Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins

Huan, Yonghong; Adelsberg, Janet van

doi:10.1172/jci5111

Cited by 219 publications

(158 citation statements)

References 70 publications

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“…␤-Catenin has been shown to interact with PC1 to form a macromolecular complex at the adhesion junction of cells (25). The similar characteristics of the IP 3 R⅐PC1 complex and the ␤-catenin⅐PC1 complex on their distinct membranes suggest that different subcellular pools of PC1 may interact with various partners for different functions.…”

Section: Discussionmentioning

confidence: 99%

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Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

Santoso

et al. 2009

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…PC1 is also expressed in the adherens junction and focal adhesions of the plasma membrane (25,26). Interestingly, significant amounts of polycystins have also been found in the endoplasmic reticulum (ER) (27)(28)(29)(30)(31).…”

mentioning

confidence: 99%

Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

Santoso

et al. 2009

Journal of Biological Chemistry

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“…endogenous polycystin-1 in the plasma membrane (23,25,26). The housekeeping protein MSH2 was incorporated as a loading control (Fig.…”

Section: The Role Of Polycystin-1 In Wnt Signaling and Ap-1 Activationmentioning

confidence: 99%

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

Bent

Huls

et al. 2004

Journal of Biological Chemistry

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Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, ␤-catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.Progressive development of fluid-filled cysts in autosomal dominant polycystic kidney disease (ADPKD) 1 results in chronic renal failure. In the majority of patients, the disease can be accounted for by a mutation in the PKD1 gene (1, 2), whereas a minority suffers from a mutation in the PKD2 gene (3, 4). The precise function of polycystin-1 and polycystin-2, the proteins encoded by the PKD1 and PKD2 gene, respectively, remains to be elucidated. Polycystin-1 is predicted to be a transmembrane protein of ϳ460 kDa. The large extracellular N terminus contains multiple domains thought to be involved in cell-cell and cell-matrix interactions. The intracellular C terminus of polycystin-1 contains putative phosphorylation sites and a coiled-coil domain that can mediate protein-protein interactions.Several studies have implicated a role for polycystin-1 in signal transduction. Overexpression of the C-terminal region of polycystin-1 in human embryonic kidney 293T (HEK293T) cells has been shown to activate the Wnt signaling pathway (5) and the activator protein-1 (AP-1) transcription factor complex (6, 7). Furthermore, overexpression of a full-length polycystin-1 construct has been reported to activate the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway (8). These signaling pathways are all involved in key cellular processes such as proliferation and differentiation, cell cycle regulation, and cell survival. Since these cellular processes are essential for normal function, the signaling pathways governing them are tightly regulated. We ...

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“…Analysis-Methanol-fixed organ cultures were stained en bloc as described previously (21). Briefly, the fixed organ cultures were re-hydrated in PBS and blocked for 6 h in 1% bovine serum albumin or 10% donkey serum (Jackson ImmunoResearch).…”

Section: Confocal Microscopy Of Fetal Kidney Rudiments and Imagementioning

confidence: 99%

“…Each kidney rudiment was scanned 10 times 5-m apart. The scans were recorded as TIFF files and used for image analysis as described previously (21).…”

Section: Confocal Microscopy Of Fetal Kidney Rudiments and Imagementioning

confidence: 99%

Activation of Hepatocyte Growth Factor (HGF) by Endogenous HGF Activator Is Required for Metanephric Kidney Morphogenesis in Vitro

Adelsberg

Sehgal

Kukes

et al. 2001

Journal of Biological Chemistry

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The interaction of hepatocyte growth factor (HGF) with c-Met has been implicated in morphogenesis of the kidney, lung, mammary gland, liver, placenta, and limb bud. HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling. We show here that a serine protease specific for HGF, HGF activator (HGFA), is expressed and activated by the ureteric bud of the developing kidney in vivo and in vitro. Inhibition of HGFA activity with serine protease inhibitors reduced ureteric bud branching and inhibited glomerulogenesis and nephrogenesis. Activated HGF rescued developing kidneys from the effects of inhibitors. HGFA was localized around the tips of the ureteric bud in developing kidneys, while HGF was expressed diffusely throughout the mesenchyme. These data show that expression of HGF is not sufficient for development, but that its activation is also required. The localization of HGFA to the ureteric bud and the mesenchyme immediately adjacent to it suggests that HGFA creates a gradient of HGF activity in the developing kidney. The creation and shape of gradients of activated HGF by the localized secretion of HGF activators could play an important role in pattern formation by HGF responsive tissues.

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Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins

Cited by 219 publications

References 70 publications

Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

Polycystin-1 Interacts with Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling with Implications for Polycystic Kidney Disease

Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected

Activation of Hepatocyte Growth Factor (HGF) by Endogenous HGF Activator Is Required for Metanephric Kidney Morphogenesis in Vitro

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