PP2A activation by β2-adrenergic receptor agonists -: Novel regulatory mechanism of keratinocyte migration

Understanding the mechanisms that regulate cell migration is important for devising novel therapies to control metastasis or enhance wound healing. Previously, we demonstrated that beta(2)-adrenergic receptor (beta(2)- AR) activation in keratinocytes inhibited their migration by decreasing the phosphorylation of a critical promigratory signaling component, the extracellular signal- related kinase ( ERK). Here we demonstrate that beta(2)-AR-induced inhibition of migration is mediated by the activation of the serine/ threonine phosphatase PP2A. Pretreating human keratinocytes with the PP2A inhibitor, okadaic acid, prevented the beta(2)-AR- induced inhibition of migration, either as isolated cells or as a confluent sheet of cells repairing an in vitro wound and also prevented the beta(2)- AR- induced reduction in ERK phosphorylation. Similar results were obtained with human corneal epithelial cells. In keratinocytes, immunoprecipitation studies revealed that beta(2)- AR activation resulted in the rapid association of beta(2)- AR with PP2A as well as a 37% increase in association of PP2A with ERK2. Finally, beta(2)- AR activation resulted in a rapid and transient 2- fold increase in PP2A activity. Thus, we provide the first evidence that beta(2)- AR activation in keratinocytes modulates migration via a novel pathway utilizing PP2A to alter the promigratory signaling cascade. Exploiting this pathway may result in novel therapeutic approaches for control of epithelial cell migration.