EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2)

2012-03-01   William L Blalock , Lucio Cocco 

IGM-CNR, Bologna, Rizzoli Orthopedic Institute,via di Barbiano, 1\\\/10, 40136 Bologna, Italy (WLB); Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, Via Irnerio, 48 I-40126 Bologna, Italy (LC)

Identity

HGNC
LOCATION
2p22.2
LOCUSID
ALIAS
EIF2AK1,LEUDEN,PKR,PPP1R83,PRKR
FUSION GENES

DNA/RNA

Atlas Image
The stick diagram shows the splicing of the exons that compose PKR as well as confirmed and unconfirmed (suggested by cDNA libraries from the Mammalian Gene Collection (MGC) only) splicing products and the length of their resulting protein products. The coding sequence for PKR initiates in exon 3 at the 17th nucleotide. The coding sequence of PKR is 1656 base pairs; the individual exons contain the following coding nucleotides: exon 3 (1-118); exon 4 (119-240); exon 5 (241-389); exon 6 (390-516); exon 7 (517-593); exon 8 (594-687); exon 9 (688-722); exon 10 (723-785); exon 11 (786-908); exon 12 (909-1067); exon 13 (1068-1248); exon 14 (1249-1377); exon 15 (1378-1479); exon 16 (1480-1533); exon 17 (1534-1656).

Description

The EIF2AK2 gene spans approximately 50 kb and contains 17 exons. The coding sequence initiates in exon 3 (Kuhen et al., 1996).

Transcription

Key Promoter Elements: TATA-less (No TATA Box).
1. KCS (Kinase Conserved Sequence): Nucleotides -67 to -81 from the transcriptional start site. Required for basal expression utilizing Sp factors. Also required in combination with the ISRE for interferon-stimulated expression (Kuhen and Samuel, 1997; Kuhen et al., 1998; Kuhen and Samuel, 1999; Ward and Samuel, 2002).
2. ISRE (Interferon-stimulated response element): Nucleotides -50 to -62 from the transcriptional start site. Required for the interferon-inducible expression of EIF2AK2. Regulated by the binding of STAT1, STAT2 and IRF9 (Kuhen and Samuel, 1997; Kuhen and Samuel, 1999; Ward and Samuel, 2002; Ward and Samuel, 2003).
3. P53RE (p53 response element): Two p53RE domains were identified flanking the ISRE. Acts to enhance EIF2AK2 expression following genotoxic stress (Yoon et al., 2009).

Transcripts:
Three (3) transcripts have been identified based on alternate splicing of exon 1 with exon 2 in the 5UTR. No change to the protein is observed with these transcripts (Kawakubo et al., 1999).
One (1) alternately spliced transcript (Tissue: Placenta) resulting in the loss of exon 12 (Gerhard et al., 2004).
One (1) alternately spliced transcript (Tissue: Brain/Lung) resulting in the loss of exon 11 (Gerhard et al., 2004).
One (1) transcript (Tissue: Brain) which results from an alternate splice acceptor site in exon 17 (Gerhard et al., 2004).

Pseudogene

None.

Proteins

Note

The protein product of the EIF2AK2 gene is typically referred to as PKR in the literature.
Atlas Image
The primary amino acid sequence of PKR. The alternate exons to which the individual amino acids belong are indicated by shading. Translation of PKR initiates in exon 3 and terminates in exon 17.

Description

EIF2AK2/PKR is a 551 amino acid protein with a predicted molecular weight of 62,1 kDa (68-72 kDa in SDS-PAGE) and a predicted pI of 8,58. PKR first described as an interferon-inducible antiviral kinase which phosphorylated eIF2-alpha on Ser 51, is now best described as a general stress/inflammatory kinase which phosphorylates an increasing list of substrates which includes eIF2-alpha (Colthurst et al., 1987), p53 (Cuddihy et al., 1999), B56-alpha (Xu and Williams, 2000), cyclin dependent kinase (CDK)-1 (Yoon et al., 2010), and vinsulin receptor substrate-1 (Nakamura et al., 2010).
Atlas Image
The primary protein structure for PKR. Key domains of the protein and the amino acids that compose them are shown, as are the key phosphorylation site(s) which are required for kinase activity (T451) (Romano et al., 1998; Zhang et al., 2001) or enhance kinase activity (Y101, Y162, S242, T255, T258, Y293 and T446) (Romano et al., 1998; Alisi et al., 2005; Su et al., 2006).

Expression

Ubiquitous.

Localisation

Cytoplasm, nuclear, nucleolar.
Atlas Image
Post-translational modification. (Taylor et al., 2001)a; (Su et al., 2006)b; (Romano et al., 1998)c; (Alisi et al., 2005)d; (Zhang et al., 2001)e; (Olsen et al., 2010)f; (Dephoure et al., 2008)g; (CST Curation Set Data available from Phosphosite Plus at http://www.phosphosite.org)h; (Christensen et al., 2010)i; (Kim et al., 2011)j; (Wagner et al., 2011)k.

