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.
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.
To
Ciric
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Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Kulkarni
Sarang
S
Pawson
Tony
T
Honda
Tadashi
T
Gribble
Gordon W
GW
Sporn
Michael B
MB
Wrana
Jeffrey L
JL
Di Guglielmo
Gianni M
GM
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*
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D007093:Imidazoles; D016212:Transforming Growth Factor beta; D009828:Oleanolic Acid