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

Written2012-03William 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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesregulatory subunit 83
PRKR
Alias_symbol (synonym)PKR
EIF2AK1
PPP1R83
Other aliasp68 kinase
PRKR,
HGNC (Hugo) EIF2AK2
LocusID (NCBI) 5610
Atlas_Id 41866
Location 2p22.2  [Link to chromosome band 2p22]
Location_base_pair Starts at 37105141 and ends at 37157047 bp from pter ( according to hg19-Feb_2009)  [Mapping EIF2AK2.png]
Local_order HEAT repeat containing 5B (HEATR5B); coiled-coil domain containing 75 (CCDC75); Eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2); sulfotransferase family member, cytosolic, 6B, member 1 (SULT6B1); ribosomal protein L31 pseudogene 16 (RPL31P16).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EIF2AK2 (2p22.2) / CEBPZ (2p22.2)EIF2AK2 (2p22.2) / PRKD3 (2p22.2)EIF2AK2 (2p22.2) / RMDN2 (2p22.2)
EIF2AK2 (2p22.2) / SULT6B1 (2p22.2)

DNA/RNA

 
  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 5'UTR. 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.

Protein

Note The protein product of the EIF2AK2 gene is typically referred to as PKR in the literature.
 
  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).
 
  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.
 
  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 (Alzheimer's, Huntington's and Parkinson's) 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

Note
  
Entity 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 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.
  
  
Entity Acute myelogenous leukemia (AML)
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.
  
  
Entity Acute lymphocytic leukemia (ALL)
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 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 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 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 5'Florourocil (5'FU) 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 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 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 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 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 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 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 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 Alzheimer's 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 5'UTR was found to be associated with Alzheimer's disease (Bullido et al., 2008).
Cytogenetics Alzheimer's associated EIF2AK2 SNP (C/T; rs2254958).
  
  
Entity Parkinson's 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 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 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 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.
  

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Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease.
Bando Y, Onuki R, Katayama T, Manabe T, Kudo T, Taira K, Tohyama M.
Neurochem Int. 2005 Jan;46(1):11-8.
PMID 15567511
 
Role of double-stranded RNA-activated protein kinase in human hematological malignancies.
Basu S, Panayiotidis P, Hart SM, He LZ, Man A, Hoffbrand AV, Ganeshaguru K.
Cancer Res. 1997 Mar 1;57(5):943-7.
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The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and activation, leading to G1 arrest.
Bennett RL, Pan Y, Christian J, Hui T, May WS Jr.
Cell Cycle. 2012 Jan 15;11(2):407-17. Epub 2012 Jan 15.
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Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase.
Berlanga JJ, Santoyo J, De Haro C.
Eur J Biochem. 1999 Oct;265(2):754-62.
PMID 10504407
 
PKR activity is required for acute leukemic cell maintenance and growth: a role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation.
Blalock WL, Grimaldi C, Fala F, Follo M, Horn S, Basecke J, Martinelli G, Cocco L, Martelli AM.
J Cell Physiol. 2009 Oct;221(1):232-41.
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The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex.
Bonnet MC, Daurat C, Ottone C, Meurs EF.
Cell Signal. 2006 Nov;18(11):1865-75. Epub 2006 Feb 28.
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PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex.
Bonnet MC, Weil R, Dam E, Hovanessian AG, Meurs EF.
Mol Cell Biol. 2000 Jul;20(13):4532-42.
PMID 10848580
 
Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease.
Bullido MJ, Martinez-Garcia A, Tenorio R, Sastre I, Munoz DG, Frank A, Valdivieso F.
Neurobiol Aging. 2008 Aug;29(8):1160-6. Epub 2007 Apr 8.
PMID 17420072
 
Reduction of double-stranded RNA-activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus.
Chen GG, Lai PB, Ho RL, Chan PK, Xu H, Wong J, Lau WY.
J Med Virol. 2004 Jun;73(2):187-94.
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Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias.
Chen JJ.
Blood. 2007 Apr 1;109(7):2693-9. (REVIEW)
PMID 17110456
 
