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J Clin Invest
2000 Jun 01;10512:1711-21. doi: 10.1172/JCI9622.
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Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase.
Hallows KR
,
Raghuram V
,
Kemp BE
,
Witters LA
,
Foskett JK
.
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The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated Cl(-) channel that regulates other epithelial transport proteins by uncharacterized mechanisms. We employed a yeast two-hybrid screen using the COOH-terminal 70 residues of CFTR to identify proteins that might be involved in such interactions. The alpha1 (catalytic) subunit of AMP-activated protein kinase (AMPK) was identified as a dominant and novel interacting protein. The interaction is mediated by residues 1420-1457 in CFTR and by the COOH-terminal regulatory domain of alpha1-AMPK. Mutations of two protein trafficking motifs within the 38-amino acid region in CFTR each disrupted the interaction. GST-fusion protein pull-down assays in vitro and in transfected cells confirmed the CFTR-alpha1-AMPK interaction and also identified alpha2-AMPK as an interactor with CFTR. AMPK is coexpressed in CFTR-expressing cell lines and shares an apical distribution with CFTR in rat nasal epithelium. AMPK phosphorylated full-length CFTR in vitro, and AMPK coexpression with CFTR in Xenopus oocytes inhibited cAMP-activated CFTR whole-cell Cl(-) conductance by approximately 35-50%. Because AMPK is a metabolic sensor in cells and responds to changes in cellular ATP, regulation of CFTR by AMPK may be important in inhibiting CFTR under conditions of metabolic stress, thereby linking transepithelial transport to cell metabolic state.
Altschul,
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
1997, Pubmed
Altschul,
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
1997,
Pubmed
Anderson,
Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia.
1992,
Pubmed
Bradbury,
Role of membrane trafficking in plasma membrane solute transport.
1994,
Pubmed
Brézillon,
ATP depletion induces a loss of respiratory epithelium functional integrity and down-regulates CFTR (cystic fibrosis transmembrane conductance regulator) expression.
1997,
Pubmed
Carling,
Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities.
1989,
Pubmed
Carson,
The two nucleotide-binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity.
1995,
Pubmed
Chen,
AMP-activated protein kinase phosphorylation of endothelial NO synthase.
1999,
Pubmed
Cheng,
Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis.
1990,
Pubmed
Cheng,
Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel.
1991,
Pubmed
Corton,
5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?
1995,
Pubmed
Crute,
Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase.
1998,
Pubmed
Devidas,
The cystic fibrosis transmembrane conductance regulator and ATP.
1997,
Pubmed
Dyck,
Regulation of 5'-AMP-activated protein kinase activity by the noncatalytic beta and gamma subunits.
1996,
Pubmed
Estojak,
Correlation of two-hybrid affinity data with in vitro measurements.
1995,
Pubmed
Foskett,
ClC and CFTR chloride channel gating.
1998,
Pubmed
Fraser,
Modulation of ion channels: a "current" view of AKAPs.
1999,
Pubmed
Gabriel,
CFTR and outward rectifying chloride channels are distinct proteins with a regulatory relationship.
1993,
Pubmed
Haardt,
C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation.
1999,
Pubmed
Hall,
G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction.
1999,
Pubmed
Hardie,
The AMP-activated protein kinase--fuel gauge of the mammalian cell?
1997,
Pubmed
Hardie,
The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?
1998,
Pubmed
Hasegawa,
A multifunctional aqueous channel formed by CFTR.
1992,
Pubmed
,
Xenbase
Jiang,
The Snf1 protein kinase and its activating subunit, Snf4, interact with distinct domains of the Sip1/Sip2/Gal83 component in the kinase complex.
1997,
Pubmed
Jiang,
Cystic fibrosis transmembrane conductance regulator-associated ATP release is controlled by a chloride sensor.
1998,
Pubmed
,
Xenbase
Kemp,
Dealing with energy demand: the AMP-activated protein kinase.
1999,
Pubmed
Kurth-Kraczek,
5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle.
1999,
Pubmed
Leclerc,
The 5'-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex.
1998,
Pubmed
Lee,
Regulation of Cl-/ HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells.
1999,
Pubmed
Marsh,
The structural era of endocytosis.
1999,
Pubmed
McNicholas,
Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the ATP-binding cassette transporter cystic fibrosis transmembrane regulator.
1996,
Pubmed
,
Xenbase
Michell,
Isoform-specific purification and substrate specificity of the 5'-AMP-activated protein kinase.
1996,
Pubmed
Naren,
Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms.
1997,
Pubmed
,
Xenbase
Naren,
Syntaxin 1A inhibits CFTR chloride channels by means of domain-specific protein-protein interactions.
1998,
Pubmed
,
Xenbase
Pasyk,
Mutant (delta F508) cystic fibrosis transmembrane conductance regulator Cl- channel is functional when retained in endoplasmic reticulum of mammalian cells.
1995,
Pubmed
Prince,
Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal.
1999,
Pubmed
Quinton,
Control of CFTR chloride conductance by ATP levels through non-hydrolytic binding.
1992,
Pubmed
Riordan,
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
1989,
Pubmed
Rommens,
Identification of the cystic fibrosis gene: chromosome walking and jumping.
1989,
Pubmed
Schreiber,
The cystic fibrosis transmembrane conductance regulator activates aquaporin 3 in airway epithelial cells.
1999,
Pubmed
,
Xenbase
Schwiebert,
CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP.
1995,
Pubmed
Sharma,
The C terminus of SUR1 is required for trafficking of KATP channels.
1999,
Pubmed
Short,
An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton.
1998,
Pubmed
Stapleton,
Mammalian 5'-AMP-activated protein kinase non-catalytic subunits are homologs of proteins that interact with yeast Snf1 protein kinase.
1994,
Pubmed
Stapleton,
Mammalian AMP-activated protein kinase subfamily.
1996,
Pubmed
Stutts,
Cystic fibrosis transmembrane conductance regulator inverts protein kinase A-mediated regulation of epithelial sodium channel single channel kinetics.
1997,
Pubmed
Takahashi,
CFTR-dependent membrane insertion is linked to stimulation of the CFTR chloride conductance.
1996,
Pubmed
,
Xenbase
Vennekens,
Inhibition of volume-regulated anion channels by expression of the cystic fibrosis transmembrane conductance regulator.
1999,
Pubmed
Weixel,
The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator binds to AP-2 clathrin adaptors.
2000,
Pubmed
Welsh,
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.
1993,
Pubmed
Wilkinson,
CFTR activation: additive effects of stimulatory and inhibitory phosphorylation sites in the R domain.
1997,
Pubmed
,
Xenbase
Wine,
Cystic fibrosis: How do CFTR mutations cause cystic fibrosis?
1995,
Pubmed
Xiong,
Structural cues involved in endoplasmic reticulum degradation of G85E and G91R mutant cystic fibrosis transmembrane conductance regulator.
1997,
Pubmed
,
Xenbase
