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

Jing Cai, Xuewen Song, Wei Wang, Terry Watnick, York Pei, Feng Qian, Duojia Pan

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)781-793
Number of pages13
JournalGenes and Development
Volume32
Issue number11-12
DOIs
StatePublished - Jun 1 2018

Fingerprint

Autosomal Dominant Polycystic Kidney
Polycystic Kidney Diseases
Kidney
Rho Guanine Nucleotide Exchange Factors
Cystic Kidney Diseases
Guanine Nucleotide Exchange Factors
rho-Associated Kinases
Monomeric GTP-Binding Proteins
Dilatation
Phosphotransferases
Mutation
Pharmaceutical Preparations

Keywords

  • 3D culture
  • ADPKD
  • C-Myc
  • Hippo signaling
  • RhoA signaling
  • YAP/TAZ

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease. / Cai, Jing; Song, Xuewen; Wang, Wei; Watnick, Terry; Pei, York; Qian, Feng; Pan, Duojia.

In: Genes and Development, Vol. 32, No. 11-12, 01.06.2018, p. 781-793.

Research output: Contribution to journalArticle

Cai, Jing ; Song, Xuewen ; Wang, Wei ; Watnick, Terry ; Pei, York ; Qian, Feng ; Pan, Duojia. / A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease. In: Genes and Development. 2018 ; Vol. 32, No. 11-12. pp. 781-793.
@article{27ac78b3910d4eae940de0fdf8371912,
title = "A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease",
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, C-Myc, Hippo signaling, RhoA signaling, YAP/TAZ",
author = "Jing Cai and Xuewen Song and Wei Wang and Terry Watnick and York Pei and Feng Qian and Duojia Pan",
year = "2018",
month = "6",
day = "1",
doi = "10.1101/gad.315127.118",
language = "English (US)",
volume = "32",
pages = "781--793",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "11-12",

}

TY - JOUR

T1 - A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease

AU - Cai, Jing

AU - Song, Xuewen

AU - Wang, Wei

AU - Watnick, Terry

AU - Pei, York

AU - Qian, Feng

AU - Pan, Duojia

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

KW - 3D culture

KW - ADPKD

KW - C-Myc

KW - Hippo signaling

KW - RhoA signaling

KW - YAP/TAZ

UR - http://www.scopus.com/inward/record.url?scp=85048825501&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048825501&partnerID=8YFLogxK

U2 - 10.1101/gad.315127.118

DO - 10.1101/gad.315127.118

M3 - Article

VL - 32

SP - 781

EP - 793

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 11-12

ER -