Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_51


Historical Background

Protein kinase R (PKR) was identified through its function in regulating host protein synthesis during virus infection (Farrell et al. 1977; Metz and Esteban 1972). This regulation is enacted through phosphorylation of the eukaryotic initiation factor 2α (EIF2α), marking PKR as a member of a small kinase family that constitutes this universal stress response pathway in eukaryotes (Roberts et al. 1976). A number of additional protein substrates for PKR have been identified, although the consequence of this is not well characterized. The transcript’s cDNA was cloned and the genetic locus (EIF2AK2) was identified on human chromosome 2 (mouse chromosome 17). Expression was predicted by gene promoter elements and then confirmed biochemically to be regulated by type I and III interferon signaling and the p53 and nuclear factor κB (NF-κB) transcription factors (Meurs et al. 1990; Barber et al. 1993; Visvanathan and Goodbourn 1989; Yoon et al. 2009). This cemented PKR as an effector molecule for the innate immune response. The generation of transgenic mice that targeted the eIF2ak2 locus confirmed the role of PKR in resisting viral infection and identified that PKR also functioned independent of EIF2α phosphorylation by interacting with adaptor molecules to regulate innate immune cell signaling pathways (Yang et al. 1995; Abraham et al. 1999). PKR encodes tandem RNA-binding motifs (RBM) at its N-terminus that enable the molecule to recognize duplex RNA (Katze et al. 1991). The structures of the RBM and kinase domain of PKR have been determined, advancing our understanding of the kinase function and RNA recognition (Dar et al. 2005; Dey et al. 2005; Nanduri et al. 1998). In addition to binding to viral RNA, PKR recognizes endogenous transcripts to control the production of specific gene products (Ben-Asouli et al. 2002). The RBMs also function as a protein-protein interacting domain and a number of other proteins that encode RBMs are phosphorylated by PKR or regulate PKR activity. Accordingly, the RBM appears to coordinate the activity of different host proteins to regulate the response to extrinsic and intrinsic RNA. The precise mechanisms of activity and the biological consequences of PKR-dependent cell signaling are still emerging.

PKR Function

PKR function is predominantly associated with the antiviral response and numerous mechanisms have been identified by which viruses attempt to circumvent PKR activity in order to enable their replication. In keeping with this, defective PKR activity impairs the antiviral response and increases the susceptibility to otherwise innocuous viral infections. The best-characterized activity of PKR is the phosphorylation of EIF2α, which results in general inhibition of protein translation, although a subset of transcripts continues to be expressed or are paradoxically induced (Harding et al. 2000). Perturbation of this pathway through deletion of the separate EIF2α kinases, mutation of the phosphor residue on EIF2α or mutation of sequences in transcripts that enable escape from translational control have consequences other than for the antiviral response in murine models (Dar et al. 2005; Han et al. 2005; Oner et al. 1991; Kumar et al. 1997; Mundschau and Faller 1994; Yim et al. 2016). Moreover, genetic studies in humans have correlated polymorphisms in RNA elements that permit translational initiation in defiance of EIF2α phosphorylation with disorders and have identified mutations in the separate EIF2α kinases that cause disease. Although somatic mutations have been identified in tumors, there are no reports of familial defects in the EIF2AK2 locus and analysis suggests that genetic variance is not tolerated (Petrovski et al. 2013). In addition to inhibiting the translation of viral transcripts, phosphor control of EIF2α is associated with fundamental cellular processes such as ribosomal biogenesis, autophagy, and the formation of stress granules (Talloczy et al. 2002; Blalock et al. 2014). PKR activity has been demonstrated to regulate the differentiation and function of specific cell lineages such as osteoclasts and neurons that affect bone morphogenesis and the consolidation of memory (Yoshida et al. 2005; Zhu et al. 2011; Li et al. 2015). PKR activity has also been shown to promote cell signaling pathways associated with growth receptors and cytokine signaling and innate immune receptors (Horng et al. 2001; Deb et al. 2001; Kumar et al. 1997; Mundschau and Faller 1994). This latter activity has gained attention in the context of regulating cell survival and inflammation during microbial infection and other stress stimuli such as metabolic disturbance (Yim et al. 2016; Lu et al. 2012; Nakamura et al. 2010).

The PKR Protein Network

PKR function can be accounted for through its protein partners. Cellular proteins that have been reported to interact with PKR to convey cell signals are listed in Table 1. These interactions have been segregated into three functional categories in which the interacting proteins modify the activity of PKR, are substrates for the kinase, or are regulated by PKR without being directly phosphorylated. These relationships are not mutually exclusive, and some of these protein substrates also modify the activity of PKR.
PKR, Table 1

Proteins that interact with PKR as regulators of the kinase’s activity, as substrates, or that participate in cell-signaling associations are listed. Each protein and their abbreviations are described in the text



Cell-signaling integrators










































PKR Regulators

The very first PKR activator identified was RNA that binds at the protein’s amino-terminal RNA-binding domain, which is constituted by tandem RBMs. This domain recognizes double-stranded or single-stranded RNA with secondary structures and specific features of RNA, such as 5′-triphosphate moieties. RNA with these features is characteristic of virus replication. Some endogenous mRNAs also bind and modulate PKR activity. PKR has been demonstrated to restrict the production of the tumor protein/histamine-releasing factor TPT1 and the potent inflammatory tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) cytokines (Ben-Asouli et al. 2002; Osman et al. 1999; Bommer et al. 2002). Disease transcripts such as the mutant huntingtin transcript and noncoding transcripts, such as the noncoding T-cell transcript, also modulate PKR activity (Peel et al. 2001; Delgado Andre and De Lucca 2008).

A second activating ligand is heparin oligosaccharide. Heparin with eight or more sugar residues associates with residues within the protein’s kinase domain (Fasciano et al. 2005).

PKR has been demonstrated to respond to other nonprotein ligands, for instance lipid molecules such as ceramide. The mechanisms of these interactions are not well characterized and appear to be indirect, possibly via protein regulators. The PKR protein activator (PACT) directly activates PKR (Patel and Sen 1998). Accordingly, PKR’s response to stress stimuli, such as ceramide, may be mediated by PACT-dependent activation. The effect of this protein interaction appears to be context dependent, as PACT has also been demonstrated to, alternatively, inhibit PKR during human immunodeficiency virus 1 (HIV-1) infection and in the pituitary during development (Clerzius et al. 2013; Dickerman et al. 2015). PACT must first be phosphorylated by another kinase before activating PKR, which appears to induce oligomerization of PACT (Singh and Patel 2012).

A number of other proteins that encode RBMs also interact with and modulate PKR activity. The transactivation response RNA-binding protein-2 (TARBP2), which encodes three RBMs, inhibits PKR (Park et al. 1994). The dihydrouridine synthase 2-like protein (DUS2), which catalyzes the reduction of uridine residues on the displacement loop of transfer RNA, interacts with PKR to repress its activity (Mittelstadt et al. 2008). The adenosine deaminase acting on RNA-1 (ADAR1) which encodes two RBMs also inhibits PKR (Toth et al. 2006). The protein coded double-stranded RNA-binding protein DRBP120 interacts with PKR with undetermined consequence (Watanabe et al. 2006). Additional RBM-containing proteins are substrates for PKR (as discussed below).

Formation of the active dimeric PKR enzyme proceeds by autophosphorylation, and so, the enzyme can be repressed through dephosphorylation. The protein phosphatase-1 (PPP1C) has been demonstrated to inhibit PKR (Tan et al. 2002). Other PKR inhibitors are: the PKR-interacting protein-1 (PRKRIP1) (Yin et al. 2003); the mitochondrial ribosomal protein L18 (MRPL18), which sequesters the kinase to the ribosome (Kumar et al. 1999); the methionine aminopeptidase-2 (METAP2) (Gil et al. 2000); and two cytosolic chaperones, the heat-shock proteins (HSP) 70 and 90, regulate PKR (Donze et al. 2001). The association with HSP70 mediates an interaction between PKR and mutant Fanconi anemia proteins (directly with the complementation group C protein, FANCC) (Pang et al. 2002). A cochaperone of HSP70, DNAJC3 (or P58IPK), also acts as a PKR inhibitor (Polyak et al. 1996).

PKR is also activated by caspase-3, -7, and -8 through cleavage at the asparagine residue number 251 within the linker between the RNA-binding and kinase domains (Saelens et al. 2001). This cleavage has been proposed to relieve autoinhibition of the kinase domain by the amino-terminal RBMs.

Interferon signaling also directly modulates PKR activity. The signal transducer and activator of transcription (STAT) 1 and 3 associate with PKR (Wong et al. 1997; Shen et al. 2012). This association regulates the function of both PKR and the STAT proteins (Wen et al. 1995). Additionally, the ubiquitin (UB) family modifiers, which are induced by interferon, modulate the activity of PKR. PKR activity is repressed by both K48- and K63-linked ubiquitination following treatment of cells with lipopolysaccharide (Perkins et al. 2010). Alternatively, the small ubiquitin-like modifiers (SUMO)-1 and -2 and the ubiquitin-like interferon-stimulated gene 15 (ISG15) promote PKR activity (de la Cruz-Herrera et al. 2014; Okumura et al. 2013).

