p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion

The molecular basis for contact inhibition of cell locomotion is still larg ely unknown. Cadherins, the major receptors mediating cell-cell adhesion, a ssociate in the cytoplasm with armadillo family proteins, including beta- a nd gamma -catenin and p120 catenin (p120ctn), E-cadherin-mediated contact f ormation was shown to inhibit cellular motility. We examine whether p120ctn may have a role in this regulation. We show here that overexpression of p1 20ctn in fibroblasts and epithelial cells induces pronounced changes in cel l shape, motility and adhesion to the extracellular matrix. p120ctn-transfe cted cells display increased filopodial/lamellipodial activity, decreased c ontractility and focal adhesion formation, and augmented migratory ability. These effects of p120ctn are mediated by small GTPases of the Rho family, Direct assessment of the activity of these GTPases in cells expressing a 5- fold higher level of p120ctn as compared to non-transfected control cells r evealed significant augmentation of Cdc42 and Rac activity. Moreover, co-tr ansfection of p120ctn with dominant-negative Cdc42 and Rac, or constitutive ly active Rho, suppressed morphological effects of p120ctn. Confocal immuno fluorescence visualization of the distribution of endogenous p120ctn in den se cultures showed that formation of cadherin-mediated cell-cell contacts i s accompanied by sequestering of p120ctn to the junction regions. In sparse cultures p120ctn is distributed over the cytoplasm. Co-transfection with a n excess of E-cadherin leads to sequestration of exogenous p120ctn to cell- cell junctions or to small cadherin-containing vesicles, and abolishes p120 ctn effects on cell morphology. Thus, p120ctn may couple the formation and disruption of cadherin-mediated contacts with regulation of cell motility b y triggering pathway(s) affecting Rho family GTPases.