Lead


Lay summary
Meprins (meprin? and meprin?) are proteinases that belong to the Astacin family of metalloproteinases. They are abundantly expressed at the membrane of intestinal epithelial cells facing the intestinal lumen. Membrane-bound and soluble meprin activity is finely regulated, but can be destructive if unchecked, misplaced, and/or inappropriately activated. The function of meprins in health and disease is not clear and subject of intensive research. Meprins are involved in cell migration, colon cancer, and inflammatory bowel diseases. Meprinß knockout mice are less susceptible to inflammatory bowel disease than wild-type mice and we know that in compromised tissues, meprins may be re-distributed to the cytosol and the basolateral membrane of epithelial cells thus causing damage to these cells.The aims of the project are:1) to investigate how meprins alter cell-cell and cell-matrix interactions by proteolytic processing of specific proteins involved in these processes.2) to identify proteins within cells that interact with membrane-bound meprin?3) to investigate the role of membrane-bound meprin in signalling events through the proteolytic cleavage and thus activation of memrane receptors and/or their ligands.Experimental design:Proteolytic processing of specific proteins will be studied in cultured epithelial cells and intestinal tissue explants and the functional consequences of this processing will be determined in cell adhesion and cell migration assays. A novel protein-protein interaction screen will be used to identify intracellular proteins that interact with the cytosolic domain of meprinß. The ability of meprin? to activate epidermal growth factor receptor (EGFR) in colorectal cancer cells will be studied in epithelial cell cultures. Expected value of the proposed project:Data obtained will enhance our understanding of meprin substrates by providing knowledge about specific protein substrates including those involved in cell-cell / cell-matrix interactions, as well as proteins that interact with meprinß and include membrane receptors and intracellular signalling molecules. This proposal has close links to a research project supported by the EU (http://www.ibdase.org) of which the PI is a partner.