PKR Substrates

PKR is a serine, threonine and, less established, tyrosine protein kinase. As discussed above, the best-described PKR substrate is EIF2α. Phosphorylation of the serine residue 51 on EIF2α arrests translation of cap-dependent transcripts by sequestering its guanine nucleotide exchange factor EIF2B (Farrell et al. 1977). This translational block is not complete and a number of transcripts escape repression. Prominent among these escape transcripts are the activating transcription factors (ATFs), with the best example being the induction of ATF4. Biological processes regulated by ATF4 include redox processes, mitochondrial function, and secretory pathways regulated by protein chaperones and lipid synthesis machinery. In this way, EIF2α phosphorylation, with subsequent ATF4 induction, elicits a manifold response to mitigate stress. Hence, EIF2α phosphorylation is generally considered a protective response.

The consequence of PKR’s regulation of other substrates is less well established as the functions of the protein substrates themselves or the consequences of specific modified residues involved are poorly characterized. The various substrates are discussed below.

Nucleoplasmin family member-1 (NPM1) is a PKR substrate (Pang et al. 2003). NPM1 has been ascribed in a broad range of functions. Relevant to translational control, NPM1 has been demonstrated to mediate ribosomal protein assembly. Aberrant expression of NPM1 has been observed in numerous human malignancies. Although PKR-dependent effects on NPM1 function have not been identified, NPM1 has been shown to inhibit PKR.

Phosphorylation of PPP2R5A (also called B56α) by PKR has been demonstrated to inhibit this substrate (Xu and Williams 2000). As a consequence, PKR promotes the activity of the protein phosphatase 2 catalytic subunit (PP2A), which is controlled by PPP2R5A. As PP2A is a significant modulator of global phosphorylation, PKR-dependent control of its regulatory subunit is undoubtedly of biological significance. However, control of PP2A activity is complex, with multiple regulatory factors involved besides PPP2R5A. Moreover, there are three other cytosolic serine/threonine phosphatases, in addition to PP2A, that have a degree of overlapping substrate specificity. Hence, it is difficult to discern the specific effects of the regulation of PPP2R5A by PKR.

The mitogen-activated kinase MAP2K6 is reportedly phosphorylated by PKR (Silva et al. 2004). Regulation of MAP2K6 was proposed as the mechanism by which PKR affects the downstream mitogen-activated kinase MAPK14. However, the consequence of PKR-dependent control of MAP2K6 is uncertain, as the residues phosphorylated are not known to regulate kinase activity.

PKR has also been reported to phosphorylate the tumor suppressor  p53 at the serine residue 392 (Cuddihy et al. 1999). This is potentially very interesting because of the manifold responses regulated by p53. Phosphorylation of the 392 residue is dispensable for activation of p53 target genes. Consequently, PKR-dependent phosphorylation can only affect transactivation-independent p53 pathways. Modification of this residue has been shown to affect the stability of p53 by enhancing protein oligomerization. This appears to only be of consequence for the misfolded mutant p53, as modification of the 392 site has not been shown to alter the stability of the wild-type protein. Hence, PKR could regulate non-specific binding of mutant p53 to DNA structures associated with DNA repair and recombination. Phosphorylation at serine 392 has also been correlated with tumor development, and so, PKR-dependent control of p53 may contribute to tumor progression. Notably, EIF2AK2 is a P53 target gene (Yoon et al. 2009).

It has been asserted that serine residue number 307 of the insulin receptor substrate-1 (IRS1) is phosphorylated by PKR (Nakamura et al. 2010). This was advanced as a mechanism for an assertion that PKR induces insulin resistance. However, analysis of transgenic mice with a point mutation of the 307 residue in IRS1 demonstrated that phosphorylation of this residue maintains, rather than disturbs, insulin sensitivity. Interestingly, in light of PKR-dependent control of PP2A activity, the okadaic acid inhibitor of PP2A stimulated the mammalian target of rapamycin ( mTOR)-dependent phosphorylation of the serine 307 residue in IRS1. Consistent with this, the rapamycin inhibitor of mTOR reduced phosphorylation of 307 on IRS1. PKR has been demonstrated to influence the downstream effects of a second phosphatase that influences insulin signaling, the phosphatase and tensin homolog deleted from chromosome 10 ( PTEN). Translational control in response to PTEN is diminished in PKR-null cells. Hence, it appears as if PKR is activated in PTEN-dependent signaling. Coincidentally, PTEN has also been shown to dephosphorylate IRS1. PKR has also been reported to induce the expression of IRS2 (Yang et al. 2010). Accordingly, multiple potential mechanisms exist by which PKR might regulate insulin signaling.

