Mutations inactivating the cilia-localized
Pkd1 protein result in
autosomal dominant polycystic kidney disease (
ADPKD), a serious inherited syndrome affecting ∼ 1 in 500 people, in which accumulation of renal
cysts eventually destroys kidney function. Severity of
ADPKD varies throughout the population, for reasons thought to involve differences both in intragenic Pkd1 mutations and in modifier alleles. The scaffolding
protein NEDD9, commonly dysregulated during
cancer progression, interacts with Aurora-A (
AURKA)
kinase to control ciliary resorption, and with Src and other partners to influence proliferative signaling pathways often activated in
ADPKD. We here demonstrate Nedd9 expression is deregulated in human
ADPKD and a mouse
ADPKD model. Although genetic ablation of Nedd9 does not independently influence cystogenesis, constitutive absence of Nedd9 strongly promotes
cyst formation in the
tamoxifen-inducible Pkd1fl/fl;Cre/Esr1(+) mouse model of
ADPKD. This cystogenic effect is associated with striking morphological defects in the cilia of Pkd1(-/-);Nedd9(-/-) mice, associated with specific loss of ciliary localization of adenylase cyclase III in the doubly mutant genotype. Ciliary phenotypes imply a failure of Aurora-A activation: Compatible with this idea, Pkd1(-/-);Nedd9(-/-) mice had ciliary resorption defects, and treatment of Pkd1(-/-) mice with a clinical
Aurora-A kinase inhibitor exacerbated cystogenesis. In addition, activation of the
ADPKD-associated signaling effectors Src, Erk, and the mTOR effector S6 was enhanced, and Ca(2+) response to external stimuli was reduced, in Pkd1(-/-);Nedd9(-/-) versus Pkd1(-/-) mice. Together, these results indicated an important modifier action of Nedd9 on
ADPKD pathogenesis involving failure to activate Aurora-A.