Pathway maps

wtCFTR and deltaF508 traffic / Membrane expression (norm and CF)
wtCFTR and deltaF508 traffic / Membrane expression (norm and CF)

Object List (links open in MetaCore):

<cytosol> HCO(,3)('-) = <extracellular region> HCO(,3)('-), PKA-reg type II (cAMP-dependent), SNAP-23, Syntaxin 1A, E3KARP (NHERF2), <cytosol> glutathione = <extracellular region> glutathione, PKA-reg (cAMP-dependent), MUNC18, Filamin B (TABP), CFTR, CFTR, L-Adrenaline extracellular region, Rabenosyn-5, Myosin Vb, Rabaptin-5, HCO(,3)('-), EHD1, RACK1, VIL2 (ezrin), Rab-11A, CFTR, Rab-4, Tubulin (in microtubules), Glutathione extracellular region, COMMD1 (MURR1), Beta-2 adrenergic receptor, Chloride ion extracellular region, PKA-cat (cAMP-dependent), PKC-epsilon, Chloride ion cytosol, Rab11-FIP2, HCO(,3)('-) extracellular region, Filamin A, Glutathione cytoplasm, EBP50, <cytosol> Cl(-) = <extracellular region> Cl(-)


wtCFTR and deltaF508 traffic/ Membrane expression (norm and CF)

The cystic fibrosis transmembrane conductance regulator ( CFTR ) is a member of the ATP-binding cassette transporter superfamily. It acts in apical part of the epithelial cells as a plasma-membrane cyclic AMP-activated chloride anion, bicarbonate anion and glutathione channel [1], [2], [3]. Cell surface expression of the CFTR is a highly regulated intracellular process [4], [5].

CFTR may be delivered to the cell surface from Golgi or via shot pathway from endosomes via different recycling endosomes [6], [5]. It is realized mainly via Rab-4 and/or Rab-11A -dependent mechanisms [7].

Endogenous Rab-11A, a member RAS oncogene family, in a complex with Myosin Vb and EH-domain containing 1 ( EHD1 ) facilitates recycling of CFTR from recycling endosomes to the apical plasma membrane in polarized epithelial cells [8], [9], [10]. Rab-4 group of proteins belongs to RAS oncogene family which controls recycling events from endosome to the plasma membrane, fusion, and degradation inhibits CFTR chloride channel activity by diminishing its cell surface expression [11].

CFTR stabilization in plasma membrane depends on several proteins. Cyclic adenosine monophosphate cAMP-dependent protein kinase A ( PKA ) affects CFTR channel including stabilization in plasma membrane [12]. The anchoring protein V illin 2 ( VIL2 (ezrin) ) promotes PKA- to- CFTR interaction [13]. Moreover VIL2 (ezrin) itself exists in a complex with CFTR. This interaction is mediated by the Solute carrier family 9 member 3 regulator 2 ( E3KARP (NHERF2) ) - a PDZ-containing binding partner of CFTR [14]. Formation of a VIL2 (ezrin)/ E3KARP (NHERF2)/ CFTR complex enhances the efficacy of cAMP-mediated CFTR activation [14].

Beta-2 adrenergic receptor participates in CFTR stabilization as well. Stimulation of Beta-2 adrenergic receptor increases CFTR expression on apical membrane of epithelial cells as well as its association with Solute carrier family 9 member 3 regulator 1 ( EBP50 ). Importantly this process is independent of the agonist-mediated PKA pathway [15], [16]. On the other hand, PKA-cat -mediated phosphorylation of CFTR strongly inhibits formation of the macromolecular complex consisting of Beta-2 adrenergic receptor/ EBP50/ CFTR [15]. The functional consequences of this disruption of this complex are elusive.

CFTR membrane expression is also regulated by the Tubulin/ EBP50/ Guanine nucleotide binding protein beta polypeptide 2-like 1 ( RACK1 )/ Protein kinase C epsilon ( PKC-epsilon ) pathway. PKC-epsilon phosphorylates CFTR and, thus, stabilize expression of CFTR in the apical plasma membrane of epithelial cells. [17], [18].

Moreover, Copper metabolism domain containing 1 ( COMMD1 ) (Drevillion, L et al., The 21st annual north American cystic fibrosis conference, California, 2007), Filamin A and Filamin B [19] stabilize CFTR.

Syntaxin 1A/ Synaptosomal-associated protein 23kDa ( SNAP-23 ) have negative influence on CFTR membrane expression [12], [20].

