Protein Structure Function Laboratory
Head of laboratory
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Overview of research program
The members of the Protein Structure Function Laboratory are interested in the biological actions of two members of the insulin-like growth factor binding protein family, IGFBP-3 and IGFBP-5. These proteins have complex and often contradictory effects on cellular processes intimately linked to the development and progression of cancer. Our research focuses on understanding the underlying molecular mechanisms responsible for IGFBP-3 and IGFBP-5 actions on cancer-related cellular processes. In order to understand such mechanisms, we have identified several proteins that interact with IGFBP-3 and/or IGFBP-5, including transcription factors, signal transduction molecules and molecular chaperones. We are currently examining the biological significance of IGFBP-3 or IGFBP-5 interacting with these newly identified protein partners.
Another research theme is the structure and regulation of the protein complexes which carry IGFs in the circulation. Together with the acid-labile subunit, either IGFBP-3 or IGFBP-5 forms these complexes with IGFs. We hope to understand the way in which changes in these protein complexes might affect the delivery of IGFs to the tissues, especially in pregnancy and catabolic states.
The laboratory is also interested in RACK7, a novel chromatin-binding protein that is essential for cell proliferation. We have shown that RACK7 binds histone H3 and is a component of complexes that contain various histone-modifying enzymes. RACK7 may contribute to reading the “histone code” by targeting histone-modifying enzymes to specific chromatin sites, and thereby influence fundamental processes such as genome replication and gene transcription. We are currently characterizing the interaction between RACK7 and histone H3 and the impact of RACK7 on gene transcription.
Major funding sources
- ARC
- Cancer Institute NSW
Selected publications
Graham ME, Kilby DM, Firth SM, Robinson PJ and Baxter RC (2007) The in vivo phosphorylation and glycosylation of human insulin-like growth factor binding protein-5. Mol and Cell Proteomics 6: 1392-1405
Yan X, Forbes BE, McNeil KA, Baxter RC and Firth SM (2004) Role of amino- and carboxyl residues of insulin-like growth factor (IGF) binding protein-3 in regulating IGF complex formation and receptor activation. J Biol Chem 279: 53232-53240
Scott CD and Firth SM (2004) The role of the M6P/IGF-II receptor in cancer: Tumour suppression or garbage disposal? Horm Metab Res 36: 261-271
Butt AJ, Martin JL, Dickson KA, McDougall F, Firth SM and Baxter RC (2004) Insulin-like growth factor binding protein-3 is associated with growth stimulation of T47D human breast cancer cells: the role of altered epidermal growth factor signalling. J Clin Endocrinol Metab 89: 1950-1956
Payet L, Wang X-H, Baxter RC and Firth SM (2003) Amino and carboxylterminal fragments of insulin-like growth factor binding protein-3 cooperate to bind IGFs with high affinity and inhibit IGF receptor interactions. Endocrinology 144: 2797-2806
Firth SM and Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Revs 23:824-854
Firth SM, McDougall F, Mclachlan, AJ and Baxter RC (2002) Impaired blockade of insulin-like growth factor (IGF)-I-induced hypoglycemia by IGF binding protein-3 analog with reduced ternary complex forming ability. Endocrinology 143:1669-1676
Baxter RC, Meka S and Firth SM (2002) Molecular distribution of insulin-like growth factor binding protein-5 in human serum. J Clin Endocrinol Metab 87:271-276
Firth SM, Clemmons DR and Baxter RC (2001) Mutagenesis of basic amino acids in the carboxyl-terminal region of insulin-like growth factor binding protein-5 affects acid-labile subunit binding. Endocrinology 142:2147-2150
Major collaborations
- Assoc Prof Stephen Twigg (Royal Prince Alfred Hospital)
