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Publications (2)2.35 Total impact

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    ABSTRACT: Insulin-like growth factors (IGF-I and IGF-II), and insulin are evolutionarily conserved hormonal regulators of eukaryotic growth and development. Through interactions with their cognate receptors, all three molecules can influence cellular growth, proliferation, differentiation, migration, and survival, as well as metabolic processes. As such, perturbations in signaling by IGFs and insulin are a well-documented cause of altered growth, development and survival during both embryonic and post-natal life. A key approach in understanding how IGFs and insulin elicit their biological effects has been through identifying structural features of the ligands that influence their receptor interactions. Over the years, the study of many hundreds of specifically engineered IGF and insulin analogues has provided a wealth of knowledge about how specific residues of these ligands contribute to ligand:receptor interactions. Some analogues have even provided the basis for designing therapeutic agents for the treatment of IGF and insulin-related diseases. As the list of IGF and insulin analogues continues to grow we find that, while many have been produced and studied, it would be of considerable value to have a central repository from which information about specific analogues and their receptor binding data were readily available in an easily searchable and comparable format. To address this, we have created the "Insulin-like growth factor mutation database" (IGFmdb). The IGFmdb is a web-based curated database of annotated ligand analogues and their receptor binding affinities that can be accessed via http://www.adelaide.edu.au/igfmutation. Currently the IGFmdb contains receptor-binding data for 67 IGF-II analogues that were publicly accessible prior to 2012, as well as 67 IGF-I analogues, including all of those produced and characterised in our laboratory. A small number of these are IGF species homologues. There are also 32 insulin analogues within IGFmdb that were reported within the included IGF analogue studies, representing only a small fraction of existing insulin mutants. Future developments of the IGFmdb will incorporate receptor-binding data for all publicly accessible IGF-I analogues and the data will be expanded to include IGF-binding protein (IGFBP) binding affinities.
    Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 06/2012; 22(5):158-66. · 2.35 Impact Factor
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    ABSTRACT: Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development, as well as in disease.
    Frontiers in Endocrinology 01/2012; 3:38.