Ser52
Javascript is not enabled on this browser. This site will not work properly without Javascript.
PhosphoSitePlus Homepage PhosphoSitePlus® v6.5.9.3
Powered by Cell Signaling Technology
Home > Phosphorylation Site Page: > Ser52  -  eIF2-alpha (human)

Site Information
MILLsELsRRRIRsI   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447635

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 53 ) , [32P] bio-synthetic labeling ( 59 , 61 ) , immunoprecipitation ( 4 , 6 , 10 , 12 , 13 , 59 , 61 ) , mass spectrometry ( 17 , 31 ) , mutation of modification site ( 4 , 5 , 7 , 10 , 13 , 14 , 28 , 32 , 38 , 44 , 45 , 49 , 56 , 58 , 59 , 60 , 61 ) , phospho-antibody ( 4 , 5 , 6 , 7 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 19 , 20 , 22 , 24 , 25 , 26 , 27 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 47 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ) , western blotting ( 4 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 19 , 20 , 22 , 24 , 25 , 26 , 27 , 30 , 32 , 33 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 50 , 52 , 54 , 56 , 60 )
Disease tissue studied:
adrenal cancer ( 52 ) , pheochromocytoma ( 52 ) , bone cancer ( 6 , 22 , 25 ) , breast cancer ( 20 , 28 ) , colorectal cancer ( 9 , 26 ) , colorectal carcinoma ( 9 , 26 ) , kidney cancer ( 35 ) , leukemia ( 41 ) , chronic myelogenous leukemia ( 41 ) , liver cancer ( 10 , 34 , 35 ) , hepatocellular carcinoma ( 10 ) , lung cancer ( 7 , 8 , 26 , 27 , 56 ) , non-small cell lung cancer ( 7 , 8 , 27 ) , non-small cell lung adenocarcinoma ( 7 , 8 ) , neuroblastoma ( 32 , 52 ) , ovarian cancer ( 9 ) , melanoma skin cancer ( 20 ) , fibrosarcoma of soft tissue ( 7 , 26 , 33 , 36 ) , tuberous sclerosis ( 35 )
Relevant cell line - cell type - tissue:
'muscle, skeletal' ( 18 ) , 293 (epithelial) [ACE2 (human), transfection] ( 30 ) , 293 (epithelial) ( 4 , 13 , 19 , 38 , 43 , 54 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 59 , 61 ) , 3T3 (fibroblast) ( 56 , 60 ) , A549 (pulmonary) ( 7 , 26 , 56 ) , A6 (renal) ( 16 ) , ADOR (pulmonary) ( 8 ) , AG01522 (fibroblast) ( 56 ) , BHK-21 (fibroblast) ( 5 ) , COS (fibroblast) ( 37 , 59 , 61 ) , fibroblast-lung ( 50 ) , glial ( 35 ) , HCT116 (intestinal) ( 9 , 26 ) , HEK293T (epithelial) ( 4 , 15 , 28 , 51 ) , HeLa (cervical) [PKR (human)] ( 39 ) , HeLa (cervical) ( 5 , 14 , 19 , 22 , 24 , 26 , 28 , 38 , 43 , 44 , 51 , 56 ) , Hep 3B2.1-7 (hepatic) ( 10 ) , HepG2 (hepatic) ( 34 ) , HT1080 (fibroblast) ( 7 , 26 , 33 , 36 , 53 ) , JB6 CI41 (epidermal) ( 40 ) , Jurkat (T lymphocyte) ( 31 , 41 ) , K562 (erythroid) ( 41 ) , kidney ( 35 ) , liver ( 10 , 17 , 35 ) , lymphoblastoid ( 15 ) , MCF-7 (breast cell) ( 28 ) , MEF (fibroblast) ( 4 , 7 , 9 , 11 , 14 , 20 , 35 , 43 , 44 , 56 ) , MEF (fibroblast) [IGF1R (mouse)] ( 49 ) , melanocyte-skin ( 55 ) , mononuclear-blood ( 5 ) , NCI-H1299 (pulmonary) ( 27 ) , NCI-H1975 (pulmonary) ( 8 ) , neuron-'brain, cerebellum' ( 52 ) , PC-12 (chromaffin) ( 52 ) , SF9 ( 45 ) , SH-SY5Y (neural crest) ( 32 , 52 ) , SK-MEL24 (melanocyte) ( 55 ) , SK-MEL5 (melanocyte) ( 55 ) , SKOV-3 (ovarian) ( 9 ) , T47D (breast cell) ( 20 ) , U2OS (bone cell) ( 6 , 22 , 25 ) , WM2664 (melanocyte) ( 20 )

