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J. Biol. Chem., Vol. 281, Issue 1, 59-68, January 6, 2006

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Src Activation Is Not Necessary for Transforming Growth Factor (TGF)--mediated Epithelial to Mesenchymal Transitions (EMT) in Mammary Epithelial Cells

PP1 DIRECTLY INHIBITS TGF- RECEPTORS I AND II^*

Masato Maeda1, Yasushi Shintani, Margaret J. Wheelock¶||**2, and Keith R. Johnson¶||**

From the Department of Oral Biology, College of Dentistry, the Department of Biochemistry and Molecular Biology, the ^¶Department of Genetics, Cell Biology and Anatomy, the ^||Department of Pathology and Microbiology, College of Medicine, the ^**Eppley Institute for Research in Cancer and Allied Diseases, and the Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696

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-1 (TGF-1)-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-1-mediated EMT, leading us to speculate that Src activation is not an essential component of TGF-1-mediated EMT. Unexpectedly, PP1 prevented Smad2/3 activation by TGF-1, whereas SU6656 did not. Most interestingly, an in vitro kinase assay showed that PP1 strongly inhibited the TGF- receptor type I, and to a lesser extent, the TGF- receptor type II. Taken together, our data indicated that PP1 interferes with TGF-1-mediated EMT not by inhibiting Src family kinases but by inhibiting the Smad pathway via a direct inhibition of TGF- receptor kinase activity.

Received for publication, March 25, 2005 , and in revised form, September 23, 2005.

^* This work was supported by Grants R01-DE12308 and R01-GM51188 from the National Institutes of Health (to K. R. J. and to M. J. W., respectively) and by National Institutes of Health P20-RR018759 (to M. J. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

¹ Supported by a postdoctoral fellowship from the Eppley Breast Cancer Training Program (Grant DAMD 17-00-1-0361) from the Department of Defense and by a research fellowship from the Uehara Memorial Foundation.

² To whom correspondence should be addressed: Dept. of Oral Biology, College of Dentistry, University of Nebraska Medical Center, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. Tel.: 402-559-3892; Fax: 402-559-3888; E-mail: mwheelock{at}unmc.edu.

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