Dr Colin Ward
Division: Structural Biology
The insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF-1R) are closely related members of the receptor tyrosine kinase superfamily. IR is the receptor through which insulin exerts its actions. These are the regulation of lipid, protein and carbohydrate metabolism including the maintenance of glucose homeostasis. The IGF-1R is involved in normal growth and development and there is a compelling body of evidence for involvement of the IGF signalling system in cancer progression.
Dr Mike Lawrence and Dr Colin Ward are interested in understanding the way in which insulin and the IGFs bind to these receptors on the surface of cells. Their work has led to the first structure of the intact extra-cellular part of the insulin receptor and has shown for the first time the way in which the insulin binding site is constructed. The challenge is now to find out exactly how insulin binds to this site and to understand how binding the ligand-binding signal is transmitted across the cell membrane.
Since aberrant signalling by IGF-2 binding to IR and IGF-1 and IGF-2 binding to IGF-1R has been shown to play a role in the development and progression of cancer and we are also seeking to understand ligand binding to IGF-1R.
- Ward CW, Lawrence MC. Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor. Bioessays. 2009 Mar 9;31(4):422-434 [Epub ahead of print] PMID: 19274663 [PubMed - as supplied by publisher]
- Ward C, Lawrence M, Streltsov V, Garrett T, McKern N, Lou MZ, Lovrecz G, Adams T. Structural insights into ligand-induced activation of the insulin receptor. Acta Physiol (Oxf) . 2008 Jan;192(1):3-9 PMID: 18171424 [PubMed - indexed for MEDLINE]
- Lawrence MC, McKern NM, Ward CW. Insulin receptor structure and its implications for the IGF-1 receptor. Curr Opin Struct Biol. 2007 Dec;17(6):699-705 PMID: 17851071 [PubMed - indexed for MEDLINE]
- Zahnd C, Wyler E, Schwenk JM, Steiner D, Lawrence MC, McKern NM, Pecorari F, Ward CW, Joos TO, Plückthun A. A designed ankyrin repeat protein evolved to picomolar affinity to Her2. J Mol Biol. 2007 Jun 15;369(4):1015-28 PMID: 17466328 [PubMed - indexed for MEDLINE]
- Ward CW, Lawrence MC, Streltsov VA, Adams TE, McKern NM. The insulin and EGF receptor structures: new insights into ligand-induced receptor activation. Trends Biochem Sci . 2007 Mar;32(3):129-37 PMID: 17280834 [PubMed - indexed for MEDLINE]
- Sparrow LG, Gorman JJ, Strike PM, Robinson CP, McKern NM, Epa VC, Ward CW. The location and characterisation of the O-linked glycans of the human insulin receptor. Proteins. 2007 Feb 1;66(2):261-5 PMID: 17078079 [PubMed - indexed for MEDLINE]
- McKern NM, Lawrence MC, Streltsov VA, Lou MZ, Adams TE, Lovrecz GO, Elleman TC, Richards KM, Bentley JD, Pilling PA, Hoyne PA, Cartledge KA, Pham TM, Lewis JL, Sankovich SE, Stoichevska V, Da Silva E, Robinson CP, Frenkel MJ, Sparrow LG, Fernley RT, Epa VC, Ward W.
Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature. 2006 Sep 14;443(7108):218-21 PMID: 16957736 [PubMed - indexed for MEDLINE]
- Lou M, Garrett TP, McKern NM, Hoyne PA, Epa VC, Bentley JD, Lovrecz GO, Cosgrove LJ, Frenkel MJ, Ward CW. The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12429-34 PMID: 16894147 [PubMed - indexed for MEDLINE]
- Epa VC, Ward CW. Model for the complex between the insulin-like growth factor I and its receptor: towards designing antagonists for the IGF-1 receptor. Protein Eng Des Sel. 2006 Aug;19(8):377-84 PMID: 16772308 [PubMed - indexed for MEDLINE] Denley A, Bonython ER, Booker GW, Cosgrove LJ, Forbes BE, Ward CW, Wallace JC. Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol Endocrinol. 2004 Oct;18(10):2502-12 PMID: 15205474 [PubMed - indexed for MEDLINE]
Current Laboratory Members
Faculty Member: Michael Lawrence, BSc(Hons) PhD Cape Town
Faculty Member: Colin Ward, BSc(Hons) PhD UNSW
Research Assistant: John Menting, BSc(Hons) Melb PhD LaT
Research Assistant: Mai Margetts, BAppSc RMIT