biostudies-literatureZhang YNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesPKD FoundationNIGMS NIH HHSmjac050https://www.ebi.ac.uk/biostudies/studies/S-EPMC9802383biostudies-literatureUnknown14(7)Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts, causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin (CaM) dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and PKD mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cJournal of molecular cell biologyCaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.PMC9802383P20 GM103418R01DK081579R01 DK081579Reif GAZhang YMetcalf JDaniel EAWallace DPDai YfalseCaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts, causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin (CaM) dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and PKD mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited c2022-01-01T00:00:00Z2022 Sep2025-04-05T12:09:36.546Z2025-04-05T12:09:36.546ZS-EPMC98023833600202110.1093/jmcb/mjac050