International Protease Network

Molecular Hepatology Group, Liver Immunobiology Program, Centenary Institute
University of Sydney
Sydney Medical School, The University of Sydney, NSW 2006, Australia
Email: m.gorrell@centenary.usyd.edu.au
Tel: +61-2-95656100
Fax: +61-2-95656101
Homepage: http://www.centenary.org.au/p/res/liver/molechep/

Research

We are interested in understanding the functions of the dipeptidyl peptidase 4 gene family, and the molecular pathogenesis of chronic liver disease, which can lead to severe scarring, liver failure and sometimes to liver cancer. DPP4 is now well known as the target of a new type 2 diabetes therapy that is benefiting many millions of patients. DPP4 inhibitor selectivity is preferred, so potential inhibitory compounds are counter-screened on DPP8 and DPP9, which we discovered. Both DPP4 and the DPP4-related enzyme fibroblast activation protein [FAP] are made by tumour stromal fibroblasts, so FAP is a potential target for tumor therapy. We discovered that FAP is also made in diseased but not healthy human and mouse liver and showed that both DPP4 and FAP are profibrotic in mice and influence cell adhesion, migration and death in vitro. We continue to investigate the potential for additional therapeutic applications of targeting these proteases.

Collaborations

Dr W. Bret Church, Faculty of Pharmacy, University of Sydney.
Dr Catherine Abbott, Flinders University of South Australia.
Associate Professor Stephen Twigg and Dr Sue McLennan, Endocrinology Centre, University of Sydney.
Professor John Prins, Diamantina Institute, University of Queensland.
Professor Christopher M. Overall, University of British Columbia Centre for Blood Research, University of British Columbia, Vancouver, Canada.
Dr Kemal Topaloglu, Cukurova University Faculty of Medicine, Department of Pediatric Endocrinology and Metabolism, Turkey.

Publications

Abbott CA, McCaughan GW, Gorrell MD. Two highly conserved glutamic acid residues in the predicted beta propeller domain of dipeptidyl peptidase IV are required for its enzyme activity. FEBS Lett 1999;458:278-284.
2. Abbott CA, Yu DMT, Woollatt E, Sutherland GR, McCaughan GW, Gorrell MD. Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur J Biochem 2000;267:6140-6150.
3. Ajami K, Abbott CA, Obradovic M, Gysbers V, Kähne T, McCaughan GW, et al. Structural requirements for catalysis, expression and dimerisation in the CD26/DPIV gene family. Biochemistry 2003;42:694-701.
4. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci 2005;108:277-292.
5. Wang XM, Yu DMT, McCaughan GW, Gorrell MD. Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line. Hepatology 2005;42:935-945.
6. Yu DMT, Wang XM, McCaughan GW, Gorrell MD. Extra-enzymatic functions of the dipeptidyl peptidase (DP) IV related proteins DP8 and DP9 in cell adhesion, migration and apoptosis. FEBS Journal 2006;273:2447-2461.
7. Ajami K, Pitman MR, Wilson CH, Park J, Menz RI, Starr AE, Cox JH, Abbott CA, Overall CM, Gorrell MD. Inflammatory protein-10, interferon-inducible T cell chemo-attractant and stromal cell-derived factors 1α and 1β are novel substrates of dipeptidyl peptidase 8. FEBS Lett 2008;582:819-825.
8. Wang XM, Yao T-W, Nadvi NA, Osborne B, McCaughan GW, Gorrell MD. Fibroblast activation protein and chronic liver disease. Front Biosci 2008;13:3168-3180.
9. Kirby M, Yu D, O’Connor S, Gorrell M. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clinical Sciences 2009. in press.
10. Yu D, Ajami K, Gall M, Park J, Lee CS, Evans K, McLaughlin EA, Pitman MR, Abbott CA, McCaughan GW, Gorrell MD. The in vivo expression of dipeptidyl peptidases 8 and 9. J Histochem Cytochem 2009:in press.