Quantitative phosphoproteomics dissection of seven-transmembrane receptor signaling using full and biased agonists.
Christensen GL, Kelstrup CD, Lyngso C, Sarwar U, Bogebo R, Sheikh SP, Gammeltoft S, Olsen JV, Hansen JL.
Mol Cell Proteomics. 2010 Jul;9(7):1540-53. Epub 2010 Apr 2.
PMID 20363803
 
Structure 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, Campbell DG, Proud CG.
Eur J Biochem. 1987 Jul 15;166(2):357-63.
PMID 3609013
 
Prevention of the beta-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures.
Couturier J, Paccalin M, Morel M, Terro F, Milin S, Pontcharraud R, Fauconneau B, Page G.
J Neuroinflammation. 2011 Jun 23;8:72.
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The 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, Wong AH, Tam NW, Li S, Koromilas AE.
Oncogene. 1999 Apr 29;18(17):2690-702.
PMID 10348343
 
Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3.
Deb A, Zamanian-Daryoush M, Xu Z, Kadereit S, Williams BR.
EMBO J. 2001 May 15;20(10):2487-96.
PMID 11350938
 
Knockdown of PKR expression by RNAi reduces pulmonary metastatic potential of B16-F10 melanoma cells in mice: possible role of NF-kappaB.
Delgado Andre N, De Lucca FL.
Cancer Lett. 2007 Dec 8;258(1):118-25.
PMID 17936498
 
Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein.
Delhem N, Sabile A, Gajardo R, Podevin P, Abadie A, Blaton MA, Kremsdorf D, Beretta L, Brechot C.
Oncogene. 2001 Sep 13;20(41):5836-45.
PMID 11593389
 
A quantitative atlas of mitotic phosphorylation.
Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP.
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. Epub 2008 Jul 31.
PMID 18669648
 
The protein kinase PKR: a molecular clock that sequentially activates survival and death programs.
Donze O, Deng J, Curran J, Sladek R, Picard D, Sonenberg N.
EMBO J. 2004 Feb 11;23(3):564-71. Epub 2004 Jan 29.
PMID 14749731
 
Inhibition of activation of dsRNA-dependent protein kinase and tumour growth inhibition.
Eley HL, McDonald PS, Russell ST, Tisdale MJ.
Cancer Chemother Pharmacol. 2009 Mar;63(4):651-9. Epub 2008 Jun 14.
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Increased 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, Skipworth RJ, Deans DA, Fearon KC, Tisdale MJ.
Br J Cancer. 2008 Jan 29;98(2):443-9. Epub 2007 Dec 18.
PMID 18087277
 
Regulation of internal ribosome entry site-mediated translation by eukaryotic initiation factor-2alpha phosphorylation and translation of a small upstream open reading frame.
Fernandez J, Yaman I, Merrick WC, Koromilas A, Wek RC, Sood R, Hensold J, Hatzoglou M.
J Biol Chem. 2002 Jan 18;277(3):2050-8. Epub 2001 Oct 29.
PMID 11684693
 
PKR is activated in MDS patients and its subcellular localization depends on disease severity.
Follo MY, Finelli C, Mongiorgi S, Clissa C, Bosi C, Martinelli G, Blalock WL, Cocco L, Martelli AM.
Leukemia. 2008 Dec;22(12):2267-9. Epub 2008 May 22.
PMID 18496558
 
The chemotherapeutic drug 5-fluorouracil promotes PKR-mediated apoptosis in a p53-independent manner in colon and breast cancer cells.
Garcia MA, Carrasco E, Aguilera M, Alvarez P, Rivas C, Campos JM, Prados JC, Calleja MA, Esteban M, Marchal JA, Aranega A.
PLoS One. 2011;6(8):e23887. Epub 2011 Aug 24.
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Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action.
Garcia MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M.
Microbiol Mol Biol Rev. 2006 Dec;70(4):1032-60. (REVIEW)
PMID 17158706
 
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J; MGC Project Team.
Genome Res. 2004 Oct;14(10B):2121-7.
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Phosphorylation of initiation factor-2 alpha is required for activation of internal translation initiation during cell differentiation.
Gerlitz G, Jagus R, Elroy-Stein O.
Eur J Biochem. 2002 Jun;269(11):2810-9.
PMID 12047392
 
Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31.
Giagounidis AA, Germing U, Haase S, Hildebrandt B, Schlegelberger B, Schoch C, Wilkens L, Heinsch M, Willems H, Aivado M, Aul C.
Leukemia. 2004 Jan;18(1):113-9.
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Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.
Gil J, Alcami J, Esteban M.
Oncogene. 2000 Mar 9;19(11):1369-78.
PMID 10723127
 
Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31).
Green WB, Slovak ML, Chen IM, Pallavicini M, Hecht JL, Willman CL.
Leukemia. 1999 Dec;13(12):1960-71.
PMID 10602416
 
The role of PKR/eIF2? signaling pathway in prognosis of non-small cell lung cancer.
He Y, Correa AM, Raso MG, Hofstetter WL, Fang B, Behrens C, Roth JA, Zhou Y, Yu L, Wistuba II, Swisher SG, Pataer A.
PLoS One. 2011;6(11):e24855. Epub 2011 Nov 10.
PMID 22102852
 
Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma.
Hiasa Y, Kamegaya Y, Nuriya H, Onji M, Kohara M, Schmidt EV, Chung RT.
Am J Gastroenterol. 2003 Nov;98(11):2528-34.
PMID 14638359
 
Loss of PKR activity in chronic lymphocytic leukemia.
Hii SI, Hardy L, Crough T, Payne EJ, Grimmett K, Gill D, McMillan NA.
Int J Cancer. 2004 Apr 10;109(3):329-35.
PMID 14961569
 
Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord.
Hu JH, Zhang H, Wagey R, Krieger C, Pelech SL.
J Neurochem. 2003 Apr;85(2):432-42.
PMID 12675919
 
IFN-gamma-induced upregulation of Fcgamma-receptor-I during activation of monocytic cells requires the PKR and NFkappaB pathways.
Karehed K, Dimberg A, Dahl S, Nilsson K, Oberg F.
Mol Immunol. 2007 Jan;44(4):615-24. Epub 2006 Mar 3.
PMID 16516295
 
Alternative 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, Kuhen KL, Vessey JW, George CX, Samuel CE.
Virology. 1999 Nov 10;264(1):106-14.
PMID 10544135
 
A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.
Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H.
Mol Cell. 2001 Feb;7(2):283-92.
PMID 11239457
 
Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR.
Kim SH, Forman AP, Mathews MB, Gunnery S.
Oncogene. 2000 Jun 22;19(27):3086-94.
PMID 10871861
 
Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR.
Kim SH, Gunnery S, Choe JK, Mathews MB.
Oncogene. 2002 Dec 12;21(57):8741-8.
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Systematic and quantitative assessment of the ubiquitin-modified proteome.
Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
Mol Cell. 2011 Oct 21;44(2):325-40. Epub 2011 Sep 8.
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Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2alpha. Role of the alpha- and delta-subunits of eiF2b.
Kimball SR, Fabian JR, Pavitt GD, Hinnebusch AG, Jefferson LS.
J Biol Chem. 1998 May 22;273(21):12841-5.
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CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha.
Koschmieder S, D'Alo F, Radomska H, Schoneich C, Chang JS, Konopleva M, Kobayashi S, Levantini E, Suh N, Di Ruscio A, Voso MT, Watt JC, Santhanam R, Sargin B, Kantarjian H, Andreeff M, Sporn MB, Perrotti D, Berdel WE, Muller-Tidow C, Serve H, Tenen DG.
Blood. 2007 Nov 15;110(10):3695-705. Epub 2007 Aug 1.
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Tight 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, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG.
Mol Cell Biol. 2001 Aug;21(15):5018-30.
PMID 11438658
 
Mechanism 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, Samuel CE.
Virology. 1999 Feb 1;254(1):182-95.
PMID 9927585
 
Structural organization of the human gene (PKR) encoding an interferon-inducible RNA-dependent protein kinase (PKR) and differences from its mouse homolog.
Kuhen KL, Shen X, Carlisle ER, Richardson AL, Weier HU, Tanaka H, Samuel CE.
Genomics. 1996 Aug 15;36(1):197-201.
PMID 8812437
 
Mechanism 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, Vessey JW, Samuel CE.
J Virol. 1998 Dec;72(12):9934-9.
PMID 9811730
 
