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Kidney Week

Abstract: FR-PO949

A RhoA-YAP-c-Myc Signaling Axis Promotes the Development of Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Cai, Jing, University of Texas Southwestern Medical Center, Dallas, Texas, United States

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in PKD1 or PKD2 and affects 1 in 500-1000 humans. Limited treatment is currently available for ADPKD and there is great interest in identifying molecular targets and/or pathways for the development of mechanism-based therapeutics. In mammals, the Hippo signaling pathway comprises several tumor suppressors (NF2, Sav1, Mst1/2, Lats1/2, etc.) acting through a kinase cascade to affect the phosphorylation and cytoplasmic retention of the oncoproteins YAP/TAZ, transcriptional coactivators of the TEF/TEAD family transcription factors to transactivate growth-promoting genes. In this study, we investigated the function and regulation of the Hippo signaling pathway in ADPKD.


We performed gene set enrichment analysis of YAP/TAZ/TEAD target genes after global gene profiling on human PKD1 polycystic kidney cysts compared to minimally cystic tissues using Affymetrix cDNA arrays, analyzed various genetically engineered mouse models with kidney cystogenesis, and searched for kinase inhibitors that promoted tubulogenesis in 3D-cultured Pkd1 mutant mouse kidney inner medullary collecting duct (mIMCD3) cells through an unbiased kinase inhibitor screen.


Our results showed that YAP/TAZ were activated in human ADPKD kidney cysts compared to minimally cystic tissues. While transgenic overexpression of YAP promoted proliferation and tubule dilation in mouse kidneys, loss of YAP/TAZ or their transcription target c-Myc suppressed cystogenesis in a mouse ADPKD model resulting from Pkd1 deficiency. Through the comprehensive kinase inhibitor screen, we identified a signaling pathway involving the RhoGEF 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 suppressed cystogenesis in 3D culture of Pkd1 mutant kidney cells as well as Pkd1 mutant mouse kidneys in vivo.


Taken together, our findings shed light on the mechanisms underlying ADPKD pathogenesis and implicate the RhoA-YAP-c-Myc signaling axis as a critical mediator and potential drug target in ADPKD.


  • NIDDK Support