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Mechanisms of disease

New insights into cystic fibrosis: molecular switches that regulate CFTR

Key Points

  • Cystic fibrosis transmembrane conductance regulator, (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. Mutations in ABC genes have been linked to many genetic diseases including cystic fibrosis (associated with mutations in ABCC7), Dubin–Johnson Syndrome (associated with mutations in ABCC2), age-related macular degeneration (associated with mutations in ABCA4), Tangier disease (associated with mutations in ABCA1) and sitosterolaemia (associated with mutations in ABCG5 and ABCG8).

  • CFTR is a plasma membrane, cAMP-activated Cl channel that is expressed in functionally diverse tissues, including kidney, pancreas, intestine, heart, vas deferens, sweat duct and lung. In epithelial cells, CFTR mediates Clsecretion.

  • Mutations in CFTR cause cystic fibrosis, whereas the activation of CFTR in the intestine causes secretory diarrhoea. Therefore the function and regulation of CFTR are intensively investigated.

  • CFTR assembles into large, dynamic macromolecular complexes that contain signalling molecules, kinases, transport proteins, PDZ-domain-containing proteins, myosin motors, Rab GTPases, and SNAREs. These molecular switches ensure the fidelity of signalling, amplify signals, enable efficient signalling and facilitate the interaction of CFTR with other transport proteins.

  • Understanding how molecular switches and macromolecular signalling complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases that involve CFTR-mediated Cl secretion, including secretory diarrhoea that is caused by Vibrio cholera and Clostridium difficle toxins.

  • This review discusses how molecular switches and macromolecular complexes regulate CFTR and speculates about some promising areas for additional study in this dynamic and rapidly moving area of research.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR), a Cl-selective ion channel, is a prototypic member of the ATP-binding cassette transporter superfamily that is expressed in several organs. In these organs, CFTR assembles into large, dynamic macromolecular complexes that contain signalling molecules, kinases, transport proteins, PDZ-domain-containing proteins, myosin motors, Rab GTPases, and SNAREs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases.

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Figure 1: Molecular switches that regulate CFTR activity in the plasma membrane.
Figure 2: Regulation of CFTR activity in the plasma membrane of epithelial cells.
Figure 3: Model describing how molecular switches regulate CFTR trafficking.
Figure 4: Rab GTPases regulate CFTR trafficking, and thereby the localization of CFTR in the plasma membrane.
Figure 5: NHERF1 mediates the protein–protein interaction between CFTR and ENaC and facilitates reciprocal regulation between these channels.

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Acknowledgements

Due to space limitations the authors regret that they could not cite all of the outstanding papers that have contributed to this field. The authors thank A. Swiatecka-Urban for comments on this review. National Institutes of Health Grants and Research Development Program grants from the Cystic Fibrosis Foundation supported research in the author's laboratories.

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Correspondence to Bruce A. Stanton.

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DATABASES

OMIM

ABCA1

ABCA4

ABCC2

ABCC7

ABCG5

FURTHER INFORMATION

William Guggino's homepage

Bruce Stanton's homepage

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

Cystic Fibrosis Foundation

Cystic Fibrosis Mutation Database

Cystic Fibrosis Foundation – Clinical Trials & Clinical Studies

Glossary

Cystic fibrosis transmembrane conductance regulator

(CFTR). A Cl-selective ion channel that is activated by protein kinase A, and is a regulator of other ion channels and transporters.

ATP-binding cassette (ABC) transporters

A family of transport proteins that bind ATP and use its energy to transport molecules across cell membranes. Examples include the multidrug-resistance-related proteins MRP2 and MRP4, Pglycoprotein, ABCA1 and ABCA7.

Cystic fibrosis

An autosomal recessive genetic disease that is caused by mutations in CFTR.

Dubin–Johnson Syndrome

An autosomal recessive genetic liver disease that is characterized by congenital hyperbilirubinaemia and is caused by mutations in ABCC2, the gene which encodes multidrug-resistance-related protein-2.

Molecular switches

Molecular switches are defined as molecules that exist in two different states: an activated state that regulates other molecules or signalling pathways, and an inactivated state that cannot regulate other molecules or downstream signalling pathways.

Epithelial sodium channel

(ENaC). ENaC mediates sodium absorption in airway and kidney epithelial cells and sweat ducts. In airways and kidneys, CFTR inhibits ENaC, whereas in sweat ducts CFTR activates ENaC.

Ras GTPase

The Ras GTPase superfamily of small monomeric G proteins are GDP–GTP regulated molecular switches.

SNAREs

(Soluble N-ethylmalemide-sensitive factor attachment protein receptors). These proteins mediate membrane fusion and vesicle trafficking by assembling into complexes that link vesicle-associated SNAREs (v-SNAREs) with SNAREs on target membranes (t-SNAREs).

PDZ domain

PDZ domains, which are named after the three proteins in which this domain was first described (PSD95, Dlg, and ZO-1), are 80–100 amino-acid modules that mediate protein–protein interactions by binding to short peptide sequences that are most often in the C termini of the target proteins.

Protein phosphatase-2

(PP2A). A heterotrimeric protein phosphatase that interacts with and dephosphorylates CFTR.

AMP kinase

(AMPK). A molecular switch that links ion transport to cellular metabolism. AMPK is activated when the AMP/ATP ratio increases.

Ezrin

A member of the ezrin, radixin, moesin (ERM) family of actin-binding proteins. ERM proteins link the actin cytoskeleton to plasma-membrane proteins and function as signal transducers in responses that involve cytoskeletal remodelling. Ezrin has been implicated in metastatic-tumour formation.

Na+/H+ exchanger regulatory factor isoform-1

(NHERF1). The first PDZ-domain protein that was identified to bind to and regulate CFTR. NHERF1was originally named for its capacity to inhibit the Na+/H+ exchanger.

CFTR-associated ligand

(CAL). A PDZ-domain protein that is expressed primarily in the trans-Golgi that regulates the intracellular trafficking of CFTR and several other transporters and receptors.

Fluorescent recovery after photobleaching

A fluorescent-based confocal-microscopy imaging technique that is used to monitor protein trafficking and to study protein–protein interactions in cells.

Endocytosis

A process by which extracellular material and membrane-resident proteins are taken up by cells.

Rho GTPase

Members of the Ras GTPase superfamily that regulate signalling networks that influence actin organization, the cell cycle, and gene expression.

Exocytosis

The movement of vesicles inside the cell to the plasma membrane, where the vesicles fuse with the membrane. By fusing, they release the contents of the vesicle into the extracellular space and they insert proteins that were in the vesicle membrane into the plasma membrane.

Rab GTPases

Members of the Ras GTPase superfamily that control endocytosis, vesicle trafficking, endosome fusion and exocytosis.

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Guggino, W., Stanton, B. New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat Rev Mol Cell Biol 7, 426–436 (2006). https://doi.org/10.1038/nrm1949

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