A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease
JournalGenes and Development
PublisherCold Spring Harbor Laboratory Press
MetadataShow full item record
AbstractAutosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects one in 500-1000 humans. Limited treatment is currently available for ADPKD. Here we identify the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. While transgenic overexpression of YAP promotes proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or c-Myc suppresses cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency. Through a comprehensive kinase inhibitor screen based on a novel three-dimensional (3D) culture of Pkd1 mutant mouse kidney cells, we identified a signaling pathway involving the RhoGEF (guanine nucleotide exchange factor) LARG, the small GTPase RhoA, and the RhoA effector Rho-associated kinase (ROCK) as a critical signaling module between PKD1 and YAP. Further corroborating its physiological importance, inhibition of RhoA signaling suppresses cystogenesis in 3D culture of Pkd1 mutant kidney cells as well as Pkd1 mutant mouse kidneys in vivo. Taken together, our findings implicate the RhoA-YAP-c-Myc signaling axis as a critical mediator and potential drug target in ADPKD. Copyright 2018 Cai et al.
SponsorsThis study was supported in part by grants from the Department of Defense (PR130920) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK098424, DK095036, and DK111611). This work was supported by a pilot grant from the Baltimore Polycystic Kidney Disease Research and Clinical Core Center (P30 DK090868).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85048825501&doi=10.1101%2fgad.315127.118&partnerID=40&md5=b40ce3f99a7bda4db7af3ae96aa882cd; http://hdl.handle.net/10713/9238
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