Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes

To achieve strong adhesion to their neighbors and sustain stress and tensio n, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression, with the de velopment of a fibroblastic morphology characteristic of metastatic cells. During lias transformation, Rac-signaling pathways participate in the disru ption of cadherin-dependent adhesion. We show that sustained Rac activation per se is sufficient to disassemble cadherin-mediated contacts in keratino cytes, in a concentration- and time-dependent manner. Cadherin receptors ar e removed from junctions before integrin receptors, suggesting that pathway s activated by Rac can specifically interfere with cadherin function. We ma pped an important region for disruption of junctions to the putative second effector domain of the Rac protein. Interestingly, although this region ov erlays the domain necessary to induce lamellipodia, we demonstrate that the disassembly of cadherin complexes is a new Rac activity, distinct from Rac -dependent lamellipodia formation. Because Rac activity is also necessary f or migration, Rac is a good candidate to coordinately regulate cell-cell an d cell-substratum adhesion during tumorigenesis.