Expression of double-stranded RNA-activated protein kinase (PKR) and its prognostic significance in lymph node negative rectal cancer.
Kwon HC, Moon CH, Kim SH, Choi HJ, Lee HS, Roh MS, Hwang TH, Kim JS, Kim HJ.
Jpn J Clin Oncol. 2005 Sep;35(9):545-50. Epub 2005 Sep 7.
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An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2alpha phosphorylation.
Lee YY, Cevallos RC, Jan E.
J Biol Chem. 2009 Mar 13;284(11):6661-73. Epub 2009 Jan 8.
PMID 19131336
 
The 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, O'Hara EB, Trieselmann BA, Romano PR, Dever TE.
J Biol Chem. 1999 Nov 5;274(45):32198-203.
PMID 10542257
 
Evidence of molecular links between PKR and mTOR signalling pathways in Abeta neurotoxicity: role of p53, Redd1 and TSC2.
Morel M, Couturier J, Pontcharraud R, Gil R, Fauconneau B, Paccalin M, Page G.
Neurobiol Dis. 2009b Oct;36(1):151-61. Epub 2009 Jul 23.
PMID 19631745
 
A point mutation in the RNA-binding domain I results in decrease of PKR activation in acute lymphoblastic leukemia.
Murad JM, Tone LG, de Souza LR, De Lucca FL.
Blood Cells Mol Dis. 2005 Jan-Feb;34(1):1-5.
PMID 15607693
 
Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.
Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS.
Cell. 2010 Feb 5;140(3):338-48.
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Biochemical analysis of the eIF2beta gamma complex reveals a structural function for eIF2alpha in catalyzed nucleotide exchange.
Nika J, Rippel S, Hannig EM.
J Biol Chem. 2001 Jan 12;276(2):1051-6.
PMID 11042214
 
Transcriptional upregulation of interferon-induced protein kinase, PKR, in breast cancer.
Nussbaum JM, Major M, Gunnery S.
Cancer Lett. 2003 Jul 10;196(2):207-16.
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Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.
Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M.
Sci Signal. 2010 Jan 12;3(104):ra3.
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An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer's disease.
Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T, Tohyama M, Taira K.
EMBO J. 2004 Feb 25;23(4):959-68. Epub 2004 Feb 5.
PMID 14765129
 
Role 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, Keeble W, Diaz J, Christianson TA, Fagerlie S, Rathbun K, Faulkner GR, O'Dwyer M, Bagby GC Jr.
Blood. 2001 Mar 15;97(6):1644-52.
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Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.
Paquet C, Bose A, Polivka M, Peoc'h K, Brouland JP, Keohane C, Hugon J, Gray F.
J Neuropathol Exp Neurol. 2009 Feb;68(2):190-8.
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Prognostic significance of RNA-dependent protein kinase on non-small cell lung cancer patients.
Pataer A, Raso MG, Correa AM, Behrens C, Tsuta K, Solis L, Fang B, Roth JA, Wistuba II, Swisher SG.
Clin Cancer Res. 2010 Nov 15;16(22):5522-8. Epub 2010 Oct 7.
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Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice.
Peel AL, Bredesen DE.
Neurobiol Dis. 2003 Oct;14(1):52-62.
PMID 13678666
 
Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue.
Peel AL, Rao RV, Cottrell BA, Hayden MR, Ellerby LM, Bredesen DE.
Hum Mol Genet. 2001 Jul 15;10(15):1531-8.
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PKR activation in neurodegenerative disease.
Peel AL.
J Neuropathol Exp Neurol. 2004 Feb;63(2):97-105. (REVIEW)
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Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis.
Pervin S, Tran AH, Zekavati S, Fukuto JM, Singh R, Chaudhuri G.
Cancer Res. 2008 Jun 15;68(12):4862-74.
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Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.
Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR.
EMBO J. 2000 Jan 17;19(2):263-72.
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Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis.
Roberts WK, Hovanessian A, Brown RE, Clemens MJ, Kerr IM.
Nature. 1976a Dec 2;264(5585):477-80.
PMID 1004583
 
Expression of double-stranded RNA-activated protein kinase in small-size peripheral adenocarcinoma of the lung.
Roh MS, Kwak JY, Kim SJ, Lee HW, Kwon HC, Hwang TH, Choi PJ, Hong YS.
Pathol Int. 2005 Nov;55(11):688-93.
PMID 16271080
 
