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Gene Review

CFTR  -  cystic fibrosis transmembrane conductance...

Homo sapiens

Synonyms: ABC35, ABCC7, ATP-binding cassette sub-family C member 7, CF, CFTR/MRP, ...
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Disease relevance of CFTR


Psychiatry related information on CFTR


High impact information on CFTR

  • Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF) [9].
  • Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are reviewed in section ii and addressed in disease-specific subsections on asthma, COPD, and CF [9].
  • Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels [10].
  • Cl(-) secretion in the adult colon relies on luminal CFTR, which is a cAMP-regulated Cl(-) channel and a regulator of other transport proteins [11].
  • Three molecularly distinct Cl- channel families (CLC, CFTR, and ligand-gated GABA and glycine receptors) are well established [12].

Chemical compound and disease context of CFTR


Biological context of CFTR


Anatomical context of CFTR

  • We present results from whole-cell and single-channel patch-clamp recordings, short-circuit current recordings, and [gamma-32P]ATP release assays of normal, CF, and wild-type or mutant CFTR-transfected CF airway cultured epithelial cells wherein CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell [21].
  • Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphorylation by protein kinases A and C, and two hydrophobic regions that probably interact with cell membranes [20].
  • We exposed several cystic fibrosis cell lines to the ER Ca(++) pump inhibitor thapsigargin and evaluated surface expression of Delta F508-CFTR [22].
  • Syntaxin 1A physically interacts with CFTR chloride channels and regulates CFTR-mediated currents both in Xenopus oocytes and in epithelial cells that normally express these proteins [14].
  • In contrast, in a remodeled surface epithelium associated with severe inflammation, CFTR protein presented either a diffuse distribution in the cytoplasm of ciliated cells, or was absent [23].

Associations of CFTR with chemical compounds

  • Another equally valid perspective of CFTR, however, derives from its membership in a family of transporters that transports a multitude of different substances from chemotherapeutic drugs, to amino acids, to glutathione conjugates, to small peptides in a nonconductive manner [24].
  • CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP [21].
  • We have examined Cl(-)-coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity [13].
  • Subsequent cloning of the gene showed that CFTR functions as a cyclic-AMP-regulated Cl- channel; and some CF-causing mutations inhibit CFTR Cl- channel activity [13].
  • Cells expressing wild-type CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, a phenylalanine deleted at residue 508 (delta508) [2].
  • The interaction of CK2 with NBD1 is selectively abrogated by the DeltaF508 mutation without disrupting four established CFTR-associated kinases and two phosphatases [25].
  • CFTR single-channel recordings and FRET-based intracellular cAMP dynamics suggest that a compartmentalized coupling of cAMP transporter and CFTR occurs via the PDZ scaffolding protein, PDZK1, forming a macromolecular complex at apical surfaces of gut epithelia [26].
  • Decreased trafficking of CFTR had a functional consequence as cells depleted of beta-COP showed decreased cAMP-activated chloride currents [27].
  • Results did not depend on whether GFP was added to the CFTR N terminus or fourth extracellular loop or on whether CFTR chloride conductance was stimulated by cAMP agonists [28].
  • Attenuation of CFTR by AMPK activation was detectable in the absence of cAMP-dependent stimulation but disappeared in maximally stimulated oocytes [29].

Physical interactions of CFTR

  • The earliest stage at which Hdj-2/Hsc70 could bind CFTR translation intermediates coincided with the expression of NBD1 in the cytosol [30].
  • NHERF also binds to the tail of the cystic fibrosis transmembrane conductance regulator, which ends in D-T-R-L [31].
  • Conversely, CFTR activity is stimulated by a SNAP-23 antibody that blocks the binding of this t-SNARE to the CFTR amino-terminal tail [32].
  • P-glycoprotein (P-gp) is an ideal model protein for studying how mutations disrupt folding of ATP-binding cassette proteins such as CFTR because specific chemical chaperones can be used to correct folding defects [33].
  • The finding that the YY1-binding allele causes a significant increase in CFTR expression in vitro may allow a better understanding of the milder phenotype observed in patients who carry a severe CF mutation within the same gene [34].
  • Endogenous CFTR formed a complex with endogenous myosin Vb and Rab11a [35].
  • 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 CAL.CFTR complex was constructed and used to generate a CAL mutant whose binding pocket is correctly folded but has lost its ability to bind CFTR [36].

