title: Extracellular ATP stimulates epithelial cell motility through Pyk2-mediated activation of the EGF receptor.
abstract: Wounding usually causes considerable cell damage, and released ATP promotes migration of nearby epithelium. ATP binds to purinergic receptors on the cell surface and induces transactivation of the EGF receptor through signaling by the Src family kinases (SFKs). Here we tested whether ATP activates these kinases through Pyk2, a member of the focal adhesion kinase family. Pyk2 was rapidly and potently activated by treating corneal epithelial cells with ATP, and physical interaction of Pyk2 with the SFKs was enhanced. Disruption of Pyk2 signaling either by siRNA or by expression of a dominant-negative mutant led to inhibition of ATP-induced activation of the SFKs and the EGF receptor. Inhibiting Pyk2 activity also blocked ATP stimulation of healing of wounds in epithelial cell sheets. These data suggest that ATP stimulates sequential activation of Pyk2, SFKs, and the EGF receptor to induce cell migration.
authors.affiliation: Ophthalmology and Visual Sciences Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Block
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tolino
authors.forename: Jes K
authors.initials: JK
authors.lastname: Klarlund
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology* / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D045604:Extracellular Fluid; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051418:Focal Adhesion Kinase 2; D019061:src-Family Kinases; C000631346:CSK protein, human