CDC42 AND RAC1 INDUCE INTEGRIN-MEDIATED CELL MOTILITY AND INVASIVENESS THROUGH PI(3)K

Transformation of mammary epithelial cells into invasive carcinoma res ults in alterations in their integrin-mediated responses to the extrac ellular matrix, including a loss of normal epithelial polarization and differentiation, and a switch to a more motile, invasive phenotype, C hanges in the actin cytoskeleton associated with this switch suggest t hat the small GTPases Cdc42 and Rac, which regulate actin organization (1,2), might modulate motility and invasion, However, the role of Cdc4 2 and Rad in epithelial cells, especially with respect to integrin-med iated events, has not been well characterized, Here we show that activ ation of Cdc42 and Rad disrupts the normal polarization of mammary epi thelial cells in a collagenous matrix, and promotes motility and invas ion. This motility does not require the activationof PAK, JNK, p70 S6 kinase, or Rho, but instead requires phosphatidylinositol-3-OH kinase (PI(3)K). Further, direct PI(3)K activation is sufficient to disrupt e pithelial polarization and induce cell motility and invasion. PI(3)K i nhibition also disrupts actin structures, suggesting that activation o f PI(3)K by Cdc42 and Rad alters actin organization, leading to increa sed motility and invasiveness.