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  • Original Paper
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Activation of the IκBα kinase (IKK) complex by double-stranded RNA-binding defective and catalytic inactive mutants of the interferon-inducible protein kinase PKR

Oncogene volume 20, pages 1900–1912 (2001)Cite this article

Abstract

The interferon (IFN)-inducible double stranded (ds) RNA-activated protein kinase PKR plays an important role in protein synthesis by modulating the phosphorylation of the α-subunit of eukaryotic initiation fact 2 (eIF-2α). In addition to translational control, PKR has been implicated in several signaling pathways leading to gene transcription. For example, PKR induces IκBα kinase (IKK) activity and IκBα phosphorylation leading to the induction of NF-κB-mediated gene transcription. Recent findings suggested that NF-κB activation by PKR does not require the catalytic activity of the kinase. Here, we provide novel evidence that induction of IKK and NF-κB activities proceeds independently of the dsRNA-binding properties of PKR and also verify the kinase-free role of PKR in this process. We also show that the effects of PKR mutants on IKK and NF-κB activation are independent of cell transformation but are dependent on the amount of the mutant PKR proteins expressed in cells. These data strongly support an indirect role of PKR in IκBα phosphorylation by modulating IKK activity through pathways that do not utilize the enzymatic and dsRNA-binding properties of PKR.

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Acknowledgements

We thank A Darveau and GN Barber for the anti-human PKR E8 antibody; AR Cuddihy for the construction of pEF-PKR expression vectors; R Lin for the GST-full length wt IκBα and serines 32 and 36 mutant IκBα fusion proteins; C Heylbroeck for the IKK2 K44A mutant; M Mathews for PKRLS4 and PKRLS9 cDNAs; N Sonenberg for eIF2α-S51A expressing NIH3T3 cells; S Richard for ras transformed NIH3T3 cells; A Veillette for pBABE/puro; N Beauchemin for the ψ2 retroviral packaging cell line. Supported by a grant from the Canadian Foundation for AIDS Research (CanFAR) to AE Koromilas and National Institutes of Health (NIH) grant CA71705 to G Mosialos. H Kwon is supported by a FCAR studentship. AE Koromilas, and J Hiscott are members of the Terry Fox Molecular Oncology Group and recipients from the Canadian Institutes of Health Research (CIHR) of a senior scientist and a distinguished scientist award respectively.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    Tetsu Ishii, John Hiscott & Antonis E Koromilas

  2. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Hakju Kwon, John Hiscott & Antonis E Koromilas

  3. Department of Cell Biology and Anatomy, McGill University, Montreal, Quebec, Canada

    Antonis E Koromilas

  4. Department of Oncology, McGill University, Montreal, Quebec, Canada

    Antonis E Koromilas

  5. Fleming Bioresearch Center, Vari, Attiki, Greece

    George Mosialos

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Ishii, T., Kwon, H., Hiscott, J. et al. Activation of the IκBα kinase (IKK) complex by double-stranded RNA-binding defective and catalytic inactive mutants of the interferon-inducible protein kinase PKR. Oncogene 20, 1900–1912 (2001). https://doi.org/10.1038/sj.onc.1204267

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