Autophosphorylation 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, Garcia-Barrio MT, Zhang X, Wang Q, Taylor DR, Zhang F, Herring C, Mathews MB, Qin J, Hinnebusch AG.
Mol Cell Biol. 1998 Apr;18(4):2282-97.
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PKR regulates B56(alpha)-mediated BCL2 phosphatase activity in acute lymphoblastic leukemia-derived REH cells.
Ruvolo VR, Kurinna SM, Karanjeet KB, Schuster TF, Martelli AM, McCubrey JA, Ruvolo PP.
J Biol Chem. 2008 Dec 19;283(51):35474-85. Epub 2008 Oct 28.
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An antiviral response directed by PKR phosphorylation of the RNA helicase A.
Sadler AJ, Latchoumanin O, Hawkes D, Mak J, Williams BR.
PLoS Pathog. 2009 Feb;5(2):e1000311. Epub 2009 Feb 20.
PMID 19229320
 
Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53.
Sakaguchi K, Sakamoto H, Lewis MS, Anderson CW, Erickson JW, Appella E, Xie D.
Biochemistry. 1997 Aug 19;36(33):10117-24.
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Protein kinase R as mediator of the effects of interferon (IFN) gamma and tumor necrosis factor (TNF) alpha on normal and dysplastic hematopoiesis.
Sharma B, Altman JK, Goussetis DJ, Verma AK, Platanias LC.
J Biol Chem. 2011 Aug 5;286(31):27506-14. Epub 2011 Jun 9.
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Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control.
Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC.
Mol Cell Biol. 1998 Dec;18(12):7499-509.
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Aberrant expression of double-stranded RNA-dependent protein kinase in hepatocytes of chronic hepatitis and differentiated hepatocellular carcinoma.
Shimada A, Shiota G, Miyata H, Kamahora T, Kawasaki H, Shiraki K, Hino S, Terada T.
Cancer Res. 1998 Oct 1;58(19):4434-8.
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Interferons induce tyrosine phosphorylation of the eIF2alpha kinase PKR through activation of Jak1 and Tyk2.
Su Q, Wang S, Baltzis D, Qu LK, Raven JF, Li S, Wong AH, Koromilas AE.
EMBO Rep. 2007 Mar;8(3):265-70. Epub 2007 Feb 9.
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Phosphorylation 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, Ramachandran A, Ghosh S, Hasnain SE, Kaufman RJ, Ramaiah KV.
Biochemistry. 2000 Oct 24;39(42):12929-38.
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Upstream signaling pathways leading to the activation of double-stranded RNA-dependent serine/threonine protein kinase in beta-amyloid peptide neurotoxicity.
Suen KC, Yu MS, So KF, Chang RC, Hugon J.
J Biol Chem. 2003 Dec 12;278(50):49819-27. Epub 2003 Sep 15.
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Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain.
Taylor DR, Tian B, Romano PR, Hinnebusch AG, Lai MM, Mathews MB.
J Virol. 2001 Feb;75(3):1265-73.
PMID 11152499
 
Protein expression of double-stranded RNA-activated protein kinase in thyroid carcinomas: correlations with histologic types, pathologic parameters, and Ki-67 labeling.
Terada T, Maeta H, Endo K, Ohta T.
Hum Pathol. 2000a Jul;31(7):817-21.
PMID 10923918
 
Protein 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, Ueyama J, Ukita Y, Ohta T.
Liver. 2000b Dec;20(6):450-7.
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A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. Epub 2011 Sep 1.
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The 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, Samuel CE.
Virology. 2003 Sep 1;313(2):553-66.
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Coping with stress: eIF2 kinases and translational control.
Wek RC, Jiang HY, Anthony TG.
Biochem Soc Trans. 2006 Feb;34(Pt 1):7-11. (REVIEW)
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PKR; a sentinel kinase for cellular stress.
Williams BR.
Oncogene. 1999 Nov 1;18(45):6112-20. (REVIEW)
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Physical association between STAT1 and the interferon-inducible protein kinase PKR and implications for interferon and double-stranded RNA signaling pathways.
Wong AH, Tam NW, Yang YL, Cuddihy AR, Li S, Kirchhoff S, Hauser H, Decker T, Koromilas AE.
EMBO J. 1997 Mar 17;16(6):1291-304.
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The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR.
Xu Z, Williams BR.
Mol Cell Biol. 2000 Jul;20(14):5285-99.
PMID 10866685
 