Enzymatic interactions of CFTR

  • A putative step in the CFTR folding pathway catalyzed by Hdj-2/Hsc70 is the formation of an intramolecular NBD1-R-domain complex [30].
  • On the other hand, electrophysiological studies demonstrated that NHERF is able to stimulate the cAMP-dependent protein kinase-phosphorylated CFTR channel activity in intact cells [37].
  • Earlier clinical manifestations and death before the age of 5 years are typical for GSTM1-deleted CF patients [38].

Co-localisations of CFTR


Regulatory relationships of CFTR


Other interactions of CFTR


Analytical, diagnostic and therapeutic context of CFTR



  1. Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Gill, D.R., Hyde, S.C., Higgins, C.F., Valverde, M.A., Mintenig, G.M., Sepúlveda, F.V. Cell (1992) [Pubmed]
  2. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Pier, G.B., Grout, M., Zaidi, T., Meluleni, G., Mueschenborn, S.S., Banting, G., Ratcliff, R., Evans, M.J., Colledge, W.H. Nature (1998) [Pubmed]
  3. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. Heeckeren, A., Walenga, R., Konstan, M.W., Bonfield, T., Davis, P.B., Ferkol, T. J. Clin. Invest. (1997) [Pubmed]
  4. The duct cell in cystic fibrosis. Harris, A. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
  5. Genetics of pancreatitis. Keim, V. Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. (2005) [Pubmed]
  6. Reduced expression of the cystic fibrosis transmembrane conductance regulator gene in the hypothalamus of patients with Alzheimer's disease. Lahousse, S.A., Stopa, E.G., Mulberg, A.E., de la Monte, S.M. J. Alzheimers Dis. (2003) [Pubmed]
  7. Physicians' perceived usefulness of and satisfaction with test reports for cystic fibrosis (DeltaF508) and factor V Leiden. Krousel-Wood, M., Andersson, H.C., Rice, J., Jackson, K.E., Rosner, E.R., Lubin, I.M. Genet. Med. (2003) [Pubmed]
  8. The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis. Laki, J., Laki, I., N??meth, K., Ujhelyi, R., Bede, O., Endreffy, E., Bolb??s, K., Gyurkovits, K., Csisz??r, E., S??lyom, E., Dobra, G., Hal??sz, A., Pozsonyi, E., Rajczy, K., Proh??szka, Z., Fekete, G., F??st, G. Int. Immunol. (2006) [Pubmed]
  9. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Rose, M.C., Voynow, J.A. Physiol. Rev. (2006) [Pubmed]
  10. Lung epithelial fluid transport and the resolution of pulmonary edema. Matthay, M.A., Folkesson, H.G., Clerici, C. Physiol. Rev. (2002) [Pubmed]
  11. Electrolyte transport in the mammalian colon: mechanisms and implications for disease. Kunzelmann, K., Mall, M. Physiol. Rev. (2002) [Pubmed]
  12. Molecular structure and physiological function of chloride channels. Jentsch, T.J., Stein, V., Weinreich, F., Zdebik, A.A. Physiol. Rev. (2002) [Pubmed]
  13. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Choi, J.Y., Muallem, D., Kiselyov, K., Lee, M.G., Thomas, P.J., Muallem, S. Nature (2001) [Pubmed]
  14. Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms. Naren, A.P., Nelson, D.J., Xie, W., Jovov, B., Pevsner, J., Bennett, M.K., Benos, D.J., Quick, M.W., Kirk, K.L. Nature (1997) [Pubmed]
  15. Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor. Liedtke, C.M., Yun, C.H., Kyle, N., Wang, D. J. Biol. Chem. (2002) [Pubmed]
  16. Introduction of the most common cystic fibrosis mutation (Delta F508) into human P-glycoprotein disrupts packing of the transmembrane segments. Loo, T.W., Bartlett, M.C., Clarke, D.M. J. Biol. Chem. (2002) [Pubmed]
  17. MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms. Singh, A.P., Chauhan, S.C., Andrianifahanana, M., Moniaux, N., Meza, J.L., Copin, M.C., van Seuningen, I., Hollingsworth, M.A., Aubert, J.P., Batra, S.K. Oncogene (2007) [Pubmed]
  18. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Wang, S., Yue, H., Derin, R.B., Guggino, W.B., Li, M. Cell (2000) [Pubmed]
  19. An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR. Randak, C., Welsh, M.J. Cell (2003) [Pubmed]
  20. A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. Cutting, G.R., Kasch, L.M., Rosenstein, B.J., Zielenski, J., Tsui, L.C., Antonarakis, S.E., Kazazian, H.H. Nature (1990) [Pubmed]
