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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.

SUBMITTER: Cai J

PROVIDER: S-EPMC6049514 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Cai Jing J Song Xuewen X Wang Wei W Watnick Terry T Pei York Y Qian Feng F Pan Duojia D

Genes & development 20180611 11-12

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in <i>PKD1</i> or <i>PKD2</i> 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 ...[more]

PMID: 29891559

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Project description:BACKGROUND:Osteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and consequently hold the significant promise for tumor imaging and targeted therapy. We aimed to explore the biological functions of Sphingosine 1-phosphate receptor 3 (S1PR3), one of the members of GPCRs family, in OS and the possibility of S1PR3 as an effective target for the treatment of osteosarcoma. METHODS:The quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Cell counting kit-8 (CCK8), colony formation assay and cell apoptosis assay were performed to test the cellular proliferation in vitro. Subcutaneous xenograft mouse model was generated to evaluate the functions of S1PR3 in vivo. RNA sequencing was used to compare gene expression patterns between S1PR3-knockdown and control MNNG-HOS cells. In addition, metabolic alternations in OS cells were monitored by XF96 metabolic flux analyzer. Co-immunoprecipitation (Co-IP) assay was used to explore the interaction between Yes-associated protein (YAP) and c-MYC. Chromatin immunoprecipitation was used to investigate the binding capability of PGAM1 and YAP or c-MYC. Moreover, the activities of promoter were determined by the luciferase reporter assay. FINDINGS:S1PR3 and its specific ligand Sphingosine 1-phosphate (S1P) were found elevated in OS, and the higher expression of S1PR3 was correlated with the poor survival rate. Moreover, our study has proved that the S1P/S1PR3 axis play roles in proliferation promotion, apoptosis inhibition, and aerobic glycolysis promotion of osteosarcoma cells. Mechanistically, the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted the nuclear translocation of YAP, which contributed to the formation of the YAP-c-MYC complex and enhanced transcription of the important glycolysis enzyme PGAM1. Moreover, the S1PR3 antagonist TY52156 exhibited in vitro and in vivo synergistic inhibitory effects with methotrexate on OS cell growth. INTERPRETATION:Our study unveiled a role of S1P, a bioactive phospholipid, in glucose metabolism reprogram through interaction with its receptor S1PR3. Targeting S1P/S1PR3 axis might serve as a potential therapeutic target for patients with OS. FUND: This research was supported by National Natural Science Foundation of China (81472445 and 81672587).

Dataset Information

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

Publications

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

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