Src activation is not necessary for transforming growth factor (TGF)-β-mediated epithelial to mesenchymal transitions (EMT) in mammary epithelial cells: PP1 directly inhibits TGF-β receptors I and II

Masato Maeda, Yasushi Shintani, Margaret J. Wheelock, Keith R. Johnson

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-68
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number1
DOIs
StatePublished - Jan 6 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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