Ser52

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:	immunoassay ( 9 , 11 , 12 ) , mutation of modification site ( 6 , 7 , 14 , 15 , 16 , 23 , 25 , 28 , 29 , 30 , 32 , 34 , 35 , 38 , 41 , 43 , 45 ) , peptide sequencing ( 24 ) , phospho-antibody ( 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ) , western blotting ( 6 , 7 , 8 , 9 , 10 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 36 , 37 , 38 , 41 , 43 , 44 )
Disease tissue studied:	breast cancer ( 19 ) , colorectal cancer ( 8 , 13 ) , colorectal carcinoma ( 8 , 13 ) , kidney cancer ( 31 ) , liver cancer ( 29 , 31 ) , lung cancer ( 15 , 41 ) , non-small cell lung cancer ( 15 ) , non-small cell lung adenocarcinoma ( 15 ) , pancreatic cancer ( 18 , 36 ) , pancreatic carcinoma ( 18 , 36 ) , melanoma skin cancer ( 19 ) , fibrosarcoma of soft tissue ( 15 ) , type 2 diabetes ( 27 ) , tuberous sclerosis ( 31 )
Relevant cell line - cell type - tissue:	'brain, cerebellum' ( 24 ) , 'brain, hippocampus' ( 34 ) , 'muscle, skeletal' ( 17 ) , 'stem, embryonic' ( 42 ) , 293 (epithelial) ( 8 , 33 , 37 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 43 ) , 3T3 (fibroblast) ( 41 ) , A549 (pulmonary) ( 15 , 41 ) , AG01522 (fibroblast) ( 41 ) , beta-pancreas ( 36 ) , BHK-21 (fibroblast) ( 44 ) , COS (fibroblast) ( 18 ) , DLD1 (intestinal) ( 8 ) , embryo [PPP1R15B (mouse), homozygous knockout] ( 28 ) , Fao (hepatic) ( 29 ) , glial ( 31 ) , HCT116 (intestinal) ( 8 , 13 ) , HeLa (cervical) ( 7 , 37 , 38 , 41 ) , hepatocyte-liver ( 22 ) , hepatocyte-liver [eIF2-alpha (mouse), homozygous knockout] ( 29 ) , HT1080 (fibroblast) ( 15 ) , keratinocyte ( 6 ) , kidney ( 31 ) , liver ( 22 , 31 , 45 ) , macrophage-peritoneum ( 8 ) , MEF (fibroblast) [Akt1 (mouse), homozygous knockout] ( 21 ) , MEF (fibroblast) [eIF2-alpha (mouse)] ( 35 ) , MEF (fibroblast) [GADD34 (human)] ( 33 ) , MEF (fibroblast) [IGF1R (mouse)] ( 34 , 39 ) , MEF (fibroblast) [PKR (mouse), homozygous knockout] ( 23 , 27 ) , MEF (fibroblast) [PPP1R15B (mouse), homozygous knockout] ( 28 ) , MEF (fibroblast) [XIAP (mouse), homozygous knockout] ( 26 ) , MEF (fibroblast) ( 8 , 15 , 18 , 19 , 20 , 23 , 25 , 30 , 31 , 32 , 36 , 37 , 38 , 41 , 45 ) , MIN6 (pancreatic) ( 18 , 36 ) , muscle ( 12 , 16 ) , neuron ( 9 ) , neuron-'brain, hippocampus' ( 11 ) , neuron-dorsal root ganglia ( 14 ) , pancreas ( 45 ) , RAW 264.7 (macrophage) ( 10 ) , spinal cord ( 9 ) , squamous ( 6 ) , T47D (breast cell) ( 19 ) , WM2664 (melanocyte) ( 19 )