Upstream Regulation
Regulatory protein:
ERK1 (human) ( 40 ) , ERK2 (human) ( 40 ) , GADD34 (human) ( 19 , 43 ) , NCK1 (human) ( 43 ) , NCK2 (human) ( 43 ) , OLA1 (human) ( 9 ) , P38A (human) ( 40 ) , PERK (human) ( 6 ) , PKR (human) ( 33 , 39 ) , PKR (mouse) ( 11 , 39 ) , PPP1R15B (human) ( 43 ) , Raptor (human) ( 14 ) , RHEB (human) ( 13 ) , RICTOR (human) ( 14 ) , XIAP (human) ( 26 )
Putative in vivo kinases:
PERK (human) ( 13 , 27 , 30 , 36 , 37 , 51 , 56 ) , PKR (human) ( 36 , 38 , 47 , 53 , 58 , 60 , 61 )
Kinases, in vitro:
ERK2 (human) ( 40 ) , HRI (human) ( 62 ) , P38A (human) ( 40 ) , PERK (human) ( 13 , 37 , 59 ) , PKR (human) ( 5 , 40 , 46 , 47 , 58 , 62 ) , RSK2 (human) ( 40 )
Putative upstream phosphatases:
PPP1CA (human) ( 43 )
Phosphatases, in vitro:
PPP1CA (human) ( 43 ) , PPP1CA (rabbit) ( 42 )
Treatments:
15-deoxyspergualin ( 41 ) , 2-deoxyglucose ( 26 , 29 ) , 6-OHDA ( 52 ) , A23187 ( 61 ) , afatinib ( 8 ) , amino_acid_starvation ( 34 ) , anisomycin ( 28 ) , arsenite ( 4 , 15 , 38 , 49 ) , cisplatin ( 25 ) , cobalt ( 56 ) , DMAT ( 32 ) , double-stranded_RNA ( 36 , 39 ) , DTT ( 38 , 54 ) , fasting ( 18 ) , glucose ( 57 ) , glucose_starvation ( 26 , 57 ) , H2O2 ( 7 , 15 ) , hyperoxia ( 50 ) , hypoxia ( 51 , 56 ) , hypoxia/reoxygenation ( 56 ) , IFN-alpha ( 55 ) , IFN-beta ( 30 ) , insulin ( 28 ) , LY294002 ( 23 , 33 ) , osmotic_stress ( 38 ) , ouabain ( 12 ) , oxaliplatin ( 25 ) , PD98059 ( 40 ) , PERK inhibitor 1 ( 6 ) , phorbol_ester ( 5 ) , pictilisib ( 23 ) , PKR_inhibitor ( 16 ) , rapamycin ( 14 ) , rotenone ( 32 ) , salubrinal ( 5 ) , SB202474 ( 40 ) , SB203580 ( 28 ) , sildenafil ( 8 ) , sorafenib ( 8 ) , thapsigargin ( 6 , 25 , 27 , 28 , 37 , 38 , 43 , 51 , 53 , 54 , 56 ) , TNF ( 39 ) , tunicamycin ( 32 , 38 , 43 , 54 ) , UV ( 38 , 40 ) , vanadate ( 19 ) , virus infection ( 30 , 33 , 37 )

Downstream Regulation
Effects of modification on eIF2-alpha:
activity, induced ( 44 , 58 ) , activity, inhibited ( 38 , 60 ) , molecular association, regulation ( 10 , 46 )
Effects of modification on biological processes:
apoptosis, induced ( 38 , 44 ) , apoptosis, inhibited ( 26 ) , autophagy, induced ( 14 ) , cell growth, altered ( 58 , 60 ) , RNA splicing, induced ( 5 ) , translation, altered ( 37 , 41 , 44 , 46 , 56 , 60 ) , translation, induced ( 7 , 28 ) , translation, inhibited ( 10 , 13 )
Induce interaction with:
CELF1 (human) ( 10 ) , PERK (human) ( 46 ) , eIF2-beta (human) ( 46 )

References 

1

Lu YN, et al. (2021) MARK2 phosphorylates eIF2α in response to proteotoxic stress. PLoS Biol 19, e3001096
33705388   Curated Info

2

Dejure FR, Butzer J, Lindemann RK, Mardin BR (2020) Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14. Oncotarget 11, 4490-4503
33400734   Curated Info

3

Jin S, et al. (2020) 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis. Clin Cancer Res
32054729   Curated Info

4

Goh CW, et al. (2018) Chronic oxidative stress promotes GADD34-mediated phosphorylation of the TAR DNA-binding protein TDP-43, a modification linked to neurodegeneration. J Biol Chem 293, 163-176
29109149   Curated Info

