Protein kinase RNA-like endoplasmic reticulum kinase–eukaryotic initiation factor 2 alpha pathway (PERK–eIF2α pathway)

The **Protein kinase RNA-like endoplasmic reticulum kinase–eukaryotic initiation factor 2 alpha pathway** (PERK–eIF2α pathway) is a signal transduction pathway that forms a critical arm of the unfolded protein response (UPR). PERK, an ER-resident kinase, phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α) during cellular stress, such as the accumulation of misfolded proteins in the endoplasmic reticulum. This phosphorylation event represses global protein synthesis, thereby reducing the influx of nascent polypeptides into the ER, while selectively inducing the translation of mRNAs (e.g., ATF4) that mediate adaptive or apoptotic responses. The pathway modulates cell survival and death based on the severity and duration of stress and plays roles in diverse physiological and pathological processes, including cancer progression, neurodegeneration, metabolic disease, and immunity. Therapeutic interest focuses on inhibiting the PERK–eIF2α pathway to sensitize cancer cells to treatment or protect neurons in degenerative disorders, but modulation is associated with substantial safety considerations due to its central role in cellular homeostasis[2][3][4][5][6].

Other names

PERK–eIF2α phosphorylation armPERK-mediated eIF2α phosphorylation pathwayPKR-like ER kinase–eIF2α pathwayUnfolded protein response, PERK branchEIF2AK3–eIF2S1 pathway

Inhibition of the pathway: reduces pro-survival signaling and may sensitize cancer cells to apoptosis[3]. Modulation of ER stress: restoration of protein homeostasis or induction of cell death.