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 PKR Pathway

PKR, dsRNA-dependent serine/threonine protein kinase R, (P1 Kinase; P1/eIF-2alpha kinase; p68; p67; DAI, ds1, or TIK) responds to stress signals by modulating protein synthesis, cell survival status and gene expression. PKR is a central mediator of cellular responses to viral infection and/or environmental stress. Viral infections induce expression and secretion of interferon gamma (IFN-gamma) from host cells. IFNγ induces PKR. PKR is activated by double-stranded RNA (dsRNA) and/or protein kinase, interferon-inducible double stranded RNA dependent activator, PACT (RAX), which signal viral infection or cell stress, respectively. Brief PKR activation is anti-apoptotic. Prolonged PKR activation is pro-apoptotic.

Early stimulation of PKR inhibits apoptosis by inducing the release of NFkappaB (p50/p65) heterodimer from IkappaB. Prolonged stimulation of PKR inhibits the initiation of RNA translation by phosphorylating eIF2alpha (eIF2α component of the eIF2 initiation complex. Inhibition of protein translation and prolonged PKR activation induce apoptosis through a series of down-stream pathways: the release of NFkappaB (p50/cRel), a pro-apoptotic heterodimer; activation of protein phosphatase 2A (PP2A), activation of MAPK pathways, JNK and p38; down-regulation of p53, and inhibition of signal transducer and activator of transcription-1 and -3 (STAT1 and STAT3).