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

Christine E. Pullar, Jin Chen, Roslyn Rivkah Isseroff

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Understanding the mechanisms that regulate cell migration is important for devising novel therapies to control metastasis or enhance wound healing. Previously, we demonstrated that β2-adrenergic receptor (β2-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 β2-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 β2-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 β2-AR-induced reduction in ERK phosphorylation. Similar results were obtained with human corneal epithelial cells. In keratinocytes, immunoprecipitation studies revealed that β2-AR activation resulted in the rapid association of β2-AR with PP2A as well as a 37% increase in association of PP2A with ERK2. Finally, β2-AR activation resulted in a rapid and transient 2-fold increase in PP2A activity. Thus, we provide the first evidence that β2-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.

Original languageEnglish (US)
Pages (from-to)22555-22562
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number25
DOIs
StatePublished - Jun 20 2003

ASJC Scopus subject areas

  • Biochemistry

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