Pathway maps

wtCFTR and deltaF508 traffic / Late endosome and Lysosome (norm and CF)
wtCFTR and deltaF508 traffic / Late endosome and Lysosome (norm and CF)

Object List (links open in MetaCore):

Rab-9, CFTR, Syntaxin 8, VTI1B, Rab-7, RILP, Rab-27A, VAMP8, MUNC13-4, 1,2-diacyl-glycerol 3-phosphoinositol, CFTR, ATP + 1,2-diacyl-glycerol 3-phosphoinositol = ADP + 1-(1,2-diacyl-glycerol 3-phospho)-inositol 3-phosphate, PI3K reg class III, PI3K cat class III, Slp5, 1-(1,2-diacyl-glycerol 3-phospho)-inositol 3-phosphate


wtCFTR and deltaF508 traffic/ Late endosome and Lysosome

(norm and CF)

The cystic fibrosis transmembrane conductance regulator ( CFTR ) is a member of the ATP-binding cassette transporter superfamily. It acts in the 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 internalization from plasma membrane is a very important step in CFTR regulation. CFTR may be internalizated from plasma membrane in a clathrin-dependent manner. Then coated-pit-derived primary endocytic vesicles are fused with sorting endosomes. The maturation of sorting endosomes to late endosomes is realized with participation of a member of the RAS oncogene family Rab7 via an unknown mechanism [6], [7], [8].

Late endosomes may fuse with other late endosomes or the lysosome via SNARE-mediated mechanism [9], [10], [11]. In addition, Rab7 is directly involved in the aggregation and fusion of late endocytic structures/lysosomes [12], [13].

Rab GTPase Rab-27A, which plays a pivotal role in secretions and lysosomal degradation, negatively regulates CFTR channel activity by physically interacting with it and impairing it from reaching the plasma membrane, thus increasing an internal or cytosolic CFTR pool, whereas S ynaptotagmin-like 5 ( Slp5 ) impairs CFTR ability to interact with Rab-27A and may rescue it via competition with Rab-27A [14].

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 and its lysosomal degradation is realized in the same way as wt CFTR, although more intensively [15].


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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
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  6. Feng Y, Press B, Wandinger-Ness A
    Rab 7: an important regulator of late endocytic membrane traffic. The Journal of cell biology 1995 Dec;131(6 Pt 1):1435-52
  7. Somsel Rodman J, Wandinger-Ness A
    Rab GTPases coordinate endocytosis. Journal of cell science 2000 Jan;113 Pt 2:183-92
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  9. Bilan F, Thoreau V, Nacfer M, Derand R, Norez C, Cantereau A, Garcia M, Becq F, Kitzis A
    Syntaxin 8 impairs trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits its channel activity. Journal of cell science 2004 Apr 15;117(Pt 10):1923-35
  10. Pryor PR, Mullock BM, Bright NA, Lindsay MR, Gray SR, Richardson SC, Stewart A, James DE, Piper RC, Luzio JP
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  11. Hong W
    SNAREs and traffic. Biochimica et biophysica acta 2005 Jun 30;1744(2):120-44
  12. Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B
    Rab7: a key to lysosome biogenesis. Molecular biology of the cell 2000 Feb;11(2):467-80
  13. Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A
    Human VPS34 and p150 are Rab7 interacting partners. Traffic (Copenhagen, Denmark) 2003 Nov;4(11):754-71
  14. Saxena SK, Kaur S
    Rab27a negatively regulates CFTR chloride channel function in colonic epithelia: involvement of the effector proteins in the regulatory mechanism. Biochemical and biophysical research communications 2006 Jul 21;346(1):259-67
  15. Sharma M, Pampinella F, Nemes C, Benharouga M, So J, Du K, Bache KG, Papsin B, Zerangue N, Stenmark H, Lukacs GL
    Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. The Journal of cell biology 2004 Mar 15;164(6):923-33