Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.
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.
Bhowmick
N A
NA
Vanderbilt-Ingram Cancer Center, Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Ghiassi
M
M
Bakin
A
A
Aakre
M
M
Lundquist
C A
CA
Engel
M E
ME
Arteaga
C L
CL
Moses
H L
HL
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D020558:GTP Phosphohydrolases / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008907:Mink; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000494:pharmacology*
D047908:Intracellular Signaling Peptides and Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein