Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p38 mitogen-activated protein (MAP) kinase is activated during engagement of the type I interferon (IFN) receptor and mediates signals essential for IFNalpha-dependent transcriptional activation via interferon-stimulated response elements without affecting formation of the ISGF3 complex. In the present study, we provide evidence that the small GTPase Rac1 is activated in a type I IFN-dependent manner and that its function is required for downstream engagement of the p38 MAP kinase pathway. We also demonstrate that p38 is required for IFNalpha-dependent gene transcription via GAS elements and regulates activation of the promoter of the PML gene that mediates growth inhibitory responses. In studies to determine whether the regulatory effects of p38 are mediated by serine phosphorylation of Stat1 or Stat3, we found that the p38 kinase inhibitors SB203580 or SB202190 or overexpression of a dominant negative p38 mutant do not inhibit phosphorylation of Stat1 or Stat3 on Ser-727 in several IFNalpha-sensitive cell lines. Altogether these data demonstrate that the Rac1/p38 MAP kinase signaling cascade plays a critical role in type I IFN signaling, functioning in cooperation with the Stat-pathway, to regulate transcriptional regulation of IFNalpha-sensitive genes and generation of growth inhibitory responses.
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PMID:The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. 1087 8

It is well established that engagement of the Type I interferon (IFN) receptor results in activation of JAKs (Janus kinases), which in turn regulate tyrosine phosphorylation of STAT proteins. Subsequently, the IFN-dependent tyrosine-phosphorylated/activated STATs translocate to the nucleus to regulate gene transcription. In addition to tyrosine phosphorylation, phosphorylation of Stat1 on serine 727 is essential for induction of its transcriptional activity, but the IFNalpha-dependent serine kinase that regulates such phosphorylation remains unknown. In the present study we provide evidence that PKC-delta, a member of the protein kinase C family of proteins, is activated during engagement of the Type I IFN receptor and associates with Stat1. Such an activation of PKC-delta appears to be critical for phosphorylation of Stat1 on serine 727, as inhibition of PKC-delta activation diminishes the IFNalpha- or IFNbeta-dependent serine phosphorylation of Stat1. In addition, treatment of cells with the PKC-delta inhibitor rottlerin or the expression of a dominant-negative PKC-delta mutant results in inhibition of IFNalpha- and IFNbeta-dependent gene transcription via ISRE or GAS elements. Interestingly, PKC-delta inhibition also blocks activation of the p38 MAP kinase, the function of which is required for IFNalpha-dependent transcriptional regulation, suggesting a dual mechanism by which this kinase participates in the generation of IFNalpha responses. Altogether, these findings indicate that PKC-delta functions as a serine kinase for Stat1 and an upstream regulator of the p38 MAP kinase and plays an important role in the induction of Type I IFN-biological responses.
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PMID:Protein kinase C-delta (PKC-delta ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727. 1183 38