Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling
| العنوان: | Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling |
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| المؤلفون: | Albert C.M. Ong, Andrew J. Streets, Philipp P. Prosseda |
| المصدر: | JCI Insight, Vol 5, Iss 16 (2020) JCI Insight |
| بيانات النشر: | American Society for Clinical investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, TRPP Cation Channels, RHOA, Mice, Transgenic, Proximity ligation assay, urologic and male genital diseases, Cell Line, 03 medical and health sciences, 0302 clinical medicine, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, medicine, Genetics, Animals, Guanine Nucleotide Exchange Factors, Humans, Cyst, Cilia, Rho-associated protein kinase, Protein Kinase C, Centrosome, rho-Associated Kinases, PKD1, biology, Chemistry, urogenital system, Cilium, General Medicine, Polycystic Kidney, Autosomal Dominant, medicine.disease, Actin cytoskeleton, Phenotype, Actins, female genital diseases and pregnancy complications, Cell biology, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, Nephrology, 030220 oncology & carcinogenesis, Mutation, biology.protein, Medicine, rhoA GTP-Binding Protein, Signal Transduction, Research Article, Genetic diseases |
| الوصف: | Mutations in PKD1 (encoding for polycystin-1 [PC1]) are found in 80%–85% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from PKD1 mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from patients with PKD1 and was associated with an increase in total and centrosomal active RhoA and ROCK signaling. Using cilia length as a phenotypic readout for centrosomal RhoA activity, we identified ARHGAP5, -29, and -35 as essential regulators of ciliation in normal human renal tubular cells. Importantly, a specific decrease in centrosomal ARHGAP35 was observed in PKD1-null cells using a centrosome-targeted proximity ligation assay and by dual immunofluorescence labeling. Finally, the ROCK inhibitor hydroxyfasudil reduced cyst expansion in both human PKD1 3D cyst assays and an inducible Pkd1 mouse model. In summary, we report a potentially novel interaction between PC1 and ARHGAP35 in the regulation of centrosomal RhoA activation and ROCK signaling. Targeting the RhoA/ROCK pathway inhibited cyst formation in vitro and in vivo, indicating its relevance to ADPKD pathogenesis and for developing new therapies to inhibit cyst initiation. Polycystin-1, the major protein mutated in autosomal dominant polycystic kidney disease, activates centrosomal RhoA activity via interaction with the Rho-GAP protein ARHGAP35, resulting in shorter cilia. |
| اللغة: | English |
| تدمد: | 2379-3708 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c7b6e24a5355dd56a31a16701681a0e6 https://doaj.org/article/5a9969d7d28a4e509127941488dce554 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c7b6e24a5355dd56a31a16701681a0e6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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