title: Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration.
abstract: The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and.
authors.forename: Young
authors.initials: Y
authors.lastname: Ou
authors.affiliation: the Department of Oncology and Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Zuo
authors.affiliation: Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada and.
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Rattner
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and fvdhoorn@ucalgary.ca.
authors.forename: Frans A
authors.initials: FA
authors.lastname: van der Hoorn
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D043704:Receptor, Adenosine A2B; D000255:Adenosine Triphosphate; C116753:RAP1B protein, human; D020668:rap GTP-Binding Proteins
keywords: ATP; Ras-related protein 1 (Rap1); cell migration; guanine nucleotide exchange factor (GEF); hypoxia; microtubule