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Review
. 2016 Mar 10;35(10):1207-15.
doi: 10.1038/onc.2015.178. Epub 2015 Jun 1.

Tumor progression and the different faces of the PERK kinase

D Pytel  1 , I Majsterek  2 , J A Diehl  1
Affiliations
Review

Tumor progression and the different faces of the PERK kinase

D Pytel et al. Oncogene. .

Abstract

The serine/threonine endoplasmic reticulum (ER) kinase, protein kinase R (PKR)-like ER kinase (PERK), is a pro-adaptive protein kinase whose activity is regulated indirectly by protein misfolding within the ER. As the oxidative folding environment in the ER is sensitive to a variety of cellular stresses, many of which occur during neoplastic transformation and in the tumor microenvironment, there has been considerable interest in defining whether PERK positively contributes to tumor progression and whether it represents a significant therapeutic target. Herein, we review the current knowledge of PERK-dependent signaling pathways, the contribution of downstream substrates including recently characterized new PERK substrates transcription factors Forkhead box O protein and diacyglycerol a lipid signaling second messenger, and efforts to develop small molecule PERK inhibitors.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PERK activation caused by a variety of cellular stresses. PERK can be activated by physiologically relevant stresses such as glucose deprivation, oxygen restriction (hypoxia), viral infection, proteotoxicity (increased load of misfolded/unfolded proteins in ER) and increased lipid biosynthesis.
Figure 2
Figure 2
Direct PERK substrates. Activated PERK, in response to ER stress, phophorylates downstream substrates such as: translation initiation factor 2α (eIF2α), transcription factors FOXO (Forkhead box O protein), nuclear factor erythroid-derived 2 transcription factor (Nrf2) and a lipid signaling second messenger diacyglycerol (DAG) and regulates cell homeostasis.
Figure 3
Figure 3
PERK lipid kinase activity and regulation of downstream effectors. PERK possesses lipid kinase activity toward its substrate diacyglycerol (DAG), forming phosphatidic acid (PA) and activating AKT, mTOR and MAP kinase pathways.
See this image and copyright information in PMC

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