Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum

The unfolded protein response (UPR) is an evolutionarily conserved stress response to intra- and extracellular conditions that disrupt endoplasmic reticulum (ER) protein-folding capacity. The UPR is engaged by a variety of disease conditions, including most cancers as well as both metabolic and neurodegenerative disorders. Three transmembrane transducers-PERK, IRE1, and ATF6-are responsible for activating downstream signaling pathways that mediate the UPR and subsequent stress response pathways. PERK, an ER resident transmembrane protein kinase, initiates both pro-apoptotic and pro-survival signaling pathways. In the context of neoplasia, PERK and its downstream targets alter gene expression that can be both pro- and anti-tumorigenic. In this review, we discuss recent advances in understanding how canonical and non-canonical PERK-mediated signaling pathways influence cell fate, tumor progression, and tumor suppression and avenues for therapeutic intervention.