PKR Pathway
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PKR Pathway

PKR (Protein kinase-R) is a ubiquitously expressed serine-threonine kinase that has been implicated as a signal integrator in translational and transcriptional control pathways. PKR mediates apoptosis induced by many different stimuli, such as LPS (Lipopolysaccharides), Ifn-Gamma (Interferon-Gamma), cytokines, growth factor, viral infection, or serum starvation. PKR activity is regulated by external signals, which act on proteins, which interact with PKR. Among the proteins identified so far are p58, a cellular protein, K3L, the product of a gene of vaccinia virus, PACT (Protein Activator Of Interferon-Induced Protein Kinase) and p67, an interferon-induced glycoprotein (Ref.1). Human PKR is 68 kDa with a 20 kDa N-terminal dsRBD (dsRNA-Binding Domain) and a C-terminal protein kinase domain. The dsRBD is composed of two copies of the dsRNA-binding motif (dsRBM I and dsRBM II), a sequence motif found in many dsRNA-binding proteins. These proteins bind dsRNA in a largely sequence-independent fashion and are involved in a myriad of biological processes, such as RNA editing, RNA trafficking, RNA processing and transcriptional and translational regulation. Binding of RNA to the PKR dsRBD causes a conformational change in the enzyme that alters the ATP-binding site in the kinase domain and leads to autophosphorylation at multiple serine and threonine residues throughout the PKR sequence. As a vital component of the cellular antiviral response pathway, PKR is autophosphorylated and activated on binding to dsRNA. Once the protein binds dsRNA it is phosphorylated by the enzyme PP1 (Protein phosphatase-1) that allows for the dimerization of PKR. This phosphorylated dimer is the active form of PKR. Once activated, PKR has the ability to phosphorylate the protein eIF2Alpha (Eukaryotic Initiation Factor-Alpha). eIF2Alpha is a translation initiation factor that is only funtional in its non-phosphorylated form. PKR phosphorylates serine 51 of eIF2Alpha, leading to limitations in functional eIF2, a concomitant inhibition of mRNA translation initiation, and repression of cell growth. In addition, PKR has been shown to participate in transcriptional regulation of the E-selectin and immunoglobulin Kappa light chain genes (Ref.2). Besides, it also controls the activation of several transcription factors such as NF-KappaB (Nuclear Factor-KappaB), p53, or STATs (Signal Transducer and Activator of Transcription). Along with RNaseL, PKR constitutes the antiviral arm of a group of mammalian stress response proteins that have counterparts in yeast.

Cytokines and bacterial products activate PKR through upstream activators that could be kinases or other types of protein activators. Bacterial products or cellular stress activates PKR by an endogenous gene product called PACT. The binding of PACT to PKR promotes conformational changes that allow PKR to activate the downstream substrates, including the B56-Alpha subunit of PP2A (Protein Phosphatase 2A) and the Alpha subunit of initiation factor eIF2 (Ref.3). Transcriptional control is mediated by PKR interactions with signaling modules of either the stress-activated protein kinase family (p38, JNK) or IKKs (I-KappaB Kinases). PKR-mediated signaling can also regulate transcription factors, including NF-KappaB, which are also activated by a variety of stimuli. PKR signals in the stress-activated protein kinase (p38) and JNK (c-Jun NH2-terminal kinase) pathways in response to extracellular signals acting through cell surface receptors results in activation of transcriptional factors (c-Fos, c-Jun and ATF2). The activity of the tumor suppressor p53 in cellular stress responses may also be subject to regulation by PKR, and the activation of the transcription factor IRF-1 (Interferon Regulatory Factor-1) is PKR dependent. The transcription factors STAT1 (Signal Transducer And Activator Of Transcription 1) and STAT3 can depend on PKR for DNA binding activity or for enhancing transcriptional activity by serine phosphorylation. PKR contributes to the increased expression of c-Fos and other immediate early genes in cells exposed to PDGF (Platelet-Derived Growth Factor) through the regulation of transcription factor STAT3 (Ref.4).

PKR has also been implicated in the control of splicing of the TNF-Alpha (Tumor Necrosis Factor-Alpha) mRNA in a kinase-dependent pathway. PKR also mediates apoptosis by regulating FADD (Fas Associated Death Domain), TRADD (TNFR-Associated Death Domain protein), and RIP (Receptor-Interacting Protein) leading to caspase activation. The requirement for PKR does not extend to stress stimuli that are not coupled to cell surface receptors, such as anisomycin, ultraviolet light, osmotic shock, arsenite, hydrogen peroxide, or heat shock. PKR has emerged as an important signaling mediator in a wide variety of cellular responses to extracellular stimuli. This kinase is not essential in most of these pathways, but is required for the maintenance and propagation of signals necessary to sustain balanced host responses in proinflammatory and apoptotic situations (Ref.5).