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Angiotensin II Type 2 Receptor Stimulation Increases the Rate of NG108–15 Cell Migration via Actin Depolymerization

Départment de Physiologie et Biophysique (P.K., S.C., L.B., N.G.-P., M.D.P.) and Service d'Endocrinologie (M.-O.G., C.R., N.G.-P.), Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4

Address all correspondence and requests for reprints to: Marcel Daniel Payet, Ph.D., Département de Physiologie et Biophysique, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke 3001, 12^e Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4. E-mail: Marcel.Payet{at}USherbrooke.ca.

Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108–15 cell migration. This effect was antagonized by PD123319, a selective AT₂ receptor antagonist, but not by DUP753, a selective AT₁ receptor antagonist, and was mimicked by the specific AT₂ receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT₂ receptor, guanylyl cyclase/cyclic GMP or p42/p44^mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108–15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT₂ receptor increases the migration speed of NG108–15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT₂ receptor action, in the context of cellular migration.