Signaling in cell migration and metastasis
Disruption of normal cell-cell adhesion in transformed cells may contribute to tumor cells enhanced migration and proliferation, leading to invasion and metastasis. Our results have shed light on the mechanism controlling the transition from cell adhesion to migration. The loosening of intracellular adhesiveness at invasive carcinomas is due to functional disturbance cell-cell contacts. Several mechanisms for disruption of cell-cell adhesion have been proposed in human cancer. The majority of epithelial tumors show reduced expression of molecules that are important in keeping cell-cell adhesion contacts, like the cadherin proteins. A correlation between reduced E-cadherin expression, loss of tumor differentiation and increased invasiveness has been found. These findings are consistent with the hypothesis that inhibition of E-cadherin function enhances the release of cancer cells from the primary site. The E-cadherin protein binds to different proteins, which in turn links the adhesive complex to the cytoskeleton inside the cell and stabilizes the contacts between cells. One candidate regulator of adhesion that binds to the cytoplasmic tail of cadherins is the catenin p120. It is still not clear how this protein controls the adhesion contacts but it is known that its interaction to the cadherin is necessary to keep the adhesion between cells. Our group has recently started a new line of research at the Department of Biomedicine investigating a possible mechanism of regulation of the catenin p120ctn. Our initial findings, published in the prestigious journal Proc. Natl. Acad. Sci. (Krastad et al. PNAS), described a link between the catenin p120 and a protein involved in signaling through cell surface receptors. This protein belongs to the family of heterotrimeric G proteins, G12. After our initial findings, many questions were still left open. Therefore our objectives are now to understand by what mechanism does G12-p120 interaction regulate cadherin function and in turn cell-cell adhesion. Bente Johansson more recent experiments have unraveled a possible mechanism through which G12 and p120ctn interaction is controlled. The results suggest that de-phosphorylation of p120ctn is necessary for G12 binding. Also G12 interaction produces a change in the conformation of p120ctn. It is likely that the change in p120ctn structure also affects its association with the adhesion complexes. Taking together our findings have open a new avenue on the field of cell adhesion since it postulates a model of how signaling proteins can affect cadherin-cadherin interaction between cells.