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J Biol Chem. 2016 Jul 15;291(29):15388-403. doi: 10.1074/jbc.M116.721241. Epub 2016 May 13.

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration.

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From the Departments of Biochemistry and Molecular Biology and.
the Department of Oncology and Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada and.
From the Departments of Biochemistry and Molecular Biology and


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.


ATP; Ras-related protein 1 (Rap1); cell migration; guanine nucleotide exchange factor (GEF); hypoxia; microtubule

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