainly focuses on the molecular mechanisms underlying the control of insulin like growth factors (IGFs) and insulin in normal growth and development and in cancer. IGFs and insulin play an essential role in growth, metabolism, and longevity and they are conserved across a diverse range of species from flies to mammals. IGFs promote cell proliferation, survival and migration via the tyrosine kinase type 1 IGF receptor (IGF-1R) and insulin promotes metabolic signalling via the insulin receptor (IR). IGFs promote survival, proliferation and migration of cancer cells and thus play a role in promoting survival and progression of primary tumours as well as metastasis.
Our primary research goals are:
i) to understand the molecular basis of IGF-1R and IR activation upon ligand binding,
ii) to define the mechanisms leading to specific mitogenic and metabolic signalling outcomes,
iii) to understand structural and functional determinants of IGFBPs and the IGF2R which are important for control of IGF action,
iv) to take a comparative genomic approach to understand mechanisms controlling metabolism.
Through these research goals we aim to develop inhibitors of the IGF system for the treatment of cancer and also to develop improved diabetes treatments.
Through site-directed mutagenesis we have defined two ligand-binding surfaces on IGFs and insulin required for high affinity interaction with their receptors. We have recently shown that IGF-II is also able to bind with high affinity to the insulin receptor isoform A (IR-A) splice variant, and we have identified structural determinants important for receptor binding specificity. Signalling via the IR-A leads to cancer cell proliferation, survival and migration. This information is vital in designing inhibitors of IGF action for the treatment of cancer and for improved insulin mimetics with minimal mitogenic activity through the IGF-1R and IR-A.
A family of 6 high affinity IGF binding proteins (IGFBPs) and an IGF-II specific receptor (IGF2R) regulate the availability of IGFs to bind the signalling receptors. We have contributed significantly to understanding the mechanisms of interaction of the IGFBPs and IGF2R with the IGFs. However, it has recently become evident that binding of both IGFBPs and the IGF2R to other molecules also influences cancer cell growth and migration. We are currently characterising these interactions to build a comprehensive picture of the regulation of IGF action by IGFBPs and the IGF2R. Furthermore, through our detailed understanding of IGFBP-2 structure and function we are developing an inhibitor of IGF action as a potential treatment of cancer.
Selected publications 2006-
BF1 Brown J, Jones EY, Forbes BE. Interaction of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor: mechanism and biological outcomes. (2009) Vitam. Horm. Chapter 25, 700-719
BF2 Jitrapakdee, S. and Forbes, B.E. Insulin Secretion and Actions In: Medical Complications of Type 2 Diabetes, ISBN 978-953-307-363-7, Colleen Croniger Ed (2011) pp 1-24.
BF3. Rajapaksha H., Alvino C., McCarthy P. and Forbes B.E. The Insulin-like Growth Factor Mutation Database (IGFmdb). Growth Hormone & IGF Res. (2012) in press, accepted May 21.
BF4. Forbes, B.E., McCarthy, P., Norton, R.S. Insulin-like growth factor binding proteins: a structural perspective. Front. Endocrin.(2012) 3:38. doi: 10.3389/fendo.2012.00038
BF5. Alvino, C.L., Ong, SC, McNeil, K.A., Delaine, C., Booker, G.W., Wallace, J.C., Forbes, B.E. Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II PlosONE (2011) 6(11):e27488.
BF6. Galea CA, Mobli M, McNeil KA, Mulhern TD, Wallace JC, King GF, Forbes BE, Norton RS Insulin-like growth factor binding protein-2: NMR analysis and structural characterization of the N-terminal domain. Biochimie. (2011) 94(3):608-16
BF7. Forbes, B.E. Molecular mechanisms underlying insulin-like growth factor action: How mutations in the GH:IGF axis lead to short stature Pediatr Endocrinol Rev (2011) 8(4):374-81
BF8. Kwak S-Y, Forbes BE, Lee Y-S, Belgi A, Wade JD, Hossain MA Solid Phase Synthesis of an Analogue of Insulin, A0:R glargine, that exhibits decreased mitogenic activity Int J Pept Res Ther (2010) 16:153–158.
BF9. Brierley, G.V., Macaulay, S.L., Forbes, B.E., Wallace, J.C., Cosgrove, L.J. & Macaulay V.M. (2010) Silencing of the IR-A favours formation of IGF-1R homodimers and enhances ligand-induced IGF-1R activation and proliferation of human colon carcinoma cells Endocrinology 51(4):1418-27. [IF=4.75, C=3]
BF10. Brown J, Jones EY, Forbes BE Keeping IGF-II under control: Lessons from the IGF-II-IGF2R crystal structure. (2009) TIBS 34(12):612-9. [IF=14.1, C=12]
BF11. Alvino CL, McNeil KA, Ong SC, Delaine C, Booker GW, Wallace JC, Whittaker J, Forbes BE. A novel approach to identify two distinct receptor binding surfaces of insulin-like growth factor II. (2009) J Biol Chem. 284(12): 7656-7664.