  21. CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Schwiebert, E.M., Egan, M.E., Hwang, T.H., Fulmer, S.B., Allen, S.S., Cutting, G.R., Guggino, W.B. Cell (1995) [Pubmed]
  22. Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells. Egan, M.E., Glöckner-Pagel, J., Ambrose, C., Cahill, P.A., Pappoe, L., Balamuth, N., Cho, E., Canny, S., Wagner, C.A., Geibel, J., Caplan, M.J. Nat. Med. (2002) [Pubmed]
  23. CFTR and differentiation markers expression in non-CF and delta F 508 homozygous CF nasal epithelium. Dupuit, F., Kälin, N., Brézillon, S., Hinnrasky, J., Tümmler, B., Puchelle, E. J. Clin. Invest. (1995) [Pubmed]
  24. CFTR is a conductance regulator as well as a chloride channel. Schwiebert, E.M., Benos, D.J., Egan, M.E., Stutts, M.J., Guggino, W.B. Physiol. Rev. (1999) [Pubmed]
  25. Protein kinase CK2, cystic fibrosis transmembrane conductance regulator, and the deltaF508 mutation: F508 deletion disrupts a kinase-binding site. Treharne, K.J., Crawford, R.M., Xu, Z., Chen, J.H., Best, O.G., Schulte, E.A., Gruenert, D.C., Wilson, S.M., Sheppard, D.N., Kunzelmann, K., Mehta, A. J. Biol. Chem. (2007) [Pubmed]
  26. Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia. Li, C., Krishnamurthy, P.C., Penmatsa, H., Marrs, K.L., Wang, X.Q., Zaccolo, M., Jalink, K., Li, M., Nelson, D.J., Schuetz, J.D., Naren, A.P. Cell (2007) [Pubmed]
  27. Cystic fibrosis transmembrane conductance regulator trafficking is mediated by the COPI coat in epithelial cells. Rennolds, J., Tower, C., Musgrove, L., Fan, L., Maloney, K., Clancy, J.P., Kirk, K.L., Sztul, E., Cormet-Boyaka, E. J. Biol. Chem. (2008) [Pubmed]
  28. Monomeric CFTR in plasma membranes in live cells revealed by single molecule fluorescence imaging. Haggie, P.M., Verkman, A.S. J. Biol. Chem. (2008) [Pubmed]
  29. Mechanistic insight into control of CFTR by AMPK. Kongsuphol, P., Cassidy, D., Hieke, B., Treharne, K.J., Schreiber, R., Mehta, A., Kunzelmann, K. J. Biol. Chem. (2009) [Pubmed]
  30. The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. Meacham, G.C., Lu, Z., King, S., Sorscher, E., Tousson, A., Cyr, D.M. EMBO J. (1999) [Pubmed]
  31. A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. Hall, R.A., Ostedgaard, L.S., Premont, R.T., Blitzer, J.T., Rahman, N., Welsh, M.J., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  32. CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex. Cormet-Boyaka, E., Di, A., Chang, S.Y., Naren, A.P., Tousson, A., Nelson, D.J., Kirk, K.L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  33. Processing mutations located throughout the human multidrug resistance P-glycoprotein disrupt interactions between the nucleotide binding domains. Loo, T.W., Bartlett, M.C., Clarke, D.M. J. Biol. Chem. (2004) [Pubmed]
  34. A naturally occurring sequence variation that creates a YY1 element is associated with increased cystic fibrosis transmembrane conductance regulator gene expression. Romey, M.C., Pallares-Ruiz, N., Mange, A., Mettling, C., Peytavi, R., Demaille, J., Claustres, M. J. Biol. Chem. (2000) [Pubmed]
  35. Myosin Vb is required for trafficking of the cystic fibrosis transmembrane conductance regulator in Rab11a-specific apical recycling endosomes in polarized human airway epithelial cells. Swiatecka-Urban, A., Talebian, L., Kanno, E., Moreau-Marquis, S., Coutermarsh, B., Hansen, K., Karlson, K.H., Barnaby, R., Cheney, R.E., Langford, G.M., Fukuda, M., Stanton, B.A. J. Biol. Chem. (2007) [Pubmed]
  36. Targeting CAL as a negative regulator of DeltaF508-CFTR cell-surface expression: an RNA interference and structure-based mutagenetic approach. Wolde, M., Fellows, A., Cheng, J., Kivenson, A., Coutermarsh, B., Talebian, L., Karlson, K., Piserchio, A., Mierke, D.F., Stanton, B.A., Guggino, W.B., Madden, D.R. J. Biol. Chem. (2007) [Pubmed]
  37. The role of the C terminus and Na+/H+ exchanger regulatory factor in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia. Benharouga, M., Sharma, M., So, J., Haardt, M., Drzymala, L., Popov, M., Schwapach, B., Grinstein, S., Du, K., Lukacs, G.L. J. Biol. Chem. (2003) [Pubmed]