Function

Major role
The double-stranded RNA dependent kinase (PKR) was initially identified as an innate immune anti-viral protein approximately 35 years ago (Roberts et al., 1976b; Roberts et al., 1976a). Since then PKR has been linked to normal cell growth and differentiation, inflammation, cytokine signaling and apoptosis (Garcia et al., 2006). Altered PKR activity has been shown to play a role in neurodegenerative diseases (Alzheimers, Huntingtons and Parkinsons) and cancer (Peel et al., 2001; Peel and Bredesen, 2003; Onuki et al., 2004; Peel, 2004; Bando et al., 2005; Eley et al., 2009). PKR belongs to the eIF2α kinase family which also includes PKR-like endoplasmic reticulum kinase (PERK), general amino acid control of gene expression, non-derepressing 2 (GCN2) and heme-regulated kinase (HRI). Whereas the activation of PERK, GCN2 and HRI are in response to more specific stresses; PKR is activated in response to diverse stress signals (Shi et al., 1998; Berlanga et al., 1999; Williams, 1999; Chen, 2007).
As the first known substrate of PKR was eIF2α, much of the research involving PKR has centered on its ability to regulate translation under varying conditions. Within the past ten years, PKR has been shown to play a significant role in signaling pathways involved in other cellular process such as cell proliferation, differentiation, metabolism, DNA repair and apoptosis (Garcia et al., 2006). Among the targets that PKR has been demonstrated to phosphorylate or directly influence the phosphorylation of are: p53, signal transducer and activators of transcription factors STAT1 and STAT3, inhibitor κB kinase (IKK)-β, inhibitor κB (IκB)-β, the B56α regulatory subunit of PP2A, and RNA helicase (Garcia et al., 2006; Sadler et al., 2009). In addition to these targets, PKR has been shown to influence signaling through the phosphatidylinositol-3 kinase (PI3K)/AKT pathway and transcription factors NF-κB, C/EBPα, C/EBPβ and ATF3. PKR also influences signaling through the MAPK signal transduction pathways. PKR activity is required for activation of p38MAPK and JNK in response to particular stresses, and signaling through these MAPKs is defective in PKR-/- cells. The PKR dependent mechanism involved in p38MAPK and JNK activation may involve the interaction of PKR with ASK1 or MKK6. Additionally, inhibition of protein synthesis may reduce the level of negative regulators of these kinases (Garcia et al., 2006).

Activation
PKR activation was originally thought to occur only in the presence of double-stranded RNA (ex. viral infection). Over time increasing evidence has indicated that PKR activation is induced by cytotoxic cytokines (tumor necrosis factor (TNF)-α and IFNγ), growth factor deprivation, oxidative stress and DNA damage (Garcia et al., 2006).
PKR is potentially serine/threonine and tyrosine phosphorylated on 105 different sites (54 Ser, 33 Thr and 18 Tyr), including 15 suspected autophosphorylation sites. Of these, only 8 sites have so far been identified, and their significance to PKR activation determined. Phosphorylation of Thr451 in the catalytic domain of PKR is required for minimal kinase activity (Romano et al., 1998; Zhang et al., 2001). An additional phosphorylation of PKR on Thr446 serves to augment PKR activity (Romano et al., 1998; Alisi et al., 2005).
In addition to Thr446/451 phosphorylation, phosphorylation on three key tyrosine residues (Tyr101/162/293) is also required for maximal PKR activity (Su et al., 2006). In cell culture, PKR appears to be constitutively tyrosine phosphorylated, but the exact tyrosine sites that are phosphorylated have not been determined nor has the kinase(s) responsible for these phosphorylations. PKR kinase assays using wild-type eIF2α or mutants Ser51Thr or Ser51Tyr revealed that PKR could phosphorylate the residue at position 51 equally (Lu et al., 1999). One suggestion is that PKR possess tyrosine kinase ability and is able to autophosphorylate (Lu et al., 1999). This is supported by the finding that a catalytically-inactive mutant (K296R) of PKR is not tyrosine phosphorylated in vitro and in vivo (Su et al., 2006). More recent, findings indicate PKR is associated with JAK1 and TYK2 kinases in resting cells. Following interferon stimulation, exogenously expressed JAK1 and TYK2 were demonstrated to phosphorylate Tyr101 and Tyr293 (Su et al., 2007). Similarly the catalytic mutant of PKR was also tyrosine phosphorylated by the JAK kinases. As tyrosine phosphorylation of PKR in response to dsRNA is not affected in cells deficient in JAK kinases, other tyrosine kinases may potentially phosphorylate these sites in response to different stresses (Su et al., 2007). The role of PKR as a non-receptor tyrosine kinase remains controversial.

eIF2α
In order to properly initiate translation, the eIF2 complex must hydrolyze GTP to GDP in the presence of Met-tRNA and the 40S ribosomal subunit. Efficient recycling of the complex then involves the removal of GDP and the re-loading of GTP to the eIF2 complex; a process carried-out by the GTP-exchange factor, eIF2B (Kimball et al., 1998). Phosphorylation of the eIF2α subunit turns the eIF2 complex into a competitive inhibitor. Those eIF2 complexes containing phosphorylated eIF2α demonstrate increased affinity for eIF2B and associate, blocking the eIF2 complex in the GDP bound state (Krishnamoorthy et al., 2001). As the eIF2 complex is in excess of eIF2B, a small amount of phosphorylated eIF2α can result in a shut-off of general translation (Kimball et al., 1998; Sudhakar et al., 2000; Krishnamoorthy et al., 2001; Nika et al., 2001; Wek et al., 2006). The inhibition of general translation is mainly thought to be pro-apoptotic, but recent evidence has suggested that this may be a cellular defense mechanism against stresses (Wek et al., 2006).
Phosphorylation of eIF2α results in a shut-off of general translation but at the same time allows for efficient translation of uORFs in particular mRNAs, such as ATF4, due to their 5 structure; or through what is termed internal ribosome entry site (IRES)-mediated translation (Fernandez et al., 2002; Gerlitz et al., 2002; Yaman et al., 2003). Many of these mRNAs encode proteins involved in the stress response (Koschmieder et al., 2007; van den Beucken et al., 2007; Lee et al., 2009). Short-term inhibition of general translation through eIF2α phosphorylation may in fact be pro-survival by allowing for cellular repair following a particular stress (Donze et al., 2004).

p53
PKR was shown to phosphorylate cytoplasmic p53 on Ser392 enhancing p53 tetramer stability and transcriptional activation of p53 targeted genes (Sakaguchi et al., 1997; Cuddihy et al., 1999; Keller et al., 2001). Among these are p21Cip1, BAX, PUMA and several pro-caspases. The implications of this phosphorylation are a PKR-mediated cell cycle arrest and induction of apoptosis. Inhibition of constitutive PKR activity in several acute leukemia cells lines with a small molecule inhibitor has been observed to lead to p53 degradation (Unpublished results). Although the exact mechanism for p53 degradation has not been determined, it likely involves the activation of AKT, whose phosphorylation and activity are observed to increase, and AKT effects upon MDM2 (Blalock et al., 2009). Additionally, the cellular PKR activator RAX/PACT was demonstrated to result in increased cellular levels of p53, p53 transcriptional activity and growth arrest in a PKR dependent manner (Bennett et al., 2012). Expression of a siRNA to RAX, which blocks the ability of most stresses to activate PKR, resulted in the decreased expression of several p53 regulated genes such as p21Cip1 and PUMA and lower constitutive levels of p53. RAX resulted in the SUMOylation of p53 in a PKR independent manner, through direct interaction and activation of the E2 ligase Ubc9 (Bennett et al., 2012).

NF-κB
PKR association with inhibitor κB kinase (IKK) was demonstrated to induce NF-κB nuclear translocation and transcriptional activity (Gil et al., 2000; Zamanian-Daryoush, et al., 2000). While initially PKR kinase activity was implicated in the activation of NF-κB, PKR catalytic activity is not a requirement. Truncated forms of PKR consisting of the amino terminus were shown to associate with the IKK complex and stimulate IκBβ phosphorylation (Bonnet et al., 2000; Bonnet et al., 2006). Later, Donze et al. showed that PKR irregardless of catalytic activity could induce NF-κB activation and the synthesis of some NF-κB dependent transcripts, but NF-κB activity and transcription of other NF-κB dependent genes was greatly potentiated when PKR kinase activity remained intact (Donze et al., 2004). These data suggest that both PKR association with IKK and PKR catalytic activity are important for PKR mediated effects on NF-κB. To this end the current understanding is that PKR activity is required for the full effects of PKR on NF-κB, although whether PKR catalytic activity influences NF-κB activation at the point of IκB phosphorylation and release or at later points, has not been sorted-out.

STATs
PKR has also been demonstrated to affect the transactivation of STATs 1 and 3 (Karehed et al., 2007). STAT1 activity is enhanced by phosphorylation on Ser727. Phosphorylation of this site is defective in PKR-/- fibroblasts resulting in a decrease of STAT1 transactivation (Ramana et al., 2000). PKR kinase activity is not necessary for PKR effects on STAT1 (Wong et al., 1997); instead, PKR associates through its NH2-terminus with STAT1, which apparently enhances mitogen activated protein kinase (MAPK)-mediated phosphorylation of STAT1 on Ser727 (Deb et al., 2001). Similar to STAT1, PKR has also been demonstrated to be required for proper phosphorylation and transactivation of STAT3. Like STAT1, PKR effects were mediated through MAPK-dependent phosphorylation of STAT3 (Deb et al., 2001). In the absence of PKR, activation of STAT3 by platelet derived growth factor (PDGF) is impaired (Deb et al., 2001).

PP2A
PKR was shown in a yeast-two hybrid system to associate with B56α in a manner dependent on PKR catalytic activity. PKR phosphorylated B56α at multiple sites in vitro (among these Ser28) leading to enhanced PP2A activity (Xu and Williams, 2000). The enhancement of PP2A activity via PKR phosphorylation of B56α resulted in decreased phosphorylation of eIF4E and a lower rate of translation. More recently additional effects of PKR on PP2A activity have been observed. The lymphocytic leukemia cell line REH contains both elevated levels of active PKR and a BCL2 targeted phosphatase activity. PKR was shown to phosphorylate B56α on Ser28 in REH cells which led to PP2A targeting to the mitochondria and dephosphorylation of BCL2 (Ruvolo et al., 2008). PKR activity was also shown to stabilize B56α, but this stabilization was not dependent on Ser28 phosphorylation but instead on eIF2α phosphorylation.

CDK1
Yoon et al. demonstrated that during genotoxic stress PKR is responsible for phosphorylating Cdc2 (CDK1) on Tyr4. Phosphorylation at this site was shown to result in ubiquitination and proteosomal degradation of Cdc2 thus resulting in a G2 arrest (Yoon et al., 2010).

IRS-1
PKR was found to link chronic inflammatory responses to metabolic signaling through the phosphorylation of the insulin response substrate (IRS)-1 on Ser312. Phosphorylation at this site inhibits the phosphorylation of key tyrosine residues required for insulin induced signaling (Nakamura et al., 2010; Yang et al., 2010a).

Homology

H. sapiens: (100%)
P. troglodytes: (98%)
C. lupus: (55%)
B. taurus: (62%)
M. musculus: (58%)
R. norvegicus: (51%)
G. gallus: (39%)
D. rerio: (30%)

Mutations

Note

Although the 2p22-p21 locus is often rearranged in leukemia no data supports these alterations affecting EIF2AK2.
A single nucleotide mutation was documented in a single pediatric T-ALL patient. The mutation occurred in the first double-stranded RNA binding domain and resulted in a protein that could not be activated by polyI:C (Murad et al., 2005).
In a murine model of chronic lymphocytic leukemia (CLL), a rearrangement in one locus of EIF2AK2 results in the deletion of 550 nucleotides and the production of a truncated protein with dominant-negative activity (Abraham et al., 1998).

Germinal

None.

Somatic

- DNA: nt50 (A to G); Protein: aa17 (Tyr to Cys); Source: Pediatric T-ALL; Influence on pathology not determined.
- DNA: nt1872 (C to G); Protein: aa439 (Leu to Val); Source: adenocarcinoma; Influence on pathology not determined.

Single Nucleotide Polymorphisms
SNP analysis revealed V428E (T1840A; source unknown), I506V (A2073G; source unknown).
Additional polymorphisms (1084) identified in the genomic sequence in the locus of EIF2AK2 can be found at PheGenI.

Implicated in

Entity name
Myelodysplastic syndromes (MDS)
Note
The presence of phospho-T451 PKR (p-T451 PKR) is slightly elevated in the cytoplasm of bone-marrow mononuclear cells (BMMC) from low-risk/INT-1 MDS patients. In contrast, BMMCs from INT-2/high-risk MDS patients show an enhanced presence of p-T451 PKR with primarily nuclear localization (Follo et al., 2008).
Inhibition of PKR kinase activity or expression reverses the suppressive effects of IFNγ and TNFα on colony formation from CD34+ hematopoietic progenitors and increases hematopoietic colony formation from human isolated MDS progenitors (Sharma et al., 2011).
Loss of PKR expression is observed in 5q- and 5q:31-33 myelodysplasias (Green et al., 1999; Giagounidis et al., 2004).
Disease
Bone marrow failure disorder.
Prognosis
The presence of p-T451 PKR in the cytoplasm is associated with low-risk disease.
The presence of p-T451 PKR in the nucleus is associated with high-risk disease and thus an enhanced probability of progression to acute myelogenous leukemia (AML).
Loss of PKR in 5q- and 5q32-33 myelodysplasias is associated with low-risk disease, while loss of PKR in 5q31 myelodysplasias with complex cytogenetics is associated with high-risk disease.
Oncogenesis
Progression to acute myelogenous leukemia.
Entity name
Fanconi anemia (FA)
Note
PKR activity is constitutively elevated in bone marrow cells from Fanconi anemia patients and cells lines and contributes to the hypersensitivity of these cells to TNFα and IFNγ (Pang et al., 2001; Zhang et al., 2004). Inhibition of PKR activity by either expressing a dominant negative PKR kinase or a dominant-negative form of the cellular PKR activator RAX/PACT (S18A) reduces apoptosis and sensitivity to TNFα and IFNγ (Pang et al., 2001; Bennett et al., 2006).
Disease
Bone marrow failure disorder.
Prognosis
Unknown.
Oncogenesis
Progression to acute myelogenous leukemia.
Note
PKR is overexpressed in blasts from AML patients, and is a functional kinase (Basu et al., 1997). AML derived cell lines contain elevated levels of p-T451 PKR as compared to control peripheral blood lymphocytes (Blalock et al., 2009). AML cell lines were highly dependent on PKR activity for cell maintenance as treatment of the cells with the commercial PKR inhibitor resulted in cell cycle arrest and cell death (Blalock et al., 2009).
Disease
Cancer; myelo-/monocytic leukemia.
Prognosis
Unknown.
Oncogenesis
Contributes to cancer cell maintenance.
Note
PKR is overexpressed in blasts from ALL patients, and is a functional kinase (Basu et al., 1997). T-ALL derived cell lines contain elevated levels of p-T451 PKR as compared to control peripheral blood lymphocytes (Blalock et al., 2009). T-ALL cell lines were highly dependent on PKR activity for cell maintenance as treatment of the cells with the commercial PKR inhibitor resulted in cell cycle arrest (Blalock et al., 2009).
A somatic point mutation was detected in the coding region of dsRNA-binding domain I (coding nucleotide 50 (A to G); amino acid Y17C) of PKR in a patient with T-ALL. Although activation of the mutant PKR kinase by polyI:C was impaired, the exact role of this mutation in the T-ALL was not determined (Murad et al., 2005).
Disease
Cancer; T-cell derived lymphoblastic leukemia.
Prognosis
Unknown.
Cytogenetics
Somatic point mutation in the coding region of dsRNA-binding domain I (coding nucleotide 50 (A to G); amino acid Y17C); Source: T-ALL.
Oncogenesis
Contributes to cancer cell maintenance.
Entity name
Chronic lymphocytic leukemia (CLL)
Note
PKR mRNA is underexpressed in CLL as compared to controls, and the kinase is inactive due to the presence of a soluble cellular inhibitor (Basu et al., 1997; Hii et al., 2004).
Disease
Cancer; B-cell lymphocytic leukemia.
Prognosis
Unknown.
Entity name
Lung carcinoma
Note
Elevated phospho-T446 PKR and/or p-S51 eIF2α were associated with longer median survival in patients with non-small cell lung cancer (NSCLC). Combinations of p-PKR/PKR expression or p-eIF2α/PKR expression were valuable prognostic markers for survival (Pataer et al., 2010; He et al., 2011). Lower levels of PKR expression though correlated with aggressive tumor behavior, increased lymph node metastasis and shorter survival in the patients (Pataer et al., 2010).
In contrast to NSCLC, a high level of PKR expression was associated with shorter overall survival in patients with small-size lung adenocarcinomas (Roh et al., 2005).
Disease
Cancer; Non-small cell lung cancer (NSCLC) and small cell adenocarcinoma of the lung.
Prognosis
PKR expression and activation as determined by immunocytochemistry (p-T446 PKR) are associated with a positive prognosis in NSCLC.
PKR expression in small-size lung adenocarcinomas is associated with a poor prognosis.
Oncogenesis
Low levels of PKR expression favor aggressive behavior and metastasis in NSCLC.
Entity name
Breast carcinoma
Note
Breast carcinoma cells contain elevated PKR protein and activity (7-40 fold) as compared to controls (Kim et al., 2000; Nussbaum et al., 2003). Stimulation of the PKR promoter ISRE is responsible for enhanced PKR expression (Nussbaum et al., 2003).
Elevated PKR activity is further linked to macrophage-migration inhibitory factor (MIF) expression which favors breast cancer cell growth, but also sensitizes breast cancer cells to PKR-mediated killing as the system is already primed (Armstrong et al., 2008; Pervin et al., 2008).
PKR may assist in the therapeutic response of 5Florourocil (5FU) in p53-null breast cancer (Garcia et al., 2011).
Disease
Cancer; breast.
Prognosis
Unknown.
Oncogenesis
Activated PKR may promote growth of breast carcinoma cells.
Entity name
Colon carcinoma
Note
Elevated PKR expression and activity are associated with progressive transformation from normal mucosa to adenoma and colon carcinoma (Kim et al., 2002).
The activation state of PKR also influences the drug sensitivity of colon cancer cells (Yoon et al., 2009; Yang et al., 2010b; Garcia et al., 2011).
Disease
Cancer; colon adenoma and colon carcinoma.
Prognosis
Unknown; associated with progressive transformation and drug-sensitivity.
Oncogenesis
Progressive transformation to adenomas or carcinomas.
Entity name
Melanoma
Note
Melanomas contain elevated levels of PKR protein, p-S51 eIF2α and PKR activity as compared to controls (Kim et al., 2002). PKR was highly expressed in melanoma lymph node metastasis (Kim et al., 2002). Knock-down of PKR mRNA and protein in B16-F10 melanoma tumor cells using shRNA led to decreased metastatic nodes in mice (Delgado Andre and De Lucca, 2007).
Disease
Cancer; skin (melanoma).
Prognosis
Elevated PKR activity associated with disease progression and metastasis.
Oncogenesis
Elevated PKR expression and activity are associated with metastasis.
Entity name
Thyroid cancer
Note
PKR is overexpressed in 90% of thyroid cancers, and its expression is higher in papillary versus nonpapillary carcinoma. Elevated PKR expression was associated with vascular invasion and satellite tumor nodules. PKR expression was linked to a low proliferative activity of the tumor (Terada et al., 2000a).
Disease
Cancer; thyroid.
Prognosis
Unknown.
Oncogenesis
Increased invasiveness and satellite tumor formation.
Entity name
Pancreatic cancer
Note
PKR is upregulated during interferon treatment of pancreatic cancer where lower PKR expression predicted a shorter anti-cancer response and length of survival following IFN treatment (Zhou et al., 1998).
Disease
Cancer; neuroendocrine.
Prognosis
Enhanced expression is associated with a favorable outcome to interferon therapy. Could represent a prognostic indicator.
Oncogenesis
Role uncharacterized.
Entity name
Gastric cancer
Note
Levels of phosphorylated forms of PKR and eIF2α were elevated in the rectus abdominus muscle of oesophago-gastric cancer patients as compared to control (Eley et al., 2008).
Disease
Cancer-related cachexia.
Prognosis
Poor; Phospho-PKR and Phospho-eIF2α are associated with muscle wasting.
Entity name
Rectal carcinoma
Note
PKR protein expression is associated with smaller sized tumors, a lower relapse rate and greater 5-year disease-free and overall survival (Kwon et al., 2005).
Disease
Cancer; lymph node negative rectal carcinoma.
Prognosis
Favorable; PKR expression is associated with a lower relapse rate and higher disease free and overall survival.
Oncogenesis
Role uncharacterized.
Entity name
Hepatocellular carcinoma (HCC)
Note
PKR mRNA and protein are overexpressed and PKR kinase activity enhanced in hepatocellular carcinoma (Hiasa et al., 2003; Alisi et al., 2005). PKR protein levels were observed to increase in bile duct tissue during progression to carcinoma, and this increase was associated with duct inflammation and duct cell proliferation (Terada et al., 2000b). Increased PKR expression was associated with both chronic hepatitis and HCC (Shimada et al., 1998). Importantly, elevated PKR expression is associated with better differentiated HCC and cholangiocarcinoma (Shimada et al., 1998; Terada et al., 2000b).
The core protein of hepatitis C virus (HCV), a major contributor to HCC, was seen to bind to and activate PKR (pT446) in HCC cells and tissue (Delhem et al., 2001; Alisi et al., 2005). In contrast, hepatitis B virus infected HCC liver tissue showed decreased PKR expression as determined by real-time PCR and immunohistochemistry and no association between the status of tumor differentiation was observed (Chen et al., 2004).
Disease
Cancer; hepatocellular carcinoma (HCC) HCV-associated HCC, HBV-associated HCC.
Oncogenesis
Expression increases with progression toward HCC but is associated with better differentiated tumors (except in HBV-associated HCC).
Entity name
Alzheimers disease
Note
Phospho-PKR accumulates in the nuclei of AD brain tissue (Onuki et al., 2004). Neurons from AD patient brains contain elevated levels of p-T446 and/or T451 PKR, and p-S51 eIF2α (Peel and Bredesen, 2003; Suen et al., 2003) and treatment of cell lines with Aβ peptide results in PKR activation, eIF2α phosphorylation and the co-localization of p-PKR with Redd1 and FADD in the nucleus (Suen et al., 2003; Morel et al., 2009b; Couturier et al., 2010a).
Phospho-PKR is associated with phospho-Tau and phospho-p38 in AD brain (Peel and Bredesen, 2003). Inhibition of PKR attenuates inflammation as well as TNFα, IL-1α, IL-1β, IL-6 expression and apoptosis stimulated by Aβ peptide (Couturier et al., 2010b; Couturier et al., 2011).
Elevated levels of p-PKR, p-eIF2α and secretion of TNFα, IL-1α, IL-1β and IL-6 are observed in peripheral blood mononuclear cells from AD patients (Morel et al., 2009a; Couturier et al., 2010b).
Disease
Neurodegenerative.
Prognosis
The presence of elevated p-PKR in brain neuronal tissue is an indicator of cellular stress and degeneration. Possible disease indicator.
An EIF2AK2 SNP (C/T; rs2254958) at position 250 in the 5UTR was found to be associated with Alzheimers disease (Bullido et al., 2008).
Cytogenetics
Alzheimers associated EIF2AK2 SNP (C/T; rs2254958).
Entity name
Parkinsons disease (PD)
Note
Hippocampal neurons from PD patients contain elevated levels of nuclear p-T446 PKR (Bando et al., 2005).
Disease
Neurodegenerative.
Prognosis
Unknown.
Entity name
Huntington chorea
Note
PKR binds CAG repeats in mutated Huntington transcripts. Affected Huntington tissues contain elevated levels of p-PKR (active) with a particular increase in the nuclei of hippocampal neurons (Peel et al., 2001; Bando et al., 2005).
Disease
Neurodegenerative.
Prognosis
Unknown.
Entity name
Creutzfeldt-Jakob disease (CJD)
Note
Neuronal tissue (frontal, occipital, temporal cortex, striatum and cerebellum) from CJD patients contained elevated levels of p-T451 PKR localized exclusively to the nucleus. The levels of p-T451 PKR were associated with apoptosis, spongiosis, astrocytosis and disease severity (Paquet et al., 2009).
Disease
Neurodegenerative.
Prognosis
The levels of p-T451 PKR are associated with disease severity in CJD patients.
Entity name
Amyotrophic lateral sclerosis (ALS)
Note
The presence of p-T451 PKR increases in spinal cord tissue from ALS patients 2600% (cytosolic) and 3300% (particulate) as compared to controls (Hu et al., 2003).
Disease
Neurodegenerative.
Prognosis
Unknown.

Bibliography

Pubmed IDLast YearTitleAuthors
98067901998The murine PKR tumor suppressor gene is rearranged in a lymphocytic leukemia.Abraham N et al
158804552005Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells.Alisi A et al
184907112008Small interfering RNAs induce macrophage migration inhibitory factor production and proliferation in breast cancer cells via a double-stranded RNA-dependent protein kinase-dependent mechanism.Armstrong ME et al
155675112005Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease.Bando Y et al
90411991997Role of double-stranded RNA-activated protein kinase in human hematological malignancies.Basu S et al
222146622012The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G₁ arrest.Bennett RL et al
105044071999Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase.Berlanga JJ et al
195071912009PKR activity is required for acute leukemic cell maintenance and growth: a role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation.Blalock WL et al
166005702006The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex.Bonnet MC et al
108485802000PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex.Bonnet MC et al
174200722008Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease.Bullido MJ et al
151227912004Reduction of double-stranded RNA-activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus.Chen GG et al
171104562007Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias.Chen JJ et al
203638032010Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists.Christensen GL et al
36090131987Structure and regulation of eukaryotic initiation factor eIF-2. Sequence of the site in the alpha subunit phosphorylated by the haem-controlled repressor and by the double-stranded RNA-activated inhibitor.Colthurst DR et al
216997262011Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures.Couturier J et al
103483431999The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.Cuddihy AR et al
113509382001Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3.Deb A et al
179364982007Knockdown of PKR expression by RNAi reduces pulmonary metastatic potential of B16-F10 melanoma cells in mice: possible role of NF-kappaB.Delgado André N et al
115933892001Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein.Delhem N et al
186696482008A quantitative atlas of mitotic phosphorylation.Dephoure N et al
147497312004The protein kinase PKR: a molecular clock that sequentially activates survival and death programs.Donzé O et al
185530832009Inhibition of activation of dsRNA-dependent protein kinase and tumour growth inhibition.Eley HL et al
180872772008Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2alpha may signal skeletal muscle atrophy in weight-losing cancer patients.Eley HL et al
116846932002Regulation of internal ribosome entry site-mediated translation by eukaryotic initiation factor-2alpha phosphorylation and translation of a small upstream open reading frame.Fernandez J et al
184965582008PKR is activated in MDS patients and its subcellular localization depends on disease severity.Follo MY et al
218873392011The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer cells.García MA et al
171587062006Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action.García MA et al
154893342004The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).Gerhard DS et al
120473922002Phosphorylation of initiation factor-2 alpha is required for activation of internal translation initiation during cell differentiation.Gerlitz G et al
145864792004Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31.Giagounidis AA et al
107231272000Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.Gil J et al
106024161999Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31).Green WB et al
221028522011The role of PKR/eIF2α signaling pathway in prognosis of non-small cell lung cancer.He Y et al
146383592003Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma.Hiasa Y et al
149615692004Loss of PKR activity in chronic lymphocytic leukemia.Hii SI et al
126759192003Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord.Hu JH et al
165162952007IFN-gamma-induced upregulation of Fcgamma-receptor-I during activation of monocytic cells requires the PKR and NFkappaB pathways.Kårehed K et al
105441351999Alternative splice variants of the human PKR protein kinase possessing different 5'-untranslated regions: expression in untreated and interferon-treated cells and translational activity.Kawakubo K et al
112394572001A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.Keller DM et al
108718612000Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR.Kim SH et al
124835272002Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR.Kim SH et al
219069832011Systematic and quantitative assessment of the ubiquitin-modified proteome.Kim W et al
95823121998Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2alpha. Role of the alpha- and delta-subunits of eiF2b.Kimball SR et al
176712352007CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha.Koschmieder S et al
114386582001Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation.Krishnamoorthy T et al
99275851999Mechanism of interferon action: functional characterization of positive and negative regulatory domains that modulate transcriptional activation of the human RNA-dependent protein kinase Pkr promoter.Kuhen KL et al
88124371996Structural organization of the human gene (PKR) encoding an interferon-inducible RNA-dependent protein kinase (PKR) and differences from its mouse homolog.Kuhen KL et al
98117301998Mechanism of interferon action: identification of essential positions within the novel 15-base-pair KCS element required for transcriptional activation of the RNA-dependent protein kinase pkr gene.Kuhen KL et al
161480232005Expression of double-stranded RNA-activated protein kinase (PKR) and its prognostic significance in lymph node negative rectal cancer.Kwon HC et al
191313362009An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation.Lee YY et al
105422571999The interferon-induced double-stranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2alpha.Lu J et al
196317452009Evidence of molecular links between PKR and mTOR signalling pathways in Abeta neurotoxicity: role of p53, Redd1 and TSC2.Morel M et al
156076932005A point mutation in the RNA-binding domain I results in decrease of PKR activation in acute lymphoblastic leukemia.Murad JM et al
201447592010Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.Nakamura T et al
110422142001Biochemical analysis of the eIF2beta gamma complex reveals a structural function for eIF2alpha in catalyzed nucleotide exchange.Nika J et al
128602792003Transcriptional upregulation of interferon-induced protein kinase, PKR, in breast cancer.Nussbaum JM et al
200682312010Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.Olsen JV et al
147651292004An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease.Onuki R et al
112381032001Role of double-stranded RNA-dependent protein kinase in mediating hypersensitivity of Fanconi anemia complementation group C cells to interferon gamma, tumor necrosis factor-alpha, and double-stranded RNA.Pang Q et al
191516232009Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.Paquet C et al
209300422010Prognostic significance of RNA-dependent protein kinase on non-small cell lung cancer patients.Pataer A et al
136786662003Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice.Peel AL et al
114682702001Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue.Peel AL et al
149895952004PKR activation in neurodegenerative disease.Peel AL et al
185595342008Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis.Pervin S et al
106372302000Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.Ramana CV et al
10045831976Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis.Roberts WK et al
162710802005Expression of double-stranded RNA-activated protein kinase in small-size peripheral adenocarcinoma of the lung.Roh MS et al
95287991998Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2alpha kinases PKR and GCN2.Romano PR et al
189574152008PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells.Ruvolo VR et al
192293202009An antiviral response directed by PKR phosphorylation of the RNA helicase A.Sadler AJ et al
92546081997Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53.Sakaguchi K et al
216595352011Protein kinase R as mediator of the effects of interferon (IFN) gamma and tumor necrosis factor (TNF) alpha on normal and dysplastic hematopoiesis.Sharma B et al
98194351998Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control.Shi Y et al
97666751998Aberrant expression of double-stranded RNA-dependent protein kinase in hepatocytes of chronic hepatitis and differentiated hepatocellular carcinoma.Shimada A et al
172902882007Interferons induce tyrosine phosphorylation of the eIF2alpha kinase PKR through activation of Jak1 and Tyk2.Su Q et al
110418582000Phosphorylation of serine 51 in initiation factor 2 alpha (eIF2 alpha) promotes complex formation between eIF2 alpha(P) and eIF2B and causes inhibition in the guanine nucleotide exchange activity of eIF2B.Sudhakar A et al
129753762003Upstream signaling pathways leading to the activation of double-stranded RNA-dependent serine/threonine protein kinase in beta-amyloid peptide neurotoxicity.Suen KC et al
111524992001Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain.Taylor DR et al
109239182000Protein expression of double-stranded RNA-activated protein kinase in thyroid carcinomas: correlations with histologic types, pathologic parameters, and Ki-67 labeling.Terada T et al
111690592000Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma.Terada T et al
218904732011A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.Wagner SA et al
129542212003The PKR kinase promoter binds both Sp1 and Sp3, but only Sp3 functions as part of the interferon-inducible complex with ISGF-3 proteins.Ward SV et al
162461682006Coping with stress: eIF2 kinases and translational control.Wek RC et al
105571021999PKR; a sentinel kinase for cellular stress.Williams BR et al
91351451997Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways.Wong AH et al
108666852000The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR.Xu Z et al
127577122003The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader.Yaman I et al
201300182010The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta).Yang H et al
206859592010The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells.Yang X et al
194168612009PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53.Yoon CH et al
203959572010New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses.Yoon CH et al
106486142000NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase.Zamanian-Daryoush M et al
113375012001Binding of double-stranded RNA to protein kinase PKR is required for dimerization and promotes critical autophosphorylation events in the activation loop.Zhang F et al
152990302004The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR).Zhang X et al
100703091998Expression of p68 protein kinase and its prognostic significance during IFN-alpha therapy in patients with carcinoid tumours.Zhou Y et al
174998662007Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia.van den Beucken T et al

Other Information

Locus ID:

NCBI: 5610
MIM: 176871
HGNC: 9437
Ensembl: ENSG00000055332

Variants:

dbSNP: 5610
ClinVar: 5610
TCGA: ENSG00000055332
COSMIC: EIF2AK2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000055332ENST00000233057P19525
ENSG00000055332ENST00000390013F8WBH4
ENSG00000055332ENST00000395127P19525
ENSG00000055332ENST00000405334P19525
ENSG00000055332ENST00000411537C9JZT2
ENSG00000055332ENST00000647926P19525

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
DiseaseREACTOMER-HSA-1643685
Infectious diseaseREACTOMER-HSA-5663205
Influenza InfectionREACTOMER-HSA-168254
Host Interactions with Influenza FactorsREACTOMER-HSA-168253
NS1 Mediated Effects on Host PathwaysREACTOMER-HSA-168276
Inhibition of PKRREACTOMER-HSA-169131
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Antiviral mechanism by IFN-stimulated genesREACTOMER-HSA-1169410
ISG15 antiviral mechanismREACTOMER-HSA-1169408

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
228014942012Novel role of PKR in inflammasome activation and HMGB1 release.247
174518622007The dsRNA protein kinase PKR: virus and cell control.244
164667632006Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA.155
1804868920075'-triphosphate-dependent activation of PKR by RNAs with short stem-loops.120
200068402009Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation.106
193535192009Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R.103
249920362014G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.96
230844762012Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.84
195157682009Ebola virus VP35 antagonizes PKR activity through its C-terminal interferon inhibitory domain.69
129449782003Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR.68

Citation

William L Blalock ; Lucio Cocco

EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version: http://atlasgeneticsoncology.org/gene/41866/eif2ak2-(eukaryotic-translation-initiation-factor-2-alpha-kinase-2)