Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we demonstrate that overexpression of the human A(2A) adenosine receptor (A(2A)AR) in vascular endothelial cells confers an ability of interferon-alpha and a soluble IL-6 receptor/IL-6 (sIL-6R alpha/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 A(2A)AR-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 A(2A)AR-overexpressing cells with sIL-6R alpha/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 A(2A)AR overexpression attenuated the JAK/STAT-dependent up-regulation of vascular endothelial growth factor receptor-2 by sIL-6R alpha/IL-6. Consistent with a role for endogenous A(2A)ARs in regulating STAT protein levels, prolonged exposure of endogenous A(2A)ARs in endothelial cells with ZM241385 in vitro triggered the up-regulation of STAT3, whereas deletion of the A(2A)AR in vivo potentiated STAT1 expression and phosphorylation. Together, these experiments support a model whereby the A(2A)AR 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.
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PMID:Priming of signal transducer and activator of transcription proteins for cytokine-triggered polyubiquitylation and degradation by the A 2A adenosine receptor. 2018 53