Pathway maps

Delta508-CFTR traffic / Sorting endosome formation in CF
Delta508-CFTR traffic / Sorting endosome formation in CF

Object List (links open in MetaCore):

Rabaptin-5, VPS45A, Rab-7, CHMP4B, 1-(1,2-diacyl-glycerol 3-phospho)-inositol 3-phosphate, delta508-CFTR, RABGEF1, VAMP2, Rab-5A, delta508-CFTR, Syntaxin 12, SNAP-25, Rabenosyn-5, STAM2,, PI3K cat class III, PI3K reg class III, TSG101, 1,2-diacyl-glycerol 3-phosphoinositol, Hrs, Ubiquitin, EEA1, Vps25, NSF


Delta508-CFTR traffic/ Sorting endosome formation in 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].

The most common CFTR mutation is the loss of a Phe residue at position 508 ( deltaF508-CFTR ). The mutant protein is recognized as misfolded by the endoplasmic reticulum (ER) quality control machinery and targeted for proteosomal degradation. This leads to inadequate amounts of poorly functioning CFTR reaching the cell membrane to achieve Cl(-) transport [6]. However, growth of deltaF508-CFTR expressing cells at reduced temperature allows the mutant CFTR molecules to exit the ER and reach the cell surface [5].

CFTR internalization from plasma membrane is a very important step in CFTR regulation. deltaF508-CFTR and wtCFTR may be internalizated from plasma membrane in similar clathrin-dependent manner. Then coated-pit-derived primary endocytic vesicles are fused with sorting endosomes. The fