Fibrocystin/Polyductin, Found in the Same Protein Complex with Polycystin-2, Regulates Calcium Responses in Kidney Epithelia

Wang, S.; Zhang, Jingjing; Nauli, Surya M.; Li, Yong; Starremans, Patrick G.; Luo, Ying; Roberts, Kristina A.; Zhou, Jing

doi:10.1128/mcb.00072-07

Cited by 166 publications

(151 citation statements)

References 44 publications

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“…This is especially interesting in that the exocyst was shown previously, in most studies, to be involved in basolateral, and not apical, membrane trafficking (Grindstaff et al, 1998;Lipschutz et al, 2000Lipschutz et al, , 2003. These data add to a growing body of evidence suggesting that the primary cilium, whereas it is found on the apical surface, it is not a typical "apical organelle" and helps explain the fact that primary cilia contain many proteins that also localize to the basolateral membrane, including: ␣3␤1 integrin (Praetorius et al, 2004), galectin (Bao and Hughes, 1999), and the PKD proteins polycystin-1, polycystin-2, and fibrocystin (Wang et al, 2007). In yeast, Sec4, a small Rab GTPase, is found on vesicles carrying polarized proteins and regulates the exocyst complex via interactions with Sec10/Sec15 (Guo et al, 1999).…”

Section: Discussionmentioning

confidence: 56%

The Exocyst Protein Sec10 Is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro

Zuo

Guo

Lipschutz

2009

MBoC

162

259

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Primary cilia are found on many epithelial cell types, including renal tubular epithelial cells, in which they are felt to participate in flow sensing and have been linked to the pathogenesis of cystic renal disorders such as autosomal dominant polycystic kidney disease. We previously localized the exocyst, an eight-protein complex involved in membrane trafficking, to the primary cilium of Madin-Darby canine kidney cells and showed that it was involved in cystogenesis. Here, using short hairpin RNA (shRNA) to knockdown exocyst expression and stable transfection to induce exocyst overexpression, we show that the exocyst protein Sec10 regulates primary ciliogenesis. Using immunofluorescence, scanning, and transmission electron microscopy, primary cilia containing only basal bodies are seen in the Sec10 knockdown cells, and increased ciliogenesis is seen in Sec10-overexpressing cells. These phenotypes do not seem to be because of gross changes in cell polarity, as apical, basolateral, and tight junction proteins remain properly localized. Sec10 knockdown prevents normal cyst morphogenesis when the cells are grown in a collagen matrix, whereas Sec10 overexpression results in increased cystogenesis. Transfection with human Sec10 resistant to the canine shRNA rescues the phenotype, demonstrating specificity. Finally, Par3 was recently shown to regulate primary cilia biogenesis. Par3 and the exocyst colocalized by immunofluorescence and coimmunoprecipitation, consistent with a role for the exocyst in targeting and docking vesicles carrying proteins necessary for primary ciliogenesis.

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Section: Discussionmentioning

confidence: 56%

The Exocyst Protein Sec10 Is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro

Zuo

Guo

Lipschutz

2009

MBoC

162

259

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“…Another recent report that supports a functional link suggests that FPC regulates mechanotransduced Ca 2ϩ responses, which may be induced by PC2, in cultured Pkhd1-knockdown cells. 43 In this study, the evidence that the COOHterminus of FPC directly interacts with the NH2-terminus of PC2 suggests that FPC and PC2 are able physically to form a heterodimeric complex in vivo. Lack of FPC downregulates Pkd2-channel activities in either the Pkhd1-knockout renal epithelial cells in primary culture or the Pkhd1-knockdown IMCD cells that we generated previously.…”

Section: Discussionmentioning

confidence: 63%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

129

105

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Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway. For investigation of this, a mouse model with a gene-targeted mutation in Pkhd1 that recapitulates phenotypic characteristics of human autosomal recessive polycystic kidney disease was produced. The absence of FPC is associated with aberrant ciliogenesis in the kidneys of Pkhd1-deficient mice. It was found that the COOH-terminus of FPC and the NH2-terminus of PC2 interact and that lack of FPC reduced PC2 expression but not vice versa, suggesting that PC2 may function immediately downstream of FPC in vivo. PC2-channel activities were dysregulated in cultured renal epithelial cells derived from Pkhd1 mutant mice, further supporting that both cystoproteins function in a common pathway. In addition, mice with mutations in both Pkhd1 and Pkd2 had a more severe renal cystic phenotype than mice with single mutations, suggesting that FPC acts as a genetic modifier for disease severity in autosomal dominant polycystic kidney disease that results from Pkd2 mutations. It is concluded that a functional and molecular interaction exists between FPC and PC2 in vivo.

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“…44 Fibrocystin is localized to the cilium and has been recently found in the same protein complex as PC2. 18,45 This suggests that fibrocystin and the autosomal dominant disease proteins may share a common pathway. We addressed the question whether lack of PC1 or PC2 might influence location or level of fibrocystin expression by examining fibrocystic expression in orthologous cystic models because of mutation in either Pkd1 or Pkd2.…”

Section: Discussionmentioning

confidence: 99%

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher

Esquivel

Briere

et al. 2008

The American Journal of Pathology

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Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkhd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at ϳ30% of wild-type levels. Pkhd1 del4/del4 mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1 del4/del4 mice also retains this expression pattern. The hypomorphic Pkhd1 del4/del4 mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkhd1 mutations. (Am J

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Fibrocystin/Polyductin, Found in the Same Protein Complex with Polycystin-2, Regulates Calcium Responses in Kidney Epithelia

Cited by 166 publications

References 44 publications

The Exocyst Protein Sec10 Is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro

The Exocyst Protein Sec10 Is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

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