BF12. Kuang Z, Yao S, McNeil KA, Forbes BE, Wallace J C, Norton RS. Insulin-like Growth Factor-I (IGF-I): Solution Properties and NMR Chemical Shift Assignments near Physiological pH. (2009) GH&IGF Res. 19: 226–231
BF13. Gauguin L, Delaine C, Alvino CL, McNeil KA, Wallace JC, Forbes BE, De Meyts P. Alanine Scanning of a Putative Receptor Binding Surface of Insulin-like Growth Factor-I. (2008) J Biol Chem. 283(30):20821-9.
BF14. Surinya KH, Forbes BE, Occhiodoro F, Booker GW, Francis GL, Siddle K, Wallace JC, Cosgrove LJ. An investigation of the ligand binding properties and negative cooperativity of soluble insulin-like growth factor receptors. J Biol Chem. (2008) 283(9): 5355-63.
BF15. Gauguin L, Kalproth B, Sajid W, Andersen AS, McNeil KA, Forbes BE, De Meyts P. Structural basis for the lower affinity of the insulin-like growth factors for the insulin receptor. J Biol. Chem. (2008) 283(5):2604-13.
BF16. Brown J, Delaine C, Zaccheo OJ, Siebold C, Gilbert RJ, Van Boxel G, Denley A, Wallace JC, Hassan AB, Forbes BE, Jones EY. Structure and functional analysis of the IGF-II/IGF2R interaction (2008) EMBO J 27(1):265-76.
BF17. Kuang Z, Yao S, McNeil KA, Thompson JA, Bach LA, Forbes BE, Wallace JC, Norton RS Cooperativity of the N- and C-Terminal Domains of Insulin-like Growth Factor (IGF) Binding Protein 2 in IGF Binding. Biochemistry. (2007) 46(48): 13720-13732.
BF18. Belobrajdic D.P., Priebe I.K., Briony Forbes B.E., Flyvbjerg A., Chen J.-W., Cosgrove L.J., Frystyk J., Saunders I.W. Assessing the potential usefulness of IGF-related peptides and adiponectin for prediciting disease risk. Growth Hormone & IGF Research (2007) 18(3):198-204.
BF19. Williams C., Rezguiz D., Prince S.N., Zaccheo O.J., Foulstone E.J., Forbes B.E., Norton R.S., Crosby J., Hassan A.B., Crump M.P. Structural insights into the interaction of Insulin-like Growth Factor 2 (IGF2) with IGF2R domain 11. Structure (2007)15(9):1065-78
BF20. Delaine C, Alvino CL, McNeil KA, Mulhern TD, Gauguin L, De Meyts P, Jones EY, Brown J, Wallace JC, Forbes BE. A novel binding site for the human IGF-II/mannose 6-phospate receptor (IGF2R) on IGF-II. J Biol Chem. (2007) 282(26):18886-94.
BF21. Denley A., Carroll, J.M., Brierley G. V., Cosgrove L., Wallace J. C, Forbes, B.E. and Roberts, C. T. Jr. (2007) Differential activation of insulin receptor substrates-1 and 2 by IGF-activated insulin receptors. Mol. Cell Biol. 27(10):3569-77
BF22. Chandrashekaran, I.R., Yao, S., Wang, C.C., Bansal, P.S., Alewood, P.F., Forbes, B.E., Wallace, J.C., Bach, L.A., Norton, R.S. (2007) The N-Terminal Subdomain of Insulin-like Growth Factor (IGF) Binding Protein 6. Structure and Interaction with IGFs. Biochemistry 46(11):3065-74.
BF23. Keyhanfar, M., Booker, G.W., Whittaker, J., Wallace, J.C. and Forbes, B.E. (2007) Precise mapping of an IGF-I binding site on the IGF-1R Biochem. J. 401(1): 269-277
BF24. Kuang Z., Yao S., Keizer D.W., Wang C.C., Bach L.A., Forbes B.E., Wallace J.C., and Norton R.S. (2006) Structure, Dynamics and Heparin Binding of the C-terminal Domain of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2). J. Mol. Biol. 364 (4): 551-852
BF25. Keyhanfar, M., Forbes, B.E., Cosgrove, L.J., Wallace, J.C. and Booker, G.W. (2006) Production and Characterisation of Monoclonal Antibodies Against Insulin-like Growth Factor Type 1 Receptor (IGF-1R). Hybridoma. 25(4): 230-37.
BF26. Roche P, Brown J, Denley A., Forbes B.E., Wallace J.C., Jones E.Y. and. Esnouf RM (2006) A computational model for the IGF-II/IGF2R complex that is predictive of mutational and surface plasmon resonance data. Proteins: Structure, Function and Bioinformatics 64(3): 758-68.
BF27. Denley A., Brierley G. V., Carroll J. M., Lindenberg A., Booker G. W., Cosgrove L. J., Wallace J. C., Forbes B. E., Roberts, Jr. C. T. (2006) Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain. Endocrinol. 147(2):1029-36.