How Do Animal Cells Move? The Link Between Extracellular Proteases and Adhesion Receptors.

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Cell migration is important for normal development of animal embryos and tissue repair and regeneration in adults. It is controlled by environmental cues provided by diffusible factors and interactions of cells with the structural components of the three-dimensional extracellular matrix (ECM) through which they move. Two important and interacting classes of adhesion receptors in animal cells are the integrins and the syndecans.Integrins are a large family of heterodimeric molecules, the nature of the aB dimers determining their specificity for ECM ligands. Syndecans are a family of four heparan sulphate proteoglycans which bind growth factors and also act themselves as ECM-binding receptors. These two classes of molecules work together to control cell adhesion and its signalling consequences, and in particular integrins a5B1 and aVB3 and syndecan-4 are required for cell adhesion and migration on fibronectin-rich matrices via the formation and turnover of focal adhesions.Another recently discovered class of molecules known as the ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin-like motifs) also influence cell migration. The project will address the hypothesis that ADAMTS metalloproteinases regulate cell movement by affecting cell surface syndecan-4 presentation or function, leading to changes in integrin a5B1 and aVB3 trafficking and focal adhesion dynamics.This project will provide training in advanced cell and molecular techniques including immunolocalization, fluorescence activated cell sorting (FACS) and timelapse videomicroscopy to study the adhesion and migration of mouse embryo fibroblasts (MEFs) that are deficient in either integrins a5, B3, syndecan-4 or ADAMTS-1 or -15.