Translation Regulation activity of EIF2
Regulation of eIF2
Eukaryotic translation initiation factors ( eIF2 ) is a G-protein that iscomposed of 3 non-identical subunits, eIF2S1, eIF2S2 and eIF2S3,and catalyzes the first regulated step of protein synthesis initiation, promoting thebinding of the initiator tRNA to 40S ribosomal subunits. Phosphorylation of eIF2S1modulates rate of formation of the complex eIF2/GTP/tRNA [1].
Key pathways of eIF2 activity regulation are phosphorylation of eIF2S1and phosphorylation of Eukaryotic initiation factor 2 ( eIF2B ) by some proteinkinases.
Four distinct protein kinases inhibit protein synthesis in eukaryotic cells viaphosphorylation of eIF2S1 at serine-51. There are Eukaryotic translationinitiation factor 2-alpha kinase 1, 2, 3 and 4 ( EIF2AK1, PKR,EIF2AK3 and GCN2 ), that belong to the serine/threonine family of proteinkinases. Phosphorylation of eIF2S1 results in shutdown of protein synthesis.
EIF2AK1 is activated under conditions of heme deficiency, predominantly inimmature erythroid cells, and its activity is inhibited by heme [2].
PKR acts as an antiviral machinery of type I Interferons. E xpression ofPKR is induced by interferon, and its kinase activity is stimulated by lowconcentrations of double-stranded RNA. PKR -mediated inhibition is neutralizatedvia direct dephosphorylation and monomerization of PKR by Alpha catalytic subunitprotein phosphatase 1 ( PP1 ) [3]. Also, PP1 candephosphorylates eIF2S1 thereby activating eIF2 formation [4].
EIF2AK3 is activated under conditions of Endoplasmic reticulum (ER) stress. ERstress is caused by unfolded or misfolded proteins, which are accumulared byextracellular or intracellular stimuli [5].
GCN2 is activated by amino acid starvation phosphorylates. GCN2inhibites EIF2S1. It is one of the eukaryotic initiation factors that have a rolein eukaryotic peptide chain initiation process [6].
Exchange of GDP for GTP on eIF2 is stimulated by eIF2B. eIF2B isa heteromeric guanine nucleotide exchange factor that plays an important role inregulating mRNA translation. It is composed of 5 subunits termed eIF2B1-5 in orderof increasing size [7].
eIF2B has multiple phosphorylation sites in the largest, catalytic, subuniteIF2B5.
Kinases, which phosphorylate of the eIF2B5- subunit of eIF2B, areCasein kinase I and II, Glycogen synthase kinase 3 alpha and beta isoforms( GSK3 alpha/beta ), and Dual specificity tyrosine-phosphorylated and -regulatedkinases ( DYRK1a and DYRK2 ). elF2B5 phosphorylation by caseinkinases enhances eIF2B activity, whereas phosphorylation by GSK3 has aninhibitory effect [7]. Phosphorylation by GSK3 requires previouselF2B5 phosphorylation that is catalyzed by DYRKs [8].
Phosphotase PP1 deviates inhibitory effect of GSK3 via dephosphorilationof eIF2B [9]. Activity of PP1 and GSK3 is regulated bydifferent extracellular stimulus.
For example, Insulin receptor and Epidermal growth factor receptor (EGFR ) activate the enzymatic activity of Phosphatidylinositol 3-kinase class Ivia recruitment of regulatory subunit ( PI3K reg ) either directly or via adaptorproteins (e.g. Insulin receptor substrates 1 and 2 ( IRS-1 and IRS-2 ),GRB2-associated binding protein 1 ( GAB1 ) or Signal transduction protein CBL (c-Cbl )) [10], [11], [12].
Active Phosphatidylinositol 3-kinase class I catalytic ( PI3K cat ) convertsPhosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) to Phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) [13]. PtdIns(3,4,5)P3 isa second messenger. It recruits and activates V-akt murine thymoma viral oncogene homolog1 ( AKT ) and Phosphoinositide dependent protein kinase-1 ( PDK ) tomembrane via PH domain [14]. AKT, in turn, negatively regulatesGSK3 by phosphorylation thereby abrogate inhibitory effect GSK3 toeIF2B activity [7], [15].
Also EGFR induces MAPK cascade. It was shown, that MEK/Mitogen-activated protein kinase ( ERK) pathway is required for activation ofeIF2B. It was suggested that the active ERK activates phosphotasePP1. This leads to activation of eIF2B [9].
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