Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of renal, hepatic and pancreatic cysts and by non-cystic manifestations such as abnormal vasculature and embryo left–right asymmetry development. Polycystin-2 (PC2), in which mutations account for 10–15% of ADPKD, was previously shown to down-regulate cell proliferation, but the underlying mechanism was not elucidated. Here, we demonstrate that PC2, but not pathogenic mutants E837X and R872X, represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2α by pancreatic ER-resident eIF2α kinase (PERK). ER stress is known to enhance eIF2α phosphorylation through up-regulating PERK kinase activity (assessed by phosphorylated PERK). During ER stress, PC2 knockdown also repressed eIF2α phosphorylation but did not alter PERK phosphorylation, indicating that PC2 facilitates the eIF2α phosphorylation by PERK. PC2 was found to be in the same complex as PERK and eIF2α. Together, we demonstrate that PC2 negatively controls cell growth by promoting PERK-mediated eIF2α phosphorylation, presumably through physical interaction, which may underlie a pathogenesis mechanism of ADPKD and indicates that PC2 is an important regulator of the translation machinery.