A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

Stewart, Katherine; Gaitan, Yaned; Shafer, Maxwell E.R.; Aoudjit, Lamine; Hu, Di; Sharma, Richa; Tremblay, Mathieu; Ishii, Hidetaka; Marcotte, Michael; Stanga, Daniela; Tang, You Chi; Boualia, Sami Kamel; Nguyen, Alana H.T.; Takano, Tomoko; Lamarche-Vane, Nathalie; Vidal, Silvia M.; Bouchard, Maxime

doi:10.1371/journal.pgen.1005785

Cited by 22 publications

(37 citation statements)

References 63 publications

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“…We therefore conclude that the centrosome retention of ARHGAP5 and -29 are determined by their interaction with other proteins apart from PC1. A recent paper reported a glomerulocystic phenotype in an Arhgap35 (p190A RhoGAP) mutant mouse model generated in an ENU mutagenesis screen ( 25 ). The amino acid substitution (p.Leu1396Gln) leads to loss of function, resulting in increased RhoA activity and reduced ciliogenesis (number and length) rescued by ROCK inhibition ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling

Streets¹,

Prosseda²,

Ong³

2020

JCI Insight

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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.

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Section: Discussionmentioning

confidence: 99%

Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling

Streets¹,

Prosseda²,

Ong³

2020

JCI Insight

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“…RhoA activity is increased in IPF fibroblasts and associated with IPF phenotype such as expression of different markers like smooth muscle actin, collagen I, and fibronectin [115]. In glomerulocystic kidney defects, using a small-scale Nethyl-n-nitrosourea mutagenesis screen, Stewart et al highlighted a point mutation L1396G in p190A leading to an alteration on cilia elongation and its involvement in renal developmental diseases [116].…”

Section: P190rhogaps In Human Diseasesmentioning

confidence: 99%

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

Heraud

Pinault

Lagrée

et al. 2019

Cells

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Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins switch between an active and an inactive state, resulting in subsequent inhibiting or activating downstream signals, leading finally to regulation of actin-based processes. The On/Off status of Rho GTPases implicates two subsets of regulators: GEFs (guanine nucleotide exchange factors), which favor the active GTP (guanosine triphosphate) status of the GTPase and GAPs (GTPase activating proteins), which inhibit the GTPase by enhancing the GTP hydrolysis. In humans, the 20 identified Rho GTPases are regulated by over 70 GAP proteins suggesting a complex, but well-defined, spatio-temporal implication of these GAPs. Among the quite large number of RhoGAPs, we focus on p190RhoGAP, which is known as the main negative regulator of RhoA, but not exclusively. Two isoforms, p190A and p190B, are encoded by ARHGAP35 and ARHGAP5 genes, respectively. We describe here the function of each of these isoforms in physiological processes and sum up findings on their role in pathological conditions such as neurological disorders and cancers.

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“…ARHGAP35 encodes p190A RhoGAP (p190A), a large GTPase activating protein with functions implicated in cell adhesion, cell migration, cytokinesis, ciliogenesis, entosis, gene transcription, and protein translation [5][6][7][8][9][10][11][12]. Accordingly, ARHGAP35 is an essential gene, and p190A indeed exerts pivotal functions in development [13,14].…”

Section: Introductionmentioning

confidence: 99%

p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth

et al. 2020

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The ARHGAP35 gene encoding p190A RhoGAP (p190A) is significantly altered by both mutation and allelic deletion in human cancer, but the functional implications of such alterations are not known. Here, we demonstrate for the first time that p190A is a tumor suppressor using a xenograft mouse model with carcinoma cells harboring defined ARHGAP35 alterations. In vitro, restoration of p190A expression in carcinoma cells promotes contact inhibition of proliferation (CIP) through activation of LATS kinases and phosphorylation of the proto-oncogenic transcriptional co-activator YAP. In contrast, p190A forms harboring recurrent cancer mutations exhibit loss of function in modulating the Hippo pathway, inducing CIP, as well as attenuated suppression of tumor growth in mice. We determine that p190A promotes mesenchymal to epithelial transition (MET) and elicits expression of a cassette of epithelial adherens junction-associated genes in a cell density-dependent manner. This cassette includes CDH1 encoding E-cadherin, which amplifies p190A-mediated LATS activation and is necessary for CIP. Oppositely, we establish that p190A is obligatory for E-cadherin to activate LATS kinases and induce CIP. Collectively, this work defines a novel mechanism by which p190A and E-cadherin cooperate in modulating Hippo signaling to suppress tumor cell growth.

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A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects

Cited by 22 publications

References 63 publications

Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling

Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth

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