Induction of cell scattering by expression of beta 1 integrins in beta 1-deficient epithelial cells requires activation of members of the Rho family of GTPases and downregulation of cadherin and catenin function

Adhesion receptors, which connect cells to each other and to the surroundin g extracellular matrix (ECM), play a crucial role in the control of tissue structure and of morphogenesis. In this work, we have studied how intercell ular adhesion molecules and beta 1 integrins influence each other using two different beta 1-null cell lines, epithelial GE11 and fibroblast-like GD25 cells. Expression of beta 1A or the cytoplasmic splice variant beta 1D, in duced the disruption of intercellular adherens junctions and cell scatterin g in both GE11 and GD25 cells. In GE11 cells, the morphological change corr elated with the redistribution of zonula occluden (ZO)-1 from tight junctio ns to adherens junctions at high cell confluency. In addition? the expressi on of pi integrins caused a dramatic reorganization of the actin cytoskelet on and of focal contacts. Interaction of beta 1 integrins,with their respec tive ligands was required for a complete morphological transition towards t he spindle-shaped fibroblast-like phenotype. The expression of an interleuk in-2 receptor (IL2R)-beta 1A chimera and its incorporation into focal adhes ions also induced the disruption of cadherin-based adhesions and the reorga nization of ECM-cell contacts, but failed to promote cell migration on fibr onectin, in contrast to full-length beta 1A, This indicates that the disrup tion of cell-cell adhesion is not simply the consequence of the stimulated cell migration. Expression of beta 1 integrins in GE11 cells resulted in a decrease in cadherin and alpha-catenin protein levels accompanied by their redistribution from the cytoskeleton-associated fraction to the detergent-s oluble fraction, Regulation of alpha-catenin protein levels by beta 1 integ rins is likely to play a role in the morphological transition, since overex pression of alpha-catenin in GE11 cells before beta 1 prevented the disrupt ion of intercellular adhesions and cell scattering. In addition: using bioc hemical activity assays for Rho-like GTPases, we show that the expression o f beta 1A, beta 1D, or IL2R-beta 1A in GE11 or GD25 cells triggers activati on of both RhoA and Rac1, but not of Cdc42. Moreover, dominant negative Rad (N17Rac1) inhibited the disruption of cell-cell adhesions when expressed b efore beta 1. However, all three GTPases might be involved in the morpholog ical transition, since expression of either N19RhoA, N17Rac1 or N17Cdc42 re versed cell scattering and partially restored cadherin-based adhesions in G E11-beta 1A cells. Our results indicate that beta 1 integrins regulate the polarity and motility of epithelial cells by the induction of intracellular molecular events involving a downregulation of alpha-catenin function and the activation of the Rho-like G proteins Rac1 and RhoA.