Control of mRNA translation is one of the major regulatory events in eukaryotic gene expression. Recent research has established the existence of a protein kinase family in mammalian cells, whose members phosphorylate the alpha (alpha) subunit of the eukaryotic initiation factor eIF2 (eIF2alpha) at serine 51 and regulate mRNA translation under various stress conditions. The interferon (IFN)-inducible double-stranded (ds) RNA-activated protein kinase PKR is the prototype of this family. Stress conditions activate PKR by autophosphorylation which leads to inhibition of global protein (including viral protein) synthesis and the apoptosis of infected cells. PKR has been well-characterized as a serine/threonine kinase. However, the tyrosine kinase property of PKR and its functional activity remains undetermined. This study demonstrates that human PKR possesses tyrosine kinase activity and undergoes autophosphorylation at tyrosine (Tyr) residues 101, 162 and 293 in vitro and in vivo. Phosphorylation at these tyrosine residues enhances dsRNA binding-efficiency as well as the dimerization of PKR, which in turn favours the full-scale kinase activation and its substrate phosphorylation. Biologically, tyrosine phosphorylated PKR mediates the anti-viral and cellular anti-proliferation activity of the enzyme through its ability to regulate protein synthesis. In addition, the IFNs modulate PKR at both the transcriptional and posttranslational level. Specifically, tyrosine phosphorylation of PKR is inducible in response to stimulations with IFNs. The Janus kinases (Jaks), a group of cytoplasmic tyrosine kinases, are the upstream enzymes which phosphorylate PKR at Tyr101 and Tyr293 in vitro and in vivo. Moreover, induction of PKR tyrosine phosphorylation by IFNs presents a critical missing link between IFN signaling and the translational machinery which contributes to the early effect of IFNs in inhibiting viral protein synthesis. Such a prompt reaction might allow cells to induce IFN responsive-genes and further fortify the antiviral state of the host.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103184 |
| Date | January 2006 |
| Creators | Su, Qiaozhu, 1965- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Microbiology and Immunology.) |
| Rights | © Qiaozhu Su, 2006 |
| Relation | alephsysno: 002585475, proquestno: AAINR32388, Theses scanned by UMI/ProQuest. |
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