title: Tyrosine phosphorylation acts as a molecular switch to full-scale activation of the eIF2alpha RNA-dependent protein kinase.
abstract: Phosphorylation of the alpha-subunit of translation eukaryotic initiation factor-2 (eIF2) leads to the inhibition of protein synthesis in response to diverse conditions of stress. Serine/threonine RNA-dependent protein kinase (PKR) is an eIF2alpha kinase family member induced by type I IFN and activated in response to dsRNA or virus infection. Herein, we demonstrate that human PKR is a dual specificity kinase phosphorylated at Y101, Y162 and Y293 in vitro and in vivo. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. Biologically, tyrosine phosphorylation of PKR mediates the antiviral and antiproliferative properties of the kinase through its ability to control translation. Our data demonstrate an important role of tyrosine phosphorylation in biochemical and biological processes caused or mediated by the activation of the eIF2alpha kinase PKR.
authors.affiliation: Lady Davis Institute for Medical Research, McGiIl University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada H3T 1E2.
authors.forename: Qiaozhu
authors.initials: Q
authors.lastname: Su
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Dionissios
authors.initials: D
authors.lastname: Baltzis
authors.forename: Li-Ke
authors.initials: LK
authors.lastname: Qu
authors.forename: Andrew Hoi-Tao
authors.initials: AH
authors.lastname: Wong
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D019892:eIF-2 Kinase