Header image 1Header image 2Header image 3Header image 4Header image 5

Proteins in Metabolism & Cancer Laboratory

insulin, diabetes, cancer...

Assoc Prof Briony Forbes in the lab

 

Research Summary

The Proteins in Metabolism and Cancer Group are interested in the insulin and insulin-like growth factor (IGF) system in development and disease. IGFs and insulin play a major role in cancer, aging, neuronal disease, diabetes and cardiovascular disease. Using expertise in protein structure/function this laboratory has been developing inhibitors of IGF action for the treatment of cancer. As there is evolutionary, structural and functional overlap between the IGF and insulin hormones and signalling pathways, we have a broader interest in understanding mechanisms of metabolism control and the development of novel insulins for the treatment of diabetes. The lab also has a keen interest in exploring the links between metabolism and cancer.

Research Projects

We are generating a series of novel IGF molecules with unique cross-linking amino acids and fluorescent molecules incorporated into specific sites within the IGF structure. These molecules will be used to define the specific sites of contact between the ligand and receptors as there is currently no published structure of an IGF:IGF receptor or insulin:insulin receptor complex. This information will ultimately be important in the design and development of highly specific IGF receptor inhibitors for the treatment of cancer.

In collaboration with A/Prof Andrea Robinson (Monash University) we have developed insulin analogues with a modified cystine framework (dicarba insulins), which have unique properties that reveal a previously undescribed mechanism underlying insulin receptor binding and activation. The structural and functional characterisation of these new insulins will provide us with the basis to produce improved insulins for the treatment of diabetes.

IGF-II activation of the insulin receptor isoform-A promotes cancer cell proliferation and survival. Both IGF-II and IR-A are upregulated in many cancers. We are establishing a series of model cell lines, which will be used in phosphoproteomic analyses to identify key components in the signalling pathway. Importantly, using this approach we will also identify new signalling proteins in the IGF-II/IR-A signalling pathway. Having identified these signalling proteins they will in the future be used to correlate IGF-II/IR-A autocrine loop signalling with patient outcome.

Following the sequencing of the platypus genome it has become evident that metabolic control in the platypus is quite different to mammals. Monotremes have very small stomachs and they lack fundamental mammalian genes important for food breakdown eg gastrin. While the platypus appears to express metabolic control proteins such as insulin and the incretins (including glucagon-like peptide 1) these proteins and their receptors differ in their amino acid sequences in regions of the molecules important for function. The aim of this project is to understand the way in which these molecules interact with their receptors to generate a biological function. This comparative approach conducted in collaboration with A/Prof Grutzner (The University of Adelaide) will shed new light on mechanisms of metabolic control.

Selected Publications

Tsend-Ayush E, He C, Myers M, Andrikopoulos S, Wong N, Sexton PM, Wootten D, Forbes B* and Grutzner F* (2016) Monotreme glucagon-like peptide-1 in venom and gut: one gene – two very different functions. Nat Sci Rep, 6:37744. *last authors contributed equally.

 

Karas JA, Patil NA, Tailhades J, Sani MA, Scanlon DB, Forbes BE, Gardiner J, Separovic F, Wade JD, Hossain MA (2016) Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability. Angew Chem Int Ed Engl, 55(47):14743-14747

 

Forbes BE (2016) Two years in IGF research. Growth Horm IGF Res, 30-31:70-74. Review.

 

Menting JG, Gajewiak J, MacRaild CA, Chou DH, Disotuar MM, Smith NA, Miller C, Erchegyi J, Rivier JE, Olivera BM, Forbes BE, Smith BJ, Norton RS, Safavi-Hemami H, Lawrence MC (2016) A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. Nat Struct Mol Biol, 23(10):916-920

 

Cottam Jones JM, Harris PW, Scanlon DB, Forbes BE, Brimble MA, Abell AD (2016) Fluorescent IGF-II analogues for FRET-based investigations into the binding of IGF-II to the IGF-1R. Org Biomol Chem, 14(9):2698-6705

 

Henderson ST, Brierley GV, Surinya KH, Priebe IK, Catcheside DE, Wallace JC, Forbes BE, Cosgrove LJ (2015) Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR. Growth Hormone & IGF Research, 25(1):20-7

 

He C, Myers MA, Forbes BE, Grützner F (2015) Immunohistochemical analysis of pancreatic islets of platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus ssp.). Journal of Anatomy, 226(4):373-80

 

Rajapaksha H, Forbes BE. (2015) Ligand-Binding Affinity at the Insulin Receptor Isoform-A and Subsequent IR-A Tyrosine Phosphorylation Kinetics are Important Determinants of Mitogenic Biological Outcomes. Frontiers in Endocrinology 6:107

 

Karas JA, Scanlon DB, Forbes BE, Vetter I, Lewis RJ, Gardiner J, Separovic F, Wade JD, Hossain MA (2014) 2-Nitroveratryl as a Photocleavable Thiol Protecting Group for Directed Disulphide Bond Formation in the Chemical Synthesis of Insulin. Chemistry, 20(31):9549-9552

 

Soh CL, McNeil K, Owczarek CM, Hardy MP, Fabri LJ, Pearse M, Delaine CA, Forbes BE (2014) Exogenous administration of protease-resistant, non matrix-binding IGFBP-2 inhibits tumor growth in a murine model of breast cancer. British Journal of Cancer, 110(12):2855-2864

 

Ziegler AN, Chidambaram S, Forbes BE, Wood TL, Levison SW (2014) Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion. Journal of Biological Chemistry, 289(8):4626-4633

 

Niu M, Klingler-Hoffmann M, Brazzatti JA, Forbes B, Akekawatchai C, Hoffmann P, McColl S (2013) Comparative proteomic analysis implicates eEF2 as a novel target of PI3Kγ in the MDA-MB-231 metastatic breast cancer cell line. Proteome Science, 11(1):1-12

 

He C, Tsend-Ayush E, Myers MM, Forbes BE and Grützner F (2013) Loss of ghrelin in platypus (Ornithorhynchus anatinus) is an indication of unique digestion and metabolic control mechanisms in the platypus. General and Comparative Endocrinology, 191:74-82

 

Williams C, Hoppe H-J, Rezgui D, Strickland M, Forbes BE, Grutzner F, Frago S, Ellis RE, Wattana-Amorn P, Prince SN, Zaccheo OJ, Nolan CM, Mungall AJ, Jones EY, Crump MP and Hassan AB (2012) An exon splice enhancer primes IGF2:IGF2R binding site evolution for parental conflict. Science, 38(6111):1209-13

 

Cottam JM, Scanlon DB, Karas JA, Calabrese AN, Pukala TL, Forbes BE, Wallace JC, Abell AD (2012) Chemical synthesis of a fluorescent IGF-II analogue. International Journal of Peptide Research and Therapeutics, 19(1):61-69

 

Forbes BE, McCarthy P, Norton RS (2012) Insulin-like growth factor binding proteins: a structural perspective. Frontiers in Endocrinology, 3(38):1-13

 

Rajapaksha H, Alvino C, McCarthy P and Forbes BE (2012) The Insulin-like Growth Factor Mutation Database (IGFmdb). Growth Hormone & IGF Research, 22(5):158-66

 


Investigator

  • Briony Forbes, BSc(Hons), PhD

Support Staff

  • Carlie Delaine, BSc(Hons), Research Assistant

Students

  • Liang Li, PhD Student

  • Shee Chee Ong, PhD Student

    Emily Crawley, PhD Student

    Govinda Poudel, Honours Student

    Riya Abraham, Honours Student

    Allanah Merriman, BMSc Placement Student


CNS page footer image
Website by Journeyman Systems