Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88/-/- mice and collecting duct epithelial cells from Ift88°rpk mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blot- ting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88°rpk mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF- like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α(TGF-α). Increased growth factor shedding induces activa- tion of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidifica- tion indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype. © 2014 the American Physiological Society.