Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.

Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL
Mol Biol Cell. 2001 12 (1): 27-36

PMID: 11160820 · PMCID: PMC30565 · DOI:10.1091/mbc.12.1.27

Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but it 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 demonstrate the acquisition of a fibroblastoid morphology, increased N-cadherin expression, loss of junctional E-cadherin localization, and increased cellular motility as markers for TGF-beta-induced EMT. The expression of a dominant-negative Smad3 or the expression of Smad7 to levels that block growth inhibition and transcriptional responses to TGF-beta do not inhibit mesenchymal differentiation of mammary epithelial cells. In contrast, we show that TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-negative mutants, inhibited TGF-beta-mediated EMT. The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.

MeSH Terms (17)

Animals Cell Differentiation Epithelial Cells GTP Phosphohydrolases Humans Intracellular Signaling Peptides and Proteins Mesoderm Mice Mink Protein-Serine-Threonine Kinases rho-Associated Kinases rhoA GTP-Binding Protein Signal Transduction Transfection Transforming Growth Factor beta Transforming Growth Factor beta1 Tumor Cells, Cultured

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