  38. Proportion of the GSTM1 0/0 genotype in some Slavic populations and its correlation with cystic fibrosis and some multifactorial diseases. Baranov, V.S., Ivaschenko, T., Bakay, B., Aseev, M., Belotserkovskaya, R., Baranova, H., Malet, P., Perriot, J., Mouraire, P., Baskakov, V.N., Savitskyi, G.A., Gorbushin, S., Deyneka, S.I., Michnin, E., Barchuck, A., Vakharlovsky, V., Pavlov, G., Shilko, V.I., Guembitzkaya, T., Kovaleva, L. Hum. Genet. (1996) [Pubmed]
  39. WNK1 and WNK4 modulate CFTR activity. Yang, C.L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D.C., Ellison, D.H. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  40. The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Burnett, B.G., Pittman, R.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  41. The chloride channel ClC-4 co-localizes with cystic fibrosis transmembrane conductance regulator and may mediate chloride flux across the apical membrane of intestinal epithelia. Mohammad-Panah, R., Ackerley, C., Rommens, J., Choudhury, M., Wang, Y., Bear, C.E. J. Biol. Chem. (2002) [Pubmed]
  42. Plasma membrane CFTR regulates RANTES expression via its C-terminal PDZ-interacting motif. Estell, K., Braunstein, G., Tucker, T., Varga, K., Collawn, J.F., Schwiebert, L.M. Mol. Cell. Biol. (2003) [Pubmed]
  43. Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane conductance regulator expression in human airway epithelial cells through a cAMP/protein kinase A-independent pathway. Taouil, K., Hinnrasky, J., Hologne, C., Corlieu, P., Klossek, J.M., Puchelle, E. J. Biol. Chem. (2003) [Pubmed]
  44. Ezrin controls the macromolecular complexes formed between an adapter protein Na+/H+ exchanger regulatory factor and the cystic fibrosis transmembrane conductance regulator. Li, J., Dai, Z., Jana, D., Callaway, D.J., Bu, Z. J. Biol. Chem. (2005) [Pubmed]
  45. Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator. Swiatecka-Urban, A., Boyd, C., Coutermarsh, B., Karlson, K.H., Barnaby, R., Aschenbrenner, L., Langford, G.M., Hasson, T., Stanton, B.A. J. Biol. Chem. (2004) [Pubmed]
  46. Cysteine string protein promotes proteasomal degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) by increasing its interaction with the C terminus of Hsp70-interacting protein and promoting CFTR ubiquitylation. Schmidt, B.Z., Watts, R.J., Aridor, M., Frizzell, R.A. J. Biol. Chem. (2009) [Pubmed]
  47. Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl(-) currents. Naren, A.P., Di, A., Cormet-Boyaka, E., Boyaka, P.N., McGhee, J.R., Zhou, W., Akagawa, K., Fujiwara, T., Thome, U., Engelhardt, J.F., Nelson, D.J., Kirk, K.L. J. Clin. Invest. (2000) [Pubmed]
  48. Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Noone, P.G., Zhou, Z., Silverman, L.M., Jowell, P.S., Knowles, M.R., Cohn, J.A. Gastroenterology (2001) [Pubmed]
  49. Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50. Mohler, P.J., Kreda, S.M., Boucher, R.C., Sudol, M., Stutts, M.J., Milgram, S.L. J. Cell Biol. (1999) [Pubmed]
  50. Vasoactive intestinal peptide, forskolin, and genistein increase apical CFTR trafficking in the rectal gland of the spiny dogfish, Squalus acanthias. Acute regulation of CFTR trafficking in an intact epithelium. Lehrich, R.W., Aller, S.G., Webster, P., Marino, C.R., Forrest, J.N. J. Clin. Invest. (1998) [Pubmed]
  51. The DeltaF508 mutation results in loss of CFTR function and mature protein in native human colon. Mall, M., Kreda, S.M., Mengos, A., Jensen, T.J., Hirtz, S., Seydewitz, H.H., Yankaskas, J., Kunzelmann, K., Riordan, J.R., Boucher, R.C. Gastroenterology (2004) [Pubmed]
  52. Development of an epithelium-specific expression cassette with human DNA regulatory elements for transgene expression in lung airways. Chow, Y.H., O'Brodovich, H., Plumb, J., Wen, Y., Sohn, K.J., Lu, Z., Zhang, F., Lukacs, G.L., Tanswell, A.K., Hui, C.C., Buchwald, M., Hu, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
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