TY - JOUR
T1 - Src activation is not necessary for transforming growth factor (TGF)-β-mediated epithelial to mesenchymal transitions (EMT) in mammary epithelial cells
T2 - PP1 directly inhibits TGF-β receptors I and II
AU - Maeda, Masato
AU - Shintani, Yasushi
AU - Wheelock, Margaret J.
AU - Johnson, Keith R.
PY - 2006/1/6
Y1 - 2006/1/6
N2 - 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 viral Src (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 showed that Src is activated in transforming growth factor-β1 (TGF-β1)-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-β1-mediated EMT, leading us to speculate that Src activation is not an essential component of TGF-β1-mediated EMT. Unexpectedly, PP1 prevented Smad2/3 activation by TGF-β1, whereas SU6656 did not. Most interestingly, an in vitro kinase assay showed that PP1 strongly inhibited the TGF-β receptor type I, and to a lesser extent, the TGF-β receptor type II. Taken together, our data indicated that PP1 interferes with TGF-β1-mediated EMT not by inhibiting Src family kinases but by inhibiting the Smad pathway via a direct inhibition of TGF-β receptor kinase activity.
AB - 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 viral Src (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 showed that Src is activated in transforming growth factor-β1 (TGF-β1)-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-β1-mediated EMT, leading us to speculate that Src activation is not an essential component of TGF-β1-mediated EMT. Unexpectedly, PP1 prevented Smad2/3 activation by TGF-β1, whereas SU6656 did not. Most interestingly, an in vitro kinase assay showed that PP1 strongly inhibited the TGF-β receptor type I, and to a lesser extent, the TGF-β receptor type II. Taken together, our data indicated that PP1 interferes with TGF-β1-mediated EMT not by inhibiting Src family kinases but by inhibiting the Smad pathway via a direct inhibition of TGF-β receptor kinase activity.
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U2 - 10.1074/jbc.M503304200
DO - 10.1074/jbc.M503304200
M3 - Article
C2 - 16267045
AN - SCOPUS:33644849647
SN - 0021-9258
VL - 281
SP - 59
EP - 68
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -