Dr Briony Forbes

Research Interests

The IGF structure/function group is in the laboratory of Professor John Wallace (https://www.adelaide.edu.au/directory/john.wallace) and this research is directed by Dr Briony Forbes.

Research in the IGF structure/function group has two main aims:

1. To understand the molecular interactions underlying the control of IGF actions.
2. To develop specific inhibitors which block IGF action for the treatment of IGF-responsive cancers.

There is compelling evidence that the insulin-like growth factor (IGF) system is involved in development, progression and metastasis of many cancers. IGF-I and IGF-II act via the tyrosine kinase type 1 IGF receptor (IGF-1R) to promote survival and proliferation of cancer cells even in the presence of chemotherapies and promote cancer cell migration. Higher levels of circulating IGF-I and IGF-II are associated with increased risk of developing breast, colon and prostate cancers. Over 50% of cancers are IGF responsive. Targeting of the IGF system for the treatment of cancer is a major focus of my research. 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. 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. Signalling via the IR-A also leads to cancer cell proliferation, survival and migration. Both IGF-II and IR-A are upregulated in cancer. Furthermore, IGFs, but not insulin, have high affinity for hybrid IGF-1R:IR receptors which form when both receptors are co-expressed. Hybrid receptors are found on most cancer cells and signalling via hybrids also results in mitogenic outcomes. It is now likely that the IR-A and hybrid receptors play an important role in cancer biology. We believe that any therapeutic strategy against cancer must not only inhibit the action of IGFs via the IGF-1R but must also address the role of hybrids and IGF-II acting via the IR-A. Our strategy is therefore to understand the molecular interactions between the IGFs and the IGF-1R, IR-A and hybrids. This information will then provide the basis for future design of inhibitors of IGF action in cancer.

Publications

Book Chapter

1. Brown J, Jones EY, Forbes BE. Interaction of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor: mechanism and biological outcomes. (2008) Vitam. Horm. In press (October 2008).

Journal Articles
1.  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. (2008) GH&IGF Res. In press (17-10-2008.)

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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) Oct 24; [Epub ahead of print].

8. 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

9. 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.

10. 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.

11. 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.

12. 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

 
13. 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

 
14. 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.

15. 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.

16. 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

 

Patents

1.	Forbes, B. E. (2004) Altered insulin-like growth factor binding proteins PCT Patent 2003243829, published January 2004.
2.	Keyhanfar, M., Booker, G.W., Forbes, B.E. and Wallace, J.C. (2004) Antibodies to Insulin-like Growth Factor-I Receptor: Patent Number 2004901994 Provisional

 

Entry last updated: Tuesday, 26 May 2009