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Papers In Press, published online ahead of print November 1, 2005
Oral Biology and Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198-7696
Corresponding Author: mwheelock{at}unmc.edu
Epithelial to Mesenchymal Transitions (EMTs) are key events during embryonic development and cancer progression. It has been proposed that Src plays a major role in some EMT models, as shown by the overexpression of v-Src in epithelial cells. It is clear that Src family kinases can regulate the integrity of both adherens junctions and focal adhesions, however their significance in EMT, especially in the physiological context, remains to be elucidated. Here we show that Src is activated in transforming growth factor-ß1 (TGF-ß1)-mediated EMT in mammary epithelial cells and that the Src family kinase inhibitor, PP1 prevents EMT. However, neither a more specific Src family kinase inhibitor, SU6656, nor a dominant-negative Src inhibited TGF-ß1-mediated EMT, leading us to speculate that Src activation is not an essential component of TGF-ß1-mediated EMT. Unexpectedly, PP1 prevented Smad2/3 activation by TGF-ß1, while SU6656 did not. Most interestingly an in vitro kinase assay showed that PP1 strongly inhibited the TGF-ß receptor type I, and to a lesser extent the TGF-ß receptor type II. Taken together, our data indicate that PP1 interferes with TGF-ß1-mediated EMT not by inhibiting Src family kinases, but by inhibiting the Smad pathway via a direct inhibition of TGF-ß receptor kinase activity.
J. Biol. Chem, 10.1074/jbc.M503304200
Submitted on March 25, 2005
Revised on September 23, 2005
Accepted on November 1, 2005
SRC activation is not necessary for TGF-
-mediated EMT in mammary epithelial cells; PP1 directly inhibits TGF receptors l and ll
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