5

Namer LS, et al. (2017) An Ancient Pseudoknot in TNF-α Pre-mRNA Activates PKR, Inducing eIF2α Phosphorylation that Potently Enhances Splicing. Cell Rep 20, 188-200
28683312   Curated Info

6

Cabrera E, et al. (2017) PERK inhibits DNA replication during the Unfolded Protein Response via Claspin and Chk1. Oncogene 36, 678-686
27375025   Curated Info

7

Rajesh K, et al. (2016) The eIF2α serine 51 phosphorylation-ATF4 arm promotes HIPPO signaling and cell death under oxidative stress. Oncotarget 7, 51044-51058
27409837   Curated Info

8

Booth L, et al. (2016) Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo. Oncotarget 7, 40398-40417
27259258   Curated Info

9

Xu D, et al. (2016) Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3β-inhibitor 2-PP1 positive feedback loop. Oncotarget 7, 3427-39
26655089   Curated Info

10

Breaux M, et al. (2015) p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways. Mol Cell Biol 35, 3005-16
26100016   Curated Info

11

Nakamura T, et al. (2015) A Critical Role for PKR Complexes with TRBP in Immunometabolic Regulation and eIF2α Phosphorylation in Obesity. Cell Rep 11, 295-307
25843719   Curated Info

12

Wei C, et al. (2015) Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms. Mol Biol Cell 26, 1044-57
25589675   Curated Info

13

Tyagi R, et al. (2015) Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade. Cell Rep
25660019   Curated Info

14

Wengrod J, et al. (2015) Phosphorylation of eIF2α triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma. Sci Signal 8, ra27
25759478   Curated Info

15

Mamais A, et al. (2014) Arsenite Stress Down-regulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2), Promoting Self-association and Cellular Redistribution. J Biol Chem 289, 21386-400
24942733   Curated Info

16

Shiina N, Nakayama K (2014) RNA Granule Assembly and Disassembly Modulated by Nuclear Factor Associated with Double-stranded RNA 2 and Nuclear Factor 45. J Biol Chem 289, 21163-21180
24920670   Curated Info

17

Bian Y, et al. (2014) An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics 96, 253-62
24275569   Curated Info

18

Vendelbo MH, et al. (2014) Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling. PLoS One 9, e102031
25020061   Curated Info

19

Zhou W, Jeyaraman K, Yusoff P, Shenolikar S (2013) Phosphorylation at Tyrosine 262 Promotes GADD34 Protein Turnover. J Biol Chem 288, 33146-55
24092754   Curated Info

20

Bhattacharya S, et al. (2013) Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses. Oncogene 32, 4214-21
23045272   Curated Info

21

Wippich F, et al. (2013) Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell 152, 791-805
23415227   Curated Info

22

Shen S, et al. (2011) Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene 30, 4544-56
21577201   Curated Info

23

Mounir Z, et al. (2011) Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway. Sci Signal 4, ra62
21954288   Curated Info

24

Jin HO, et al. (2011) TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1. Oncogene 30, 3792-801
21460850   Curated Info

25

Martins I, et al. (2011) Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene 30, 1147-58
21151176   Curated Info

26

Muaddi H, et al. (2010) Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol Biol Cell 21, 3220-31
20660158   Curated Info

27

Bourougaa K, et al. (2010) Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell 38, 78-88
20385091   Curated Info

28

Chen YJ, et al. (2010) Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions. Nucleic Acids Res 38, 764-77
19934253   Curated Info

29

Zhong D, et al. (2009) The Glycolytic Inhibitor 2-Deoxyglucose Activates Multiple Prosurvival Pathways through IGF1R. J Biol Chem 284, 23225-33
19574224   Curated Info

30

Krähling V, et al. (2009) Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity. J Virol 83, 2298-309
19109397   Curated Info

31

Mayya V, et al. (2009) Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal 2, ra46
19690332   Curated Info

32

Sugeno N, et al. (2008) Serine 129 phosphorylation of alpha-synuclein induces unfolded protein response-mediated cell death. J Biol Chem 283, 23179-88
18562315   Curated Info

33

Krishnamoorthy J, Mounir Z, Raven JF, Koromilas AE (2008) The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation. Cell Cycle 7, 2346-51
18677106   Curated Info

34

Thiaville MM, et al. (2008) Deprivation of protein or amino acid induces C/EBPbeta synthesis and binding to amino acid response elements, but its action is not an absolute requirement for enhanced transcription. Biochem J 410, 473-84
18052938   Curated Info

35

Ozcan U, et al. (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29, 541-51
18342602   Curated Info

36

Raven JF, et al. (2008) PKR and PKR-like endoplasmic reticulum kinase induce the proteasome-dependent degradation of cyclin D1 via a mechanism requiring eukaryotic initiation factor 2alpha phosphorylation. J Biol Chem 283, 3097-108
18063576   Curated Info

37

Su Q, et al. (2008) Modulation of the Eukaryotic Initiation Factor 2 {alpha}-Subunit Kinase PERK by Tyrosine Phosphorylation. J Biol Chem 283, 469-75
17998206   Curated Info

38

Fritsch RM, et al. (2007) Translational repression of MCL-1 couples stress-induced eIF2 alpha phosphorylation to mitochondrial apoptosis initiation. J Biol Chem 282, 22551-62
17553788   Curated Info

39

Zhang P, Samuel CE (2007) Protein kinase PKR plays a stimulus- and virus-dependent role in apoptotic death and virus multiplication in human cells. J Virol 81, 8192-200
17522227   Curated Info

40

Zykova TA, et al. (2007) Involvement of ERKs, RSK2 and PKR in UVA-induced signal transduction toward phosphorylation of eIF2alpha (Ser(51)). Carcinogenesis 28, 1543-51
17404396   Curated Info

41

Ramya TN, Surolia N, Surolia A (2007) 15-deoxyspergualin inhibits eukaryotic protein synthesis through eIF2alpha phosphorylation. Biochem J 401, 411-20
16952278   Curated Info

42

Wakula P, et al. (2006) The translation initiation factor eIF2beta is an interactor of protein phosphatase-1. Biochem J 400, 377-83
16987104   Curated Info

43

Latreille M, Larose L (2006) Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress. J Biol Chem 281, 26633-44
16835242   Curated Info

44

Scheuner D, et al. (2006) Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis. J Biol Chem 281, 21458-68
16717090   Curated Info

45

Suragani RN, Ghosh S, Ehtesham NZ, Ramaiah KV (2006) Expression and purification of the subunits of human translational initiation factor 2 (eIF2): phosphorylation of eIF2 alpha and beta. Protein Expr Purif 47, 225-33
16289913   Curated Info

46

Suragani RN, Kamindla R, Ehtesham NZ, Ramaiah KV (2005) Interaction of recombinant human eIF2 subunits with eIF2B and eIF2alpha kinases. Biochem Biophys Res Commun 338, 1766-72
16288713   Curated Info

47

Dey M, et al. (2005) Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 122, 901-13
16179259   Curated Info

48

Dar AC, Dever TE, Sicheri F (2005) Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell 122, 887-900
16179258   Curated Info

49

McEwen E, et al. (2005) Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem 280, 16925-33
15684421   Curated Info

50

Shenberger JS, et al. (2005) Hyperoxia alters the expression and phosphorylation of multiple factors regulating translation initiation. Am J Physiol Lung Cell Mol Physiol 288, L442-9
15542544   Curated Info

51

Blais JD, et al. (2004) Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24, 7469-82
15314157   Curated Info

52

Chen G, et al. (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J 18, 1162-4
15132987   Curated Info

53

Kazemi S, et al. (2004) Control of alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) phosphorylation by the human papillomavirus type 18 E6 oncoprotein: implications for eIF2 alpha-dependent gene expression and cell death. Mol Cell Biol 24, 3415-29
15060162   Curated Info

54

Kebache S, et al. (2004) Nck-1 antagonizes the endoplasmic reticulum stress-induced inhibition of translation. J Biol Chem 279, 9662-71
14676213   Curated Info

55

Kim SH, Gunnery S, Choe JK, Mathews MB (2002) Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR. Oncogene 21, 8741-8
12483527   Curated Info

56

Koumenis C, et al. (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 22, 7405-16
12370288   Curated Info

57

Patel J, Wang X, Proud CG (2001) Glucose exerts a permissive effect on the regulation of the initiation factor 4E binding protein 4E-BP1. Biochem J 358, 497-503
11513750   Curated Info

58

Vattem KM, Staschke KA, Wek RC (2001) Mechanism of activation of the double-stranded-RNA-dependent protein kinase, PKR: role of dimerization and cellular localization in the stimulation of PKR phosphorylation of eukaryotic initiation factor-2 (eIF2). Eur J Biochem 268, 3674-84
11432733   Curated Info

59

Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-4
9930704   Curated Info

60

Donzé O, et al. (1995) Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J 14, 3828-34
7641700   Curated Info

61

Srivastava SP, Davies MV, Kaufman RJ (1995) Calcium depletion from the endoplasmic reticulum activates the double-stranded RNA-dependent protein kinase (PKR) to inhibit protein synthesis. J Biol Chem 270, 16619-24
7622470   Curated Info

62

Pathak VK, Schindler D, Hershey JW (1988) Generation of a mutant form of protein synthesis initiation factor eIF-2 lacking the site of phosphorylation by eIF-2 kinases. Mol Cell Biol 8, 993-5
3352609   Curated Info