title: Phosphoproteins in stress-induced disease.
abstract: The integrated stress response (ISR) is an evolutionarily conserved homeostatic program activated by specific pathological states. These include amino acid deprivation, viral infection, iron deficiency, and the misfolding of proteins within the endoplasmic reticulum (ER), the so-called ER stress. Although apparently disparate, each of these stresses induces phosphorylation of a translation initiation factor, eIF2α, to attenuate new protein translation while simultaneously triggering a transcriptional program. This is achieved by four homologous stress-sensing kinases: GCN2, PKR, HRI, and PERK. In addition to these kinases, mammals possess two specific eIF2α phosphatases, GADD34 and CReP, which play crucial roles in the recovery of protein synthesis following the initial insult. They are not only important in embryonic development but also appear to play important roles in disease, particularly cancer. In this chapter, we discuss each of the eIF2α kinases, in turn, with particular emphasis on their regulation and the new insights provided by recent structural studies. We also discuss the potential for developing novel drug therapies that target the ISR.
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom.
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Dalton
authors.forename: Eleanor
authors.initials: E
authors.lastname: Healey
authors.forename: James
authors.initials: J
authors.lastname: Irving
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D019143:Evolution, Molecular; D006418:Heme / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation; D054645:Protein Phosphatase 1 / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D014777:Virus Diseases / Q000201:enzymology; D019892:eIF-2 Kinase / Q000737:chemistry / Q000502:physiology
chemical_list: D000596:Amino Acids; D015852:Eukaryotic Initiation Factor-2; D006418:Heme; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C529271:EIF2AK4 protein, human; C513256:Ppp1r15a protein, mouse; C480350:Ppp1r15b protein, mouse