PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase) or EIF2AK3 (eukaryotic translation initiation factor 2-alpha kinase 3), analogous with Ire1, is a serine/threonine transmembrane endoplasmic reticulum (ER) kinase. Established PERK substrates include the translation initiation factor eIF2α and the transcription factor Nrf2. PERK, Ire1 and ATF6 serve as a UPR control system in the ER to monitor cell homeostasis. Following stress, the UPR restores homeostasis via mechanisms that reduce ER protein load (eg. via RIDD, or eIF2α-mediated inhibition of translation), by increasing protein folding capacity (eg. transcriptional regulation of chaperones) and by activation of degradation pathways to remove unfolded proteins (ERAD, autophagy).  
PERK activation triggers an analogous response wherein activation of PERK results in the specific loss of cyclin D1 through inhibition of cyclin D1 protein synthesis rather than any acceleration in protein degradation. This loss of cyclin D1 triggers cell cycle arrest in normal cells. PERK is one of at least 4 distinct eIF2α protein kinases which include the heme-regulated kinase (HRI) also known as EIF2AK1 kinase, the interferon-inducible, RNA-dependent protein kinase (PKR) known as EIF2AK2 kinase and GCN2 known as EIF2AK4. PERK can regulate cellular redox homeostasis through activation of Nrf2. PERK phosphorylates Nrf2 on threonine 80 located within the Neh2 domain of Nrf2. The ability of PERK to directly regulate FOXO and potentially override negative regulation by Akt supports a model wherein the UPR and ER stress have the capacity to finely tune signal output downstream of Akt.  A more complete and detailed understanding of PERK downstream signaling is essential for developing such approaches.


1.Pytel D,et al. Oncogene. 2016;35(10):1207–1215.