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Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein

Fatima Lekmine1, Antonella Sassano, Shahab Uddin

  • 1Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Administration Medical Center, Chicago, IL 60611, USA.

Experimental Cell Research
|March 31, 2004
PubMed

Insights

Interferon-gamma (IFNgamma) receptor signaling activates phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and p70 S6 kinase to control protein synthesis. This pathway regulates mRNA translation essential for IFNgamma responses.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Immunology

Background:

  • The precise signaling mechanisms downstream of the Interferon-gamma (IFNgamma) receptor that regulate mRNA translation and protein production remain incompletely understood.
  • IFNgamma is a critical cytokine involved in immune responses, inflammation, and cell growth, necessitating a clear understanding of its signaling pathways.

Purpose of the Study:

  • To elucidate the IFNgamma-dependent signaling cascade involved in initiating mRNA translation and protein generation.
  • To identify the key molecular players and their roles in mediating IFNgamma responses downstream of its receptor.

Main Methods:

  • Utilized pharmacological inhibitors of PI 3-kinase and mTOR.
  • Employed double-knockout mouse embryonic fibroblasts lacking PI 3-kinase regulatory subunits.
  • Assessed phosphorylation of p70 S6 kinase, 40S S6 ribosomal protein, and 4E-BP1 using Western blotting and other biochemical assays.

Main Results:

  • Demonstrated rapid phosphorylation and activation of p70 S6 kinase upon IFNgamma receptor engagement.
  • Confirmed that PI 3-kinase and mTOR are essential for p70 S6 kinase activation.
  • Showed that IFNgamma-activated p70 S6 kinase phosphorylates 40S S6 ribosomal protein (Ser235/236) and 4E-BP1 (Thr37/46, Thr70, Ser65), facilitating mRNA translation initiation.

Conclusions:

  • Identified a novel IFNgamma signaling cascade involving PI 3-kinase, mTOR, and p70 S6 kinase.
  • Established that this pathway generates distinct signals regulating mRNA translation initiation.
  • Highlighted the significant role of this signaling cascade in mediating cellular responses to IFNgamma.

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