title: PP2A activation by beta2-adrenergic receptor agonists: novel regulatory mechanism of keratinocyte migration.
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 beta2-adrenergic receptor (beta2-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 beta2-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 beta2-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 beta2-AR-induced reduction in ERK phosphorylation. Similar results were obtained with human corneal epithelial cells. In keratinocytes, immunoprecipitation studies revealed that beta2-AR activation resulted in the rapid association of beta2-AR with PP2A as well as a 37% increase in association of PP2A with ERK2. Finally, beta2-AR activation resulted in a rapid and transient 2-fold increase in PP2A activity. Thus, we provide the first evidence that beta2-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.
authors.affiliation: Department of Dermatology, University of California, Davis, Davis, California 95616, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Pullar
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: R Rivkah
authors.initials: RR
authors.lastname: Isseroff
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D003315:Cornea / Q000166:cytology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007231:Infant, Newborn; D007545:Isoproterenol / Q000494:pharmacology*; D015603:Keratinocytes / Q000502:physiology*; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D019319:Okadaic Acid; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D007545:Isoproterenol