title: The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-imidazolide alters transforming growth factor beta-dependent signaling and cell migration by affecting the cytoskeleton and the polarity complex.
abstract: 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 beta (TGFbeta)-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 TGFbeta receptor degradation and trafficking. Altered TGFbeta 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, PKCzeta, Par6, and TGFbeta receptors from the leading edge of migrating cells and inhibited TGFbeta-dependent cell migration. Thus, the synthetic triterpenoid CDDO-Im interferes with TGFbeta receptor trafficking and turnover and disrupts cell migration by severing the link between members of the polarity complex and the microtubule network.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Ciric
authors.initials: C
authors.lastname: To
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Gribble
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Gianni M
authors.initials: GM
authors.lastname: Di Guglielmo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D007093:Imidazoles; D016212:Transforming Growth Factor beta; D009828:Oleanolic Acid