The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader.
Yaman I, Fernandez J, Liu H, Caprara M, Komar AA, Koromilas AE, Zhou L, Snider MD, Scheuner D, Kaufman RJ, Hatzoglou M.
Cell. 2003 May 16;113(4):519-31.
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The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta).
Yang H, Park SH, Choi HJ, Moon Y.
Carcinogenesis. 2010b Apr;31(4):703-11. Epub 2010 Feb 3.
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The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells.
Yang X, Nath A, Opperman MJ, Chan C.
Mol Biol Cell. 2010a Oct 1;21(19):3449-58. Epub 2010 Aug 4.
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PKR, a p53 target gene, plays a crucial role in the tumor-suppressor function of p53.
Yoon CH, Lee ES, Lim DS, Bae YS.
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7852-7. Epub 2009 Apr 24.
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New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses.
Yoon CH, Miah MA, Kim KP, Bae YS.
EMBO Rep. 2010 May;11(5):393-9. Epub 2010 Apr 16.
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NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase.
Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BR.
Mol Cell Biol. 2000 Feb;20(4):1278-90.
PMID 10648614
 
Binding of double-stranded RNA to protein kinase PKR is required for dimerization and promotes critical autophosphorylation events in the activation loop.
Zhang F, Romano PR, Nagamura-Inoue T, Tian B, Dever TE, Mathews MB, Ozato K, Hinnebusch AG.
J Biol Chem. 2001 Jul 6;276(27):24946-58. Epub 2001 May 3.
PMID 11337501
 
The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR).
Zhang X, Li J, Sejas DP, Rathbun KR, Bagby GC, Pang Q.
J Biol Chem. 2004 Oct 15;279(42):43910-9. Epub 2004 Aug 6.
PMID 15299030
 
Expression of p68 protein kinase and its prognostic significance during IFN-alpha therapy in patients with carcinoid tumours.
Zhou Y, Gobl A, Wang S, Jacobsen MB, Janson ET, Haines GK 3rd, Radosevich JA, Oberg K.
Eur J Cancer. 1998 Dec;34(13):2046-52.
PMID 10070309
 
Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia.
van den Beucken T, Magagnin MG, Savelkouls K, Lambin P, Koritzinsky M, Wouters BG.
Radiother Oncol. 2007 Jun;83(3):346-52. Epub 2007 May 17.
PMID 17499866
 

Citation

This paper should be referenced as such :
Blalock, WL ; Cocco, L
EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(9):601-613.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/EIF2AK2ID41866ch2p22.html