Upstream Regulation
Regulatory protein:	Akt1 (mouse) ( 21 ) , Akt2 (mouse) ( 21 ) , Akt3 (mouse) ( 21 ) , ATF-4 (mouse) ( 20 ) , DDIT3 (mouse) ( 20 ) , DUSP1 (mouse) ( 24 ) , GADD34 (human) ( 33 ) , GCN2 (human) ( 8 ) , GCN2 (mouse) ( 19 , 21 , 42 ) , HRI (human) ( 7 ) , IKKE (human) ( 8 ) , IRE1 (mouse) ( 29 ) , NCK1 (human) ( 18 ) , NCK1 (mouse) ( 37 ) , NCK2 (mouse) ( 37 ) , PERK (human) ( 7 ) , PERK (mouse) ( 19 , 21 ) , PIK3R1 (human) ( 12 ) , PKR (human) ( 7 , 8 ) , PKR (mouse) ( 14 , 19 , 27 , 38 ) , PPP1R15B (mouse) ( 28 ) , RHOT1 (human) ( 11 ) , RHOT2 (human) ( 11 ) , STING (human) ( 8 ) , TBC1D8B (human) ( 13 ) , TBK1 (human) ( 8 ) , XIAP (mouse) ( 26 )
Putative in vivo kinases:	GCN2 (mouse) ( 7 , 43 ) , PERK (mouse) ( 8 , 35 , 41 ) , PKR (mouse) ( 9 , 14 , 23 , 44 )
Kinases, in vitro:	PERK (human) ( 8 ) , PKR (mouse) ( 44 )
Putative upstream phosphatases:	PPP1CA (human) ( 36 , 37 ) , PPP1R15B (mouse) ( 40 )
Treatments:	2-AP ( 44 ) , 2-deoxyglucose ( 26 ) , adriamycin ( 23 ) , Akt_inhibitor_VIII ( 21 ) , amino_acid_starvation ( 19 , 42 ) , arsenite ( 35 , 40 ) , bortezomib ( 6 ) , butyrate ( 8 , 10 ) , BX795 ( 8 ) , cGAMP ( 8 ) , cigarette_smoke ( 10 ) , cycloheximide ( 40 ) , dexamethasone ( 12 ) , diamide ( 35 ) , dimeric amidobenzimidazole ( 8 ) , disulfiram ( 35 ) , DMXAA ( 8 ) , double-stranded_RNA ( 44 ) , DTT ( 18 , 24 , 40 , 41 ) , exercise ( 17 ) , fasting ( 22 ) , Freund's_complete_adjuvant ( 14 ) , glucagon ( 22 ) , glucose ( 36 ) , GSK2656157 ( 8 ) , H-89 ( 22 ) , H2O2 ( 21 ) , Halofuginone ( 7 ) , heparin sodium ( 19 ) , histidinol ( 42 ) , hypoxia ( 41 ) , IFN-alpha ( 38 ) , IFN-gamma ( 44 ) , injury ( 9 ) , JSH-23 ( 8 ) , LY294002 ( 21 ) , mannose ( 35 ) , NaAsO2 ( 6 ) , obesity-inducing diet ( 22 ) , okadaic_acid ( 36 , 38 ) , PERK inhibitor 1 ( 8 ) , poly(I-C) ( 38 ) , rapamycin ( 8 , 31 ) , Sal003 ( 16 , 34 ) , serum_withdrawal ( 38 ) , siRNA ( 7 , 18 ) , SP600125 ( 24 , 43 ) , tauroursodeoxycholic_acid ( 8 ) , thapsigargin ( 18 , 19 , 20 , 21 , 22 , 28 , 32 , 36 , 41 , 42 , 43 ) , TNF ( 14 , 38 ) , TPCA1 ( 8 ) , tunicamycin ( 6 , 7 , 20 , 24 , 29 , 37 , 40 ) , UV ( 39 , 43 ) , virus infection ( 8 , 30 )

Downstream Regulation
Effects of modification on eIF2-alpha:	activity, induced ( 39 ) , activity, inhibited ( 32 , 43 )
Effects of modification on biological processes:	apoptosis, induced ( 9 , 10 ) , apoptosis, inhibited ( 6 , 13 , 20 , 23 , 26 ) , autophagy, induced ( 6 ) , cell growth, altered ( 28 , 45 ) , cytoskeletal reorganization ( 6 ) , transcription, altered ( 7 ) , transcription, induced ( 45 ) , translation, altered ( 6 , 25 , 32 , 35 , 45 ) , translation, induced ( 15 ) , translation, inhibited ( 8 , 9 , 12 , 16 , 20 )

References
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15	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
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21	Mounir Z, et al. (2011) Akt determines cell fate through inhibition of the PERK-eIF2α phosphorylation pathway. Sci Signal 4, ra62 21954288 Curated Info
22	Mao T, et al. (2011) PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism. Proc Natl Acad Sci U S A 108, 15852-7 21911379 Curated Info
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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
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31	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
32	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
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35	Shang J, et al. (2007) Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. J Cell Biol 176, 605-16 17325203 Curated Info
36	Vander Mierde D, et al. (2007) Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells. Endocrinology 148, 609-17 17082262 Curated Info
37	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
38	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
39	Wu S, et al. (2004) Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J Biol Chem 279, 34898-902 15184376 Curated Info
40	Jousse C, et al. (2003) Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J Cell Biol 163, 767-75 14638860 Curated Info
41	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
42	Zhang P, et al. (2002) The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol 22, 6681-8 12215525 Curated Info
43	Deng J, et al. (2002) Activation of GCN2 in UV-irradiated cells inhibits translation. Curr Biol 12, 1279-86 12176355 Curated Info
44	Ben-Asouli Y, et al. (2002) Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR. Cell 108, 221-32 11832212 Curated Info
45	Scheuner D, et al. (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7, 1165-76 11430820 Curated Info