Cell-Cell Adhesion Signalling

Dr Vania Braga, Head of Group

Cell-cell adhesion is an important process during morphogenesis. It ensures tight contacts between neighbouring cells, which are necessary for cell segregation, the morphological and functional differentiation of different tissues. In adults, cell-cell adhesion plays an essential role in the homeostasis of healthy tissues. Importantly, during tumor progression, disruption of cell-cell contacts plays a pivotal role in metastasis as well as in the dedifferentiation process that accompanies the malignant phenotype.

Our aim is to understand how cell-cell adhesion is regulated by intracellular signalling pathways. As model system, we use primary keratinocytes, epithelial cells derived from the human epidermis, which is a well established model to investigate cell-cell contacts. We focus on the function of cadherin receptors, whose adhesion is necessary for epithelia differentiation. In addition, perturbation of cadherin-mediated adhesion is shown to be a key event during metastasis of carcinoma cells.

In order to understand how cadherin adhesiveness is regulated, we are investigating the Rho family of small GTPases, intracellular proteins that control the organization of the cytoskeleton, cell migration and attachment to the extracellular matrix. We have previously demonstrated that the function of two members, Rho and Rac, is required for cadherin-mediated contacts.  In addition, establishment of cell-cell contacts can activate Rho proteins.  Our aim is to investigate (a) how can cell-cell adhesion activate small GTPases; (b) which Rho targets play a role in cadherin-adhesion; and (c) how does new cell-cell contact formation promote the remodelling of the cytoskeleton in epithelial cells?  We are currently translating this functional relationship into molecular interactions between components of the cadherin complex, Rho proteins and actin filaments.