The catalytic activity of the eukaryotic initiation factor-2alpha kinase PKR is required to negatively regulate Stat1 and Stat3 via activation of the T-cell protein-tyrosine phosphatase.

Tyrosine phosphorylation of the transcription factors Stat1 and Stat3 is required for them to dimerize, translocate to the nucleus, and induce gene transcription. Nuclear Stat1 and Stat3 are dephosphorylated and deactivated by the T-cell protein-tyrosine phosphatase (TC-PTP), which facilitates the return of both proteins to the cytoplasm. The protein kinase PKR plays an important role in translational control through the modulation of eukaryotic initiation factor-2alpha phosphorylation.