RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling.
The double-stranded (ds) RNA-dependent protein kinase (PKR) regulates protein synthesis by phosphorylating the alpha subunit of eukaryotic initiation factor-2. PKR is activated by viral induced dsRNA and thought to be involved in the host antiviral defense mechanism. PKR is also activated by various nonviral stresses such as growth factor deprivation, although the mechanism is unknown. By screening a mouse cDNA expression library, we have identified an ubiquitously expressed PKR-associated protein, RAX. RAX has a high sequence homology to human PACT, which activates PKR in the absence of dsRNA. Although RAX also can directly activate PKR in vitro, overexpression of RAX does not induce PKR activation or inhibit growth of interleukin-3 (IL-3)-dependent cells in the presence of IL-3. However, IL-3 deprivation as well as diverse cell stress treatments including arsenite, thapsigargin, and H2O2, which are known to inhibit protein synthesis, induce the rapid phosphorylation of RAX followed by RAX-PKR association and activation of PKR. Therefore, cellular RAX may be a stress-activated, physiologic activator of PKR that couples transmembrane stress signals and protein synthesis.
Ito
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T
Sealy Center for Oncology and Hematology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston Texas 77555-1048, USA. tito@utmb.edu
Yang
M
M
May
W S
WS
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism*
D002352:Carrier Proteins; D007377:Interleukin-3; C119610:Prkra protein, mouse; D011500:Protein Synthesis Inhibitors; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D010768:Phosphoserine; D019892:eIF-2 Kinase