External links

Nomenclature
HGNC (Hugo)EIF2AK2   9437
Cards
AtlasEIF2AK2ID41866ch2p22
Entrez_Gene (NCBI)EIF2AK2  5610  eukaryotic translation initiation factor 2 alpha kinase 2
AliasesEIF2AK1; PKR; PPP1R83; PRKR
GeneCards (Weizmann)EIF2AK2
Ensembl hg19 (Hinxton)ENSG00000055332 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000055332 [Gene_View]  chr2:37105141-37157047 [Contig_View]  EIF2AK2 [Vega]
ICGC DataPortalENSG00000055332
TCGA cBioPortalEIF2AK2
AceView (NCBI)EIF2AK2
Genatlas (Paris)EIF2AK2
WikiGenes5610
SOURCE (Princeton)EIF2AK2
Genetics Home Reference (NIH)EIF2AK2
Genomic and cartography
GoldenPath hg38 (UCSC)EIF2AK2  -     chr2:37105141-37157047 -  2p22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EIF2AK2  -     2p22.2   [Description]    (hg19-Feb_2009)
EnsemblEIF2AK2 - 2p22.2 [CytoView hg19]  EIF2AK2 - 2p22.2 [CytoView hg38]
Mapping of homologs : NCBIEIF2AK2 [Mapview hg19]  EIF2AK2 [Mapview hg38]
OMIM176871   
Gene and transcription
Genbank (Entrez)AF086566 AI360504 AK290655 AK313818 AY302136
RefSeq transcript (Entrez)NM_001135651 NM_001135652 NM_002759
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)EIF2AK2
Cluster EST : UnigeneHs.131431 [ NCBI ]
CGAP (NCI)Hs.131431
Alternative Splicing GalleryENSG00000055332
Gene ExpressionEIF2AK2 [ NCBI-GEO ]   EIF2AK2 [ EBI - ARRAY_EXPRESS ]   EIF2AK2 [ SEEK ]   EIF2AK2 [ MEM ]
Gene Expression Viewer (FireBrowse)EIF2AK2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5610
GTEX Portal (Tissue expression)EIF2AK2
Human Protein AtlasENSG00000055332-EIF2AK2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP19525   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP19525  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP19525
Splice isoforms : SwissVarP19525
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
PhosPhoSitePlusP19525
Domaine pattern : Prosite (Expaxy)DS_RBD (PS50137)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)dsRBD_dom    Kinase-like_dom    PKR    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)dsrm (PF00035)    Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00035    pfam00069   
Domain families : Smart (EMBL)DSRM (SM00358)  S_TKc (SM00220)  
Conserved Domain (NCBI)EIF2AK2
DMDM Disease mutations5610
Blocks (Seattle)EIF2AK2
PDB (SRS)1QU6    2A19    2A1A    3UIU   
PDB (PDBSum)1QU6    2A19    2A1A    3UIU   
PDB (IMB)1QU6    2A19    2A1A    3UIU   
PDB (RSDB)1QU6    2A19    2A1A    3UIU   
Structural Biology KnowledgeBase1QU6    2A19    2A1A    3UIU   
SCOP (Structural Classification of Proteins)1QU6    2A19    2A1A    3UIU   
CATH (Classification of proteins structures)1QU6    2A19    2A1A    3UIU   
SuperfamilyP19525
Human Protein Atlas [tissue]ENSG00000055332-EIF2AK2 [tissue]
Peptide AtlasP19525
HPRD01468
IPIIPI00019463   IPI00807398   IPI00385404   IPI00892809   
Protein Interaction databases
DIP (DOE-UCLA)P19525
IntAct (EBI)P19525
FunCoupENSG00000055332
BioGRIDEIF2AK2
STRING (EMBL)EIF2AK2
ZODIACEIF2AK2
Ontologies - Pathways
QuickGOP19525
Ontology : AmiGOactivation of MAPKK activity  positive regulation of cytokine production  RNA binding  double-stranded RNA binding  protein kinase activity  protein kinase activity  protein serine/threonine kinase activity  eukaryotic translation initiation factor 2alpha kinase activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytosol  ribosome  transcription, DNA-templated  translation  protein phosphorylation  negative regulation of cell proliferation  response to virus  response to toxic substance  regulation of translational initiation by eIF2 alpha phosphorylation  membrane  negative regulation of translation  negative regulation of translation  peptidyl-tyrosine phosphorylation  protein phosphatase regulator activity  evasion or tolerance by virus of host immune response  endoplasmic reticulum unfolded protein response  positive regulation of chemokine production  positive regulation of stress-activated MAPK cascade  negative regulation of osteoblast proliferation  cellular response to amino acid starvation  response to interferon-alpha  negative regulation of apoptotic process  negative regulation of viral genome replication  innate immune response  protein autophosphorylation  protein autophosphorylation  perinuclear region of cytoplasm  positive regulation of NF-kappaB transcription factor activity  defense response to virus  regulation of NLRP3 inflammasome complex assembly  positive regulation of NIK/NF-kappaB signaling  regulation of hematopoietic progenitor cell differentiation  regulation of hematopoietic stem cell proliferation  regulation of hematopoietic stem cell differentiation  
