Safhi, M. M. A., Rutherford, C., Ledent, C., Sands, W. A. and Palmer, T. M. (2010) Priming of signal transducer and activator of transcription proteins for cytokine-triggered polyubiquitylation and degradation by the A2a adenosine receptor. Molecular Pharmacology, 77(6), pp. 968-978. (doi: 10.1124/mol.109.062455)
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Publisher's URL: http://dx.doi.org/10.1124/mol.109.062455
Abstract
Here we demonstrate that overexpression of the human A2a adenosine receptor (A2AAR) in vascular endothelial cells confers an ability of interferon-α and a soluble IL-6 receptor/IL-6 (sIL-6Rα/IL-6) trans-signaling complex to trigger the down-regulation of signal transducer and activator of transcription (STAT) proteins. It is noteworthy that STAT down-regulation could be reversed by coincubation with A2AAR-selective inverse agonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) but not adenosine deaminase, suggesting that constitutive activation of the receptor was responsible for the effect. Moreover, STAT down-regulation was selectively abolished by proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), whereas lysosome inhibitor chloroquine was without effect. Down-regulation required Janus kinase (JAK) activity and a Tyr705→Phe-mutated STAT3 was resistant to the phenomenon, suggesting that JAK-mediated phosphorylation of this residue is required. Consistent with this hypothesis, treatment of A2AAR-overexpressing cells with sIL-6Rα/IL-6 triggered the accumulation of polyubiquitylated wild-type but not Tyr705→Phe-mutated STAT3. Support for a functional role of this process was provided by the observation that A2AAR overexpression attenuated the JAK/STAT-dependent up-regulation of vascular endothelial growth factor receptor-2 by sIL-6Rα/IL-6. Consistent with a role for endogenous A2AARs in regulating STAT protein levels, prolonged exposure of endogenous A2AARs in endothelial cells with ZM241385 in vitro triggered the up-regulation of STAT3, whereas deletion of the A2AAR in vivo potentiated STAT1 expression and phosphorylation. Together, these experiments support a model whereby the A2AAR can prime JAK-phosphorylated STATs for polyubiquitylation and proteasomal degradation and represents a new mechanism by which an anti-inflammatory seven-transmembrane receptor can negatively regulate JAK/STAT signaling.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Sands, Dr William and Palmer, Dr Timothy and Rutherford, Dr Claire |
Authors: | Safhi, M. M. A., Rutherford, C., Ledent, C., Sands, W. A., and Palmer, T. M. |
Subjects: | Q Science > Q Science (General) |
College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Molecular Pharmacology |
Publisher: | American Society for Pharmacology and Experimental Therapeutics |
ISSN: | 0026-895X |
ISSN (Online): | 1521-0111 |
Published Online: | 25 February 2010 |
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