Role of adherens junction-associated membrane protein shrew-1 in polarized and non-polarized cells in vitro and in vivo

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Cell migration and invasion of cells into the surrounding tissue are fundamental processes in normal development and pathological conditions. In early development, particularly during neurulation and gastrulation, cells acquire a migratory, mesenchymal phenotype, not unlike that of invasive tumor cells. The invasion of single cells is often correlated with changes in the expression and function of cadherins or immunoglobulin domain-containing cell adhesion molecules and regulatory proteins, e.g. snail family members, transforming growth factor beta. We have discovered a transmembrane protein, shrew-1, which plays a central role in cell migration and invasion. In epithelial cells, shrew-1 localizes to adherens junctions. Its localization and trafficking is responsive to epidermal growth factor (EGF) and scatter factor (SF/HGF) and may mediate the loss of epithelial morphology, increase of migration and invasion and decrease of intercellular adhesion induced by these factors. Shrew-1 may play a role in the morphological plasticity of epithelial cells. We are proposing to extend our studies of the properties of this molecule by computational, bioinformatic analyses, knockdown or overexpression of wildtype or mutant variants of the protein. Cell culture experiments will be complemented by an analysis of shrew-1 function in the development of the mouse mammary gland combining knock-down technology and tissue reconstitution techniques.