Cftr!

Fuller, Catherine M.; Benos, Dale J.

doi:10.1152/ajpcell.1992.263.2.c267

Cited by 214 publications

(139 citation statements)

References 109 publications

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“…The Cl ÿ channel blocker 5-nitro-2(3-phenylpropylaminobenzoate (NPPB) at 20 mM blocked the Cl ÿ current in T cells by > 50% (data not shown) [23]. In order to verify the Cl ÿ ion selectivity of the putative CFTR channel in T cells, the reversal potential was determined by decreasing the Cl ÿ concentration in the bath to 11 mM.…”

Section: Camp-dependent Agonists Activate CL ÿ Currents In Control Bumentioning

confidence: 99%

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Moss¹,

Bocian²,

Hsu³

et al. 1996

Clinical and Experimental Immunology

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Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. Non‐transformed, antigen‐responsive CD4+ T cells cloned from healthy controls and CF patients homozygous or heterozygous for the δF508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF patients displayed equivalent Ca2+‐mediated Cl− current; however, TCC from patients with CF but not controls displayed defective cAMP‐mediated Cl− current. Although CF‐derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted ≈ 45% less IL‐10 compared with control TCC after activation with concanavalin A (Con A) (624 ± 101 versus 1564 ± 401 pg/ml per 106 cells, respectively; P = 0.04) or anti‐CD3/phorbol ester (5148 ± 1634 versus 11 788 ± 2390 pg/ml; P = 0.05). This difference was independent of atopy. Secretion of interferon‐gamma, IL‐2, and IL‐4 was comparable in CF and control TCC after both forms of activation, while IL‐5 was reduced in CF TCC following anti‐CD3/phorbol myristate acetate (PMA) but not after Con A. We conclude that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL‐10 secretion after polyclonal activation. It is possible that disruption of IL‐10‐mediated anti‐inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.

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Section: Camp-dependent Agonists Activate CL ÿ Currents In Control Bumentioning

confidence: 99%

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Moss¹,

Bocian²,

Hsu³

et al. 1996

Clinical and Experimental Immunology

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“…Others, however, retain at least partial chloride channel conductivity, but lead to incorrect folding and/or intracellular trafficking of the protein, such that the mutant CFTR does not reach the apical membrane (4,5). This applies in particular to the most common genetic lesion associated with CF, in which the codon for Phe 508 is deleted (⌬F508) (6,7).…”

mentioning

confidence: 99%

Targeting CAL as a Negative Regulator of ΔF508-CFTR Cell-Surface Expression

Wolde¹,

Fellows²,

Cheng

et al. 2007

Journal of Biological Chemistry

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PDZ domains are ubiquitous peptide-binding modules that mediate protein-protein interactions in a wide variety of intracellular trafficking and localization processes. These include the pathways that regulate the membrane trafficking and endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride channel mutated in patients with cystic fibrosis. Correspondingly, a number of PDZ proteins have now been identified that directly or indirectly interact with the C terminus of CFTR. One of these is CAL, whose overexpression in heterologous cells directs the lysosomal degradation of WT-CFTR in a dose-dependent fashion and reduces the amount of CFTR found at the cell surface. Here, we show that RNA interference targeting endogenous CAL specifically increases cell-surface expression of the disease-associated ⌬F508-CFTR mutant and thus enhances transepithelial chloride currents in a polarized human patient bronchial epithelial cell line. We have reconstituted the CAL-CFTR interaction in vitro from purified components, demonstrating for the first time that the binding is direct and allowing us to characterize its components biochemically and biophysically. To test the hypothesis that inhibition of the binding site could also reverse CAL-mediated suppression of CFTR, a three-dimensional homology model of the CAL⅐CFTR complex was constructed and used to generate a CAL mutant whose binding pocket is correctly folded but has lost its ability to bind CFTR. Although produced at the same levels as wild-type protein, the mutant does not affect CFTR expression levels. Taken together, our data establish CAL as a candidate therapeutic target for correction of post-maturational trafficking defects in cystic fibrosis.

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“…Cystic fibrosis (CF), a lethal genetic disease, is caused by mutations in the CFTR gene (1,2). The most common mutation in CFTR is ⌬F508 (4,5). ⌬F508-CFTR does not fold properly, and most is retained within the endoplasmic reticulum and is subsequently degraded (5,6).…”

mentioning

confidence: 99%

Myosin VI Regulates Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator

Swiatecka‐Urban

Boyd

Coutermarsh

et al. 2004

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-regulated Cl ؊ channel expressed in the apical plasma membrane in fluid-transporting epithelia. Although CFTR is rapidly endocytosed from the apical membrane of polarized epithelial cells and efficiently recycled back to the plasma membrane, little is known about the molecular mechanisms regulating CFTR endocytosis and endocytic recycling. Myosin VI, an actin-dependent, minus-end directed mechanoenzyme, has been implicated in clathrin-mediated endocytosis in epithelial cells. The goal of this study was to determine whether myosin VI regulates CFTR endocytosis. Endogenous, apical membrane CFTR in polarized human airway epithelial cells (Calu-3) formed a complex with myosin VI, the myosin VI adaptor protein Disabled 2 (Dab2), and clathrin. The tail domain of myosin VI, a dominant-negative recombinant fragment, displaced endogenous myosin VI from interacting with Dab2 and CFTR and increased the expression of CFTR in the plasma membrane by reducing CFTR endocytosis. However, the myosin VI tail fragment had no effect on the recycling of endocytosed CFTR or on fluid-phase endocytosis. CFTR endocytosis was decreased by cytochalasin D, an actin-filament depolymerizing agent. Taken together, these data indicate that myosin VI and Dab2 facilitate CFTR endocytosis by a mechanism that requires actin filaments.

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Cftr!

Cited by 214 publications

References 109 publications

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Targeting CAL as a Negative Regulator of ΔF508-CFTR Cell-Surface Expression

Myosin VI Regulates Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator

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