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J. Biol. Chem., Vol. 283, Issue 17, 11293-11301, April 25, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/17/11293    most recent M800154200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhao, S. Articles by Freeman, J. W. PubMed PubMed Citation Articles by Zhao, S. Articles by Freeman, J. W. Social Bookmarking                      What's this?

Smad4-dependent TGF-β Signaling Suppresses RON Receptor Tyrosine Kinase-dependent Motility and Invasion of Pancreatic Cancer Cells^*

Shujie Zhao, Sudhakar Ammanamanchi, Michael Brattain, Lin Cao, Amalraj Thangasamy, Jing Wang, and James W. Freeman^¶1

From the Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198, and ^¶Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, Texas 78229

Transforming growth factorβ (TGF-β) signals through Smad-dependent and Smad-independent pathways. However, Smad signaling is altered by allelic deletion or intragenic mutation of the Smad4 gene in more than half of pancreatic ductal adenocarcinomas. We show here that loss of Smad4-dependent signaling leads to aberrant expression of RON, a phosphotyrosine kinase receptor, and that signaling by RON cooperates with Smad4-independent TGF-β signaling to promote cell motility and invasion. Restoring Smad4 expression in a pancreatic ductal adenocarcinoma cell line that is deficient in Smad4 repressed RON expression. Conversely, small interference RNA knock down of Smad4 or blocking TGF-β signaling with a TGF-β type I receptor kinase inhibitor in Smad4-intact cell lines induced RON expression. TGF-β-induced motility and invasion were inhibited in cells that express Smad4 and that have low levels of RON compared with isogenically matched cells that were deficient in Smad4. Furthermore, knocking down RON expression in Smad4-deficient cells suppressed TGF-β-mediated motility and invasion. We further determined that Smad4-dependent signaling regulated RON expression at the transcriptional level by real-time reverse transcription PCR and RON promoter luciferase reporter assays. Functional inactivation by site-directed mutations of two Smad binding sites on the RON promoter inhibited TGF-β-mediated repression of RON promoter activity. These studies indicate that loss of Smad4 contributes to aberrant RON expression and that cross-talk of Smad4-independent TGF-β signaling and the RON pathway promotes an invasive phenotype.

Received for publication, January 7, 2008

^* This work was supported by National Institutes of Health Grant CA96122 and a Veterans Affairs merit award (to J. F.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-5298; Fax: 210-567-6687; E-mail: freemanjw{at}uthscsa.edu.

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