Eukaryotic translation initiation factor 2-alpha kinase 3 [1, 3, 10] (EIF2AK3 [1, 3, 10])

Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3), widely known as PERK, is a type I transmembrane protein located in the endoplasmic reticulum (ER) that serves as a primary sensor for the unfolded protein response (UPR) [1, 2, 10]. Under conditions of ER stress, such as the accumulation of misfolded proteins, PERK undergoes dimerization and autophosphorylation to become active [3, 10]. Once activated, it phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α), which results in a rapid, global attenuation of protein translation to reduce the workload on the ER [1, 2, 10]. Simultaneously, this signaling pathway selectively promotes the translation of specific mRNAs, including the transcription factors ATF4 and CHOP, which coordinate adaptive or apoptotic responses [2, 10, 14]. EIF2AK3 plays a dual role in disease; its overactivation is linked to neurodegeneration and proteinopathies like Alzheimer's disease, while its activity supports the survival of tumor cells in harsh microenvironments [9, 10, 14, 16]. Consequently, PERK is a significant therapeutic target, with inhibitors being explored for oncology and neuroprotection [4, 9, 10]. However, drug development is complicated by the protein's essential role in pancreatic beta-cell health, as its loss or inhibition can lead to diabetes and pancreatic insufficiency [1, 11, 16].

Other names

PERK [1, 3, 10]PEK [1, 3, 5]WRS [1, 3]HSRK [1]PRKR-like endoplasmic reticulum kinase [3, 5]

Kinase inhibition (ATP-competitive), Kinase activation [4, 10]