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Genes Dev. 2018 Jun 1;32(11-12):781-793. doi: 10.1101/gad.315127.118. Epub 2018 Jun 11.

A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease.

Author information

1
Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario M5G 2N2, Canada.
3
Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Abstract

Autosomal 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.

KEYWORDS:

3D culture; ADPKD; Hippo signaling; RhoA signaling; YAP/TAZ; c-Myc

PMID:
29891559
PMCID:
PMC6049514
DOI:
10.1101/gad.315127.118
[Indexed for MEDLINE]
Free PMC Article

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