Ontology : EGO-EBIactivation of MAPKK activity  positive regulation of cytokine production  RNA binding  double-stranded RNA binding  protein kinase activity  protein kinase activity  protein serine/threonine kinase activity  eukaryotic translation initiation factor 2alpha kinase activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytosol  ribosome  transcription, DNA-templated  translation  protein phosphorylation  negative regulation of cell proliferation  response to virus  response to toxic substance  regulation of translational initiation by eIF2 alpha phosphorylation  membrane  negative regulation of translation  negative regulation of translation  peptidyl-tyrosine phosphorylation  protein phosphatase regulator activity  evasion or tolerance by virus of host immune response  endoplasmic reticulum unfolded protein response  positive regulation of chemokine production  positive regulation of stress-activated MAPK cascade  negative regulation of osteoblast proliferation  cellular response to amino acid starvation  response to interferon-alpha  negative regulation of apoptotic process  negative regulation of viral genome replication  innate immune response  protein autophosphorylation  protein autophosphorylation  perinuclear region of cytoplasm  positive regulation of NF-kappaB transcription factor activity  defense response to virus  regulation of NLRP3 inflammasome complex assembly  positive regulation of NIK/NF-kappaB signaling  regulation of hematopoietic progenitor cell differentiation  regulation of hematopoietic stem cell proliferation  regulation of hematopoietic stem cell differentiation  
Pathways : BIOCARTADouble Stranded RNA Induced Gene Expression [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    Regulation of eIF2 [Genes]    Toll-Like Receptor Pathway [Genes]    Bone Remodelling [Genes]   
Pathways : KEGGProtein processing in endoplasmic reticulum    Hepatitis C    Measles    Influenza A    Herpes simplex infection    Epstein-Barr virus infection    Viral carcinogenesis   
REACTOMEP19525 [protein]
REACTOME PathwaysR-HSA-169131 [pathway]   
NDEx NetworkEIF2AK2
Atlas of Cancer Signalling NetworkEIF2AK2
Wikipedia pathwaysEIF2AK2
Orthology - Evolution
OrthoDB5610
GeneTree (enSembl)ENSG00000055332
Phylogenetic Trees/Animal Genes : TreeFamEIF2AK2
HOVERGENP19525
HOGENOMP19525
Homologs : HomoloGeneEIF2AK2
Homology/Alignments : Family Browser (UCSC)EIF2AK2
Gene fusions - Rearrangements
Fusion : MitelmanEIF2AK2/CEBPZ [2p22.2/2p22.2]  
Fusion : MitelmanEIF2AK2/RMDN2 [2p22.2/2p22.2]  [t(2;2)(p22;p22)]  
Fusion: TCGAEIF2AK2 2p22.2 CEBPZ 2p22.2 BLCA BRCA
Fusion: TCGAEIF2AK2 2p22.2 FAM82A1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerEIF2AK2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EIF2AK2
dbVarEIF2AK2
ClinVarEIF2AK2
1000_GenomesEIF2AK2 
Exome Variant ServerEIF2AK2
ExAC (Exome Aggregation Consortium)ENSG00000055332
GNOMAD BrowserENSG00000055332
Genetic variants : HAPMAP5610
Genomic Variants (DGV)EIF2AK2 [DGVbeta]
DECIPHEREIF2AK2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisEIF2AK2 
Mutations
ICGC Data PortalEIF2AK2 
TCGA Data PortalEIF2AK2 
Broad Tumor PortalEIF2AK2
OASIS PortalEIF2AK2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICEIF2AK2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDEIF2AK2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch EIF2AK2
DgiDB (Drug Gene Interaction Database)EIF2AK2
DoCM (Curated mutations)EIF2AK2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)EIF2AK2 (select a term)
intoGenEIF2AK2
NCG5 (London)EIF2AK2
Cancer3DEIF2AK2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM176871   
Orphanet
MedgenEIF2AK2
Genetic Testing Registry EIF2AK2
NextProtP19525 [Medical]
TSGene5610
GENETestsEIF2AK2
Target ValidationEIF2AK2
Huge Navigator EIF2AK2 [HugePedia]
snp3D : Map Gene to Disease5610
BioCentury BCIQEIF2AK2
ClinGenEIF2AK2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5610
Chemical/Pharm GKB GenePA33779
Clinical trialEIF2AK2
Miscellaneous
canSAR (ICR)EIF2AK2 (select the gene name)
Probes
Litterature
PubMed324 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineEIF2AK2
EVEXEIF2AK2
GoPubMedEIF2AK2
iHOPEIF2AK2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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