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J. Biol. Chem., Vol. 283, Issue 17, 11700-11713, April 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/17/11700    most recent M704064200v1 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 To, C. Articles by Di Guglielmo, G. M. PubMed PubMed Citation Articles by To, C. Articles by Di Guglielmo, G. M. Social Bookmarking                      What's this?

The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid-Imidazolide Alters Transforming Growth Factor β-dependent Signaling and Cell Migration by Affecting the Cytoskeleton and the Polarity Complex^*

Ciric To, Sarang Kulkarni, Tony Pawson, Tadashi Honda^¶, Gordon W. Gribble^¶, Michael B. Sporn^||1, Jeffrey L. Wrana², and Gianni M. Di Guglielmo³

From the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada, the Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, the ^¶Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, and the ^||Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755

The anti-tumor synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-imidazolide (CDDO-Im) ectopically activates the transforming growth factor β (TGFβ)-Smad pathway and extends the duration of signaling by an undefined mechanism. Here we show that CDDO-Imdependent persistence of Smad2 phosphorylation is independent of Smad2 phosphatase activity and correlates with delayed TGFβ receptor degradation and trafficking. Altered TGFβ trafficking parallels the dispersal of EEA1-positive endosomes from the perinuclear region of CDDO-Im-treated cells. The effect of CDDO-Im on the EEA1 compartment led to an analysis of the cytoskeleton, and we observed that CDDO-Im alters microtubule dynamics by disrupting the microtubule-capping protein, Clip-170. Interestingly, biotinylated triterpenoid was found to localize to the polarity complex at the leading edge of migrating cells. Furthermore, CDDO-Im disrupted the localization of IQGAP1, PKC, Par6, and TGFβ receptors from the leading edge of migrating cells and inhibited TGFβ-dependent cell migration. Thus, the synthetic triterpenoid CDDO-Im interferes with TGFβ receptor trafficking and turnover and disrupts cell migration by severing the link between members of the polarity complex and the microtubule network.

Received for publication, May 16, 2007 , and in revised form, February 8, 2008.

^* This work was supported by National Cancer Institute of Canada (NCIC) Terry Fox Foundation Grant 017189 (to G. M. D. G.). 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 supplemental Figs. 1-3 and Movies 1-4.

¹ Supported by National Institutes of Health Grant R01 CA78814, the National Foundation for Cancer Research, and Reata Pharmaceuticals, Inc.

² Work in the laboratory of this author was supported by grants from the NCIC and Canadian Institutes of Health Research Grant MOP-74692.

³ To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, Medical Sciences Bldg., University of Western Ontario, London, Ontario N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 80042); E-mail: john.diguglielmo{at}schulich.uwo.ca.

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