A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease.
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.
['Cai|Jing|J|', 'Song|Xuewen|X|', 'Wang|Wei|W|', 'Watnick|Terry|T|', 'Pei|York|Y|', 'Qian|Feng|F|', 'Pan|Duojia|D|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D018797:Cell Cycle Proteins D002460:Cell Line D002478:Cells, Cultured D004195:Disease Models, Animal D057809:HEK293 Cells D006801:Humans D007668:Kidney D051379:Mice D010750:Phosphoproteins D007690:Polycystic Kidney Diseases D016271:Proto-Oncogene Proteins c-myc D015398:Signal Transduction D000091102:YAP-Signaling Proteins D020741:rho GTP-Binding Proteins D020742:rhoA GTP-Binding Protein
ADPKD Hippo signaling c-Myc YAP/TAZ RhoA signaling 3D culture