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

Abstract

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.

Cardiac c-kit+AT2+ Cell Population is Increased in Response to Ischemic Injury and Supports Cardiomyocyte Performance

“…However, it remains to be clarified as to how and whether AT2 receptors direct the differentiation of c-kitþAT2þ cells into cardiomyocytes and/or noncardiomyocytes. Given the fact that the AT2 receptor has a stimulating role in cell migration [27,28] and MI-induced production of BM c-kitþAT2þ cell pool was observed in the present study, it appeared that AT2 receptor-mediated mobilization/migration of BM c-kitþAT2þ cells into the infarcted myocardium may contribute to an increase in cardiac ckitþAT2þ cell population following AT2 receptor activation.…”

Role of Two Types of Angiotensin II Receptors in Colorectal Carcinoma Progression

“…This function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis [9]. NG108-15-induced AT2R stimulation increases cell migration via actin depolymerization by cofilin, and these are potentially new targets of AT2R signaling in the context of cellular migration [20]. …”

Angiotensin II, a neuropeptide at the frontier between endocrinology and neuroscience: is there a link between the angiotensin II type 2 receptor and Alzheimer’s disease?

“…Ang II type 2 receptor may improve synaptic plasticity through effects on ionic channel activity, since AT2R activation decreases T-type calcium channel activity, increases K + channel activity (Kang et al, 1992, 1993; Buisson et al, 1995), and alters actin cytoskeleton dynamics (Kilian et al, 2008). …”

“…Indeed, several studies have reported that AT2R activates PP2A phosphatase (Huang et al, 1995, 1996a,2008; Kilian et al, 2008). PP2A is markedly deficient in AD, and responsible for a sustained increase in ERK1/ERK2, one of the kinases involved in glycogen synthase kinase-3 (GSK-3) inactivation.…”