Activation of PKR is mediated by autophosphorylation. Among the autophosphorylation sites identified are residues within the amino-terminal RBMs of PKR. In keeping with this substrate specificity, a number of other proteins that share the RBM are PKR substrates. PKR phosphorylates the RNA helicase A (RHA) within its RBM (Sadler et al. 2009). This phosphorylation inhibits the helicase’s association with its nucleic substrates and enables PKR to inhibit HIV-1 replication. The interleukin factor-3 (ILF3) is similarly phosphorylated within its RBMs (Langland et al. 1999). The consequence of this phosphorylation has not been identified. In addition, PKR associates with the spermatid perinuclear RNA-binding protein (STRBP) and the homologous double-stranded RNA-binding protein 76 (DRBP76). Although not reported as a substrate of PKR, STRBP was identified as being phosphorylated, at serine residues within its two RBMs. These RBM-containing proteins (RHA, ILF3, and STRBP) have been demonstrated to inhibit PKR activity, as was shown for the RBM-containing proteins TARBP2, ADAR1, and DUS2, which are not identified as substrates.

PKR Cell-Signaling Integrators

PKR participates in cell signals initiated from a variety of receptors that include Toll-like, interleukin-1, platelet-derived growth factor (PDGF), IFNγ, and the  TNFα receptors (Yang et al. 1995; Horng et al. 2001; Deb et al. 2001; Zamanian-Daryoush et al. 2000). Through these receptors, PKR modulates the activity of a number of transcription factors. The mechanism(s) by which PKR is integrated into these diverse signaling pathways has not been categorically established. Currently, evidence favors the involvement of the TNF receptor-associated factors (TRAFs). PKR encodes two TRAF-binding motifs within each of its structured domains (Gil et al. 2004). TRAF factors act as adaptor proteins and ubiquitin ligases. Through this activity, these proteins shape signaling complexes and regulate the stability of the protein components. Dependence upon TRAFs for PKR-dependent control correlates with the transcription factors activated:  NF-κB, c-jun, STAT1 and STAT3, and IFN-regulated factor-1 (IRF1). Furthermore, the association with TRAFs could account for other reported associations between PKR and signaling proteins: the I-κB kinases (IKKα and β), mitogen-activated protein kinase kinase kinase-7 (MAP3K7 or TAK1), TAK1-binding protein-2 (TAB2), the Toll/interleukin-1 (TIR) domain-containing adaptor protein (TIRAP), and the mitogen-activated protein kinase kinase kinase-5 (MAP3K5, or ASK1). Two alternatives have been proposed, by which PKR either modifies signaling components by phosphorylation or, alternatively, may act merely as a scaffold protein independent of its kinase activity. This latter point is supported by experiments that have shown that a kinase-dead PKR, mutated at the essential residue that catalyzes the transfer of the phosphate from ATP to the substrate, is competent to activate the NF-κB transcription factor (Bonnet et al. 2000).

The association with the heat shock proteins HSP90 and HSP70 present an alternative mechanism that could also account for PKR-dependent cell-signaling events. Like TRAFs, HSP90 interconnects with many of the pathways PKR is reported to regulate. HSP90 interacts with the NF-κB regulatory complex, STATs and p53. As HSP90 has been demonstrated to inhibit PKR, this interaction may support the contention that kinase activity is irrelevant in some PKR-dependent cell-signaling processes. HSP90 has been demonstrated to associate with a large number of other kinases, and so, has been suggested as a general regulator of the kinome.

PKR also interacts with and inhibits the activity of the calcium-regulated, actin-modifying protein gelsolin (GSN) (Irving et al. 2012). GSN activity is associated with cytoskeletal remodeling and inflammation, and so this association is anticipated to have broader impact on cell signaling.


The first recognized function of PKR was to combat viral infection via inhibition of protein translation. It is frequently written that the significance of PKR in the antiviral response is evident by the numerous viral inhibitors that target PKR. As is apparent from this discussion, a number of endogenous PKR regulators have been identified. This might also be taken to indicate a function for PKR in response to endogenous stimuli. Accordingly, PKR has been shown to respond to endogenous transcripts and other stress signals. Additional protein substrates, besides EIF2α, have been identified showing that PKR regulates other cellular processes. Moreover, PKR appears to modulate pathways independent of substrate phosphorylation. Together, these observations suggest a broader function for PKR outside of its regulation of protein translation and in functions other than the antiviral response, which remains to be clarified.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Cancer ResearchHudson Institute of Medical ResearchClaytonAustralia
  2. 2.Department of Molecular and Translational ScienceMonash UniversityClaytonAustralia