Phosphoproteins in stress-induced disease.

Progress in Molecular Biology and Translational Science
Lucy E DaltonStefan J Marciniak

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.

Citations

Mar 13, 2014·American Journal of Respiratory Cell and Molecular Biology·Emily F A van 't WoutStefan J Marciniak
Jan 16, 2019·American Journal of Physiology. Endocrinology and Metabolism·Yu ShaoJoseph P Bidwell
May 18, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Maria C ZarconeIngeborg M Kooter
Apr 29, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Rosa LavieriAnna Rubartelli
Oct 3, 2020·European Respiratory Review : an Official Journal of the European Respiratory Society·Giulia EmanuelliStefan J Marciniak
Feb 7, 2020·Cancers·Alberto M MartelliJames A McCubrey
Nov 14, 2020·ELife·Markus TerreySusan L Ackerman

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