The most common CFTR mutation is the loss of a Phe residue at position 508 ( deltaF508 -CFTR ). deltaF508 -CFTR membrane expression is reduced compare with wtCFTR, but stabilization in plasma membrane deltaF508 -CFTR and wtCFTR is regulated in a similar manner.


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    CFTR directly mediates nucleotide-regulated glutathione flux. The EMBO journal 2003 May 1;22(9):1981-9
  2. Chan HC, Shi QX, Zhou CX, Wang XF, Xu WM, Chen WY, Chen AJ, Ni Y, Yuan YY
    Critical role of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm. Molecular and cellular endocrinology 2006 May 16;250(1-2):106-13
  3. Gadsby DC, Vergani P, Csanady L
    The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 2006 Mar 23;440(7083):477-83
  4. Guggino WB, Stanton BA
    New insights into cystic fibrosis: molecular switches that regulate CFTR. Nature reviews. Molecular cell biology 2006 Jun;7(6):426-36
  5. Ameen N, Silvis M, Bradbury NA
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  6. Maxfield FR, McGraw TE
    Endocytic recycling. Nature reviews. Molecular cell biology 2004 Feb;5(2):121-32
  7. Saxena SK, Kaur S
    Regulation of epithelial ion channels by Rab GTPases. Biochemical and biophysical research communications 2006 Dec 22;351(3):582-7
  8. Picciano JA, Ameen N, Grant BD, Bradbury NA
    Rme-1 regulates the recycling of the cystic fibrosis transmembrane conductance regulator. American journal of physiology. Cell physiology 2003 Nov;285(5):C1009-18
  9. Swiatecka-Urban A, Brown A, Moreau-Marquis S, Renuka J, Coutermarsh B, Barnaby R, Karlson KH, Flotte TR, Fukuda M, Langford GM, Stanton BA
    The short apical membrane half-life of rescued {Delta}F508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of {Delta}F508-CFTR in polarized human airway epithelial cells. The Journal of biological chemistry 2005 Nov 4;280(44):36762-72
  10. Swiatecka-Urban A, Talebian L, Kanno E, Moreau-Marquis S, Coutermarsh B, Hansen K, Karlson KH, Barnaby R, Cheney RE, Langford GM, Fukuda M, Stanton BA
    Myosin VB is required for trafficking of CFTR in RAB11A-specific apical recycling endosomes in polarized human airway epithelial cells. The Journal of biological chemistry 2007 Apr 26;
  11. Saxena SK, Kaur S, George C
    Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane. Biochemical and biophysical research communications 2006 Mar 3;341(1):184-91
  12. Chang SY, Di A, Naren AP, Palfrey HC, Kirk KL, Nelson DJ
    Mechanisms of CFTR regulation by syntaxin 1A and PKA. Journal of cell science 2002 Feb 15;115(Pt 4):783-91
  13. Sun F, Hug MJ, Bradbury NA, Frizzell RA
    Protein kinase A associates with cystic fibrosis transmembrane conductance regulator via an interaction with ezrin. The Journal of biological chemistry 2000 May 12;275(19):14360-6
  14. Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA
    E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells. The Journal of biological chemistry 2000 Sep 22;275(38):29539-46
  15. Naren AP, Cobb B, Li C, Roy K, Nelson D, Heda GD, Liao J, Kirk KL, Sorscher EJ, Hanrahan J, Clancy JP
    A macromolecular complex of beta 2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA. Proceedings of the National Academy of Sciences of the United States of America 2003 Jan 7;100(1):342-6
  16. Taouil K, Hinnrasky J, Hologne C, Corlieu P, Klossek JM, Puchelle E
    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. The Journal of biological chemistry 2003 May 9;278(19):17320-7
  17. Liedtke CM, Yun CH, Kyle N, Wang D
    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. The Journal of biological chemistry 2002 Jun 21;277(25):22925-33
  18. Auerbach M, Liedtke CM
    Role of the scaffold protein RACK1 in apical expression of CFTR. American journal of physiology. Cell physiology 2007 Jul;293(1):C294-304
  19. Thelin WR, Chen Y, Gentzsch M, Kreda SM, Sallee JL, Scarlett CO, Borchers CH, Jacobson K, Stutts MJ, Milgram SL
    Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. The Journal of clinical investigation 2007 Feb;117(2):364-74
  20. Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL
    CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex. Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12477-82