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Proteins in Metabolism & Cancer Laboratory

insulin, diabetes, cancer...

Lab Members (L-R): Andrew Blyth, Emily Crawley,
Carlie Sawtell, Shee Chee Ong, Cher Lynn Soh,
Liang Li and Briony Forbes

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, more recently the focus has broadened to 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 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 two novel insulin analogues (dicarba insulins) with unique properties that reveal a previously undescribed mechanism underlying insulin receptor binding and activation. Dicarba insulin has a modified A6-A11 cystine framework. The structural and functional characterisation of these new insulins will provide us with the basis to produce improved insulins for the treatment of diabetes.

We are currently developing an IGF inhibitor as a novel treatment of cancer. The inhibitor is based on a mutant IGFBP-2, which acts to sequester the IGFs away from the IGF-1R. We are investigating the mechanisms underlying the ability of the mutant IGFBP-2 to inhibit tumour growth in vivo by analysing tumour and serum samples from our breast cancer xenograft model treated with mutant IGFBP-2. We are also using in vitro and in vivo models to measure the ability of mutant IGFBP-2 to inhibit metastasis.

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

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

 

Jitrapakdee S and Forbes BE (2011) Insulin Secretion and Actions In: Medical Complications of Type 2 Diabetes, ISBN 978-953-307-363-7, Colleen Croniger Ed pp1-24

 

Galea CA, Mobli M, McNeil KA, Mulhern TD, Wallace JC, King GF, Forbes BE, Norton RS (2011) Insulin-like growth factor binding protein-2: NMR analysis and structural characterization of the N-terminal domain. Biochimie, 94(3):608-16

 

Forbes BE  (2011) Molecular mechanisms underlying insulin-like growth factor action: How mutations in the GH:IGF axis lead to short stature. Pediatric Endocrinology Reviews, 8(4):374-81

 

Alvino CL, Ong SC, McNeil KA, Delaine C, Booker GW, Wallace JC, Forbes BE (2011) Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF-II. Plos ONE, 6(11):e27488

 


Investigator

  • Briony Forbes, BSc(Hons), PhD

Support Staff

  • Carlie Sawtell, BSc(Hons), Research Assistant

Students

  • Cher Lynn Soh, PhD Student

  • Liang Li, PhD Student

  • Chuan (Olivia) He, PhD Student (Co-supervised with The University of Adelaide)

  • Shee Chee Ong, PhD Student

    Emily Crawley, PhD Student

    Martin Badcock, Honours Student


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