GCN2 in and out of stress – expanding cellular functions

ABSTRACT

GCN2 (also known as EIF2AK4) is a conserved serine/threonine kinase best known for linking amino acid availability to activation of the integrated stress response (ISR) through phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). This canonical activity promotes adaptive translational and transcriptional programmes that support metabolic homeostasis and stress tolerance, which has motivated efforts to therapeutically target GCN2, particularly in cancer. Recent work, however, indicates that this framework captures only a subset of GCN2 biology. GCN2 has been shown to engage additional substrates beyond eIF2α, including the methionyl-tRNA synthetase (MARS1) and the catalytic subunits of protein phosphatase-1 (PP1), and has been implicated in a growing range of cellular processes, such as mitotic fidelity, cell migration and ribosome homeostasis. Together, these findings establish GCN2 as a multifunctional kinase whose cellular roles cannot be inferred solely from canonical ISR readouts. Here, we synthesize emerging evidence for noncanonical GCN2 activities and consider how this expanded view shapes interpretation of genetic and pharmacological perturbations and the development of therapeutic strategies targeting GCN2.