Polarity Proteins Control Ciliogenesis via Kinesin Motor Interactions

Fan, Shuling; Hurd, Toby W.; Liu, Chia Jen; Straight, Samuel W.; Weimbs, Thomas; Hurd, E. A.; Domino, Steven E.; Margolis, Ben

doi:10.1016/j.cub.2004.08.025

Cited by 199 publications

(228 citation statements)

References 48 publications

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“…Recent findings have also localized Par3, Par6, and atypical protein kinase C to primary cilia. These proteins seem to be important in ciliogenesis, perhaps through their interactions with critical ciliary proteins such as KIF3A and Crumbs3a (13,14). This is the first report to show that Cdc42 and Tuba, a Cdc42 GEF, also contribute to ciliogenesis in epithelial cells.…”

Section: Discussionmentioning

confidence: 75%

“…We previously found that the exocyst coimmunoprecipitated and colocalized with Par3 (5), a main component of the Par complex that consists of Par3, Par6, atypical protein kinase C, and Cdc42 (11,12). In addition to their studied function at cell-cell contacts, the Par complex has been immunolocalized to primary cilia and has been shown to be necessary for ciliogenesis (13,14). It is known that the exocyst is regulated by multiple Rho and Rab family GTPases (reviewed in 15), which, like the exocyst, play central roles in cell polarization, morphogenesis, membrane trafficking, cell growth, and development (16,17).…”

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confidence: 99%

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The Small GTPase Cdc42 Is Necessary for Primary Ciliogenesis in Renal Tubular Epithelial Cells

Zuo

Fogelgren

Lipschutz

2011

Journal of Biological Chemistry

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Primary cilia are found on many epithelial cell types, including renal tubular epithelial cells, where they participate in flow sensing. Disruption of cilia function has been linked to the pathogenesis of polycystic kidney disease. We demonstrated previously that the exocyst, a highly conserved eight-protein membrane trafficking complex, localizes to primary cilia of renal tubular epithelial cells, is required for ciliogenesis, biochemically and genetically interacts with polycystin-2 (the protein product of the polycystic kidney disease 2 gene), and, when disrupted, results in MAPK pathway activation both in vitro and in vivo. The small GTPase Cdc42 is a candidate for regulation of the exocyst at the primary cilium. Here, we demonstrate that Cdc42 biochemically interacts with Sec10, a crucial component of the exocyst complex, and that Cdc42 colocalizes with Sec10 at the primary cilium. Expression of dominant negative Cdc42 and shRNA-mediated knockdown of both Cdc42 and Tuba, a Cdc42 guanine nucleotide exchange factor, inhibit ciliogenesis in Madin-Darby canine kidney cells. Furthermore, exocyst Sec8 and polycystin-2 no longer localize to primary cilia or the ciliary region following Cdc42 and Tuba knockdown. We also show that Sec10 directly interacts with Par6, a member of the Par complex that itself directly interacts with Cdc42. Finally, we show that Cdc42 knockdown results in activation of the MAPK pathway, something observed in cells with dysfunctional primary cilia. These data support a model in which Cdc42 localizes the exocyst to the primary cilium, whereupon the exocyst then targets and docks vesicles carrying proteins necessary for ciliogenesis.

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Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

The Small GTPase Cdc42 Is Necessary for Primary Ciliogenesis in Renal Tubular Epithelial Cells

Zuo

Fogelgren

Lipschutz

2011

Journal of Biological Chemistry

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“…For example, we still know little about membrane trafficking to the primary cilium, which outgrows from the apical membrane during polarization. Interestingly, proteins localized at tight junctions (Par3/Par6/aPKC) or factors involved in sorting to the basolateral membrane (Rab8) have recently also been noted for their role in cilium biogenesis [57][58][59][60] or even regulation of apical protein localization (Rab8) a phenotype perhaps related to impaired cilia [61]. Furthermore, the exocyst complex has also been localized to the base of the cilium in addition to the lateral membrane [62].…”

Section: Discussionmentioning

confidence: 99%

Regulation of membrane trafficking in polarized epithelial cells

Fölsch¹

2008

Current Opinion in Cell Biology

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Polarized epithelial cells continuously sort transmembrane proteins to either apical or basolateral plasma membrane domains. Research in recent years has made tremendous progress in understanding the molecular mechanisms of the major pathways to either basolateral or apical domain. This understanding will help us elucidating how these pathways are interconnected in ensuring maintenance of cell polarity and integrity of epithelial monolayers.

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“…Several gene products, which when mutated result in the development of PKD, including polycystin-1 and polycystin-2, have been localized to and are crucial for the function of renal primary cilia (for review, see Smyth et al, 2003). It was recently shown that the postsynaptic density 95/disc-large/ zona occludens (PDZ) protein Par3 is necessary for the biogenesis of primary renal cilia (Fan et al, 2004;Sfakianos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Zuo

Guo

Lipschutz

2009

MBoC

157

256

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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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Polarity Proteins Control Ciliogenesis via Kinesin Motor Interactions

Abstract: Our findings point to a heretofore unappreciated role for polarity proteins in cilia formation and provide a potentially unique insight into the pathogenesis of human kidney and retinal disease.

Cited by 199 publications

References 48 publications

The Small GTPase Cdc42 Is Necessary for Primary Ciliogenesis in Renal Tubular Epithelial Cells

The Small GTPase Cdc42 Is Necessary for Primary Ciliogenesis in Renal Tubular Epithelial Cells

Regulation of membrane trafficking in polarized epithelial cells

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

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