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2272160 
Journal Article 
Review 
The eIF2 alpha kinases: their structures and functions 
Donnelly, N; Gorman, AM; Gupta, S; Samali, A 
2013 
Yes 
Cellular and Molecular Life Sciences (CMLS)
ISSN: 1420-682X
EISSN: 1420-9071 
70 
19 
3493-3511 
English 
23354059 
WOS:000324266700002 
Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2 alpha on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell's armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2 alpha is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2 alpha kinases in their kinase domains, underlying their common role in phosphorylating eIF2 alpha, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2 alpha kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2 alpha kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed. 
eIF2 alpha kinases; Cell stress; PKR-like ER kinase (PERK); Protein kinase double-stranded RNA-dependent (PKR); General control non-derepressible-2 (GCN2); Heme-regulated inhibitor (HRI); Activating transcription factor 4 (ATF4)