Tumor progression and the Different Faces of the PERK kinase

The serine/threonine endoplasmic reticulum (ER) kinase, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is a pro-adaptive protein kinase whose activity is regulated indirectly by protein misfolding within the ER. Since 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 FOXO (Forkhead box O protein) and diacyglycerol (DAG) a lipid signaling second messenger, and efforts to develop small molecule PERK inhibitors.