A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease.
A RhoA-YAP-c-Myc signaling axis promotes the development of polycystic kidney disease.
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DOI：
10.1101/gad.315127.118
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发表时间：
2018-06-01
影响因子：
10.5
通讯作者：
Pan D
中科院分区：
文献类型：
--
作者：
Cai J;Song X;Wang W;Watnick T;Pei Y;Qian F;Pan D
Cai et al. identified the Hippo signaling effector YAP and its transcriptional target, c-Myc, as promoters of cystic kidney pathogenesis. A comprehensive kinase inhibitor screen 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. 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.
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DOI：
10.1016/j.trsl.2014.11.003
发表时间：
2015-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
LaRiviere WB;Irazabal MV;Torres VE
通讯作者：
Torres VE
影响因子：
4
作者：
Meyer, Bruno H.;Freuler, Felix;Siehler, Sandra
通讯作者：
Siehler, Sandra
DOI：
10.1097/01.asn.0000144204.01352.86
发表时间：
2004-12-01
影响因子：
13.6
作者：
Piontek, KB;Huso, DL;Germino, GG
通讯作者：
Germino, GG
DOI：
10.1073/pnas.0605266104
发表时间：
2007-01-30
影响因子：
11.1
作者：
Hossain, Zakir;Ali, Safiah Mohamed;Hunziker, Walter
通讯作者：
Hunziker, Walter
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW