Transforming growth factor-beta 1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism

Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but i t can also enhance tumor progression by stimulating the complex process of epithelial-to-mesenchymal transdifferentiaion (EMT). The signaling pathway( s) that regulate EMT in response to TGF-beta are not well understood. We de monstrate the acquisition of a fibroblastoid morphology, increased N-cadher in expression, loss of junctional E-cadherin localization, and increased ce llular motility as markers for TGF-beta -induced EMT. The expression of a d ominant-negative Smad3 or the expression of Smad7 to levels that block grow th inhibition and transcriptional responses to TGF-beta do not inhibit mese nchymal differentiation of mammary epithelial cells. In contrast, we show t hat TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-neg ative mutants, inhibited TGF-beta -mediated EMT. The data suggest that TGF- beta rapidly activates RhoA-dependent signaling pathways to induce stress f iber formation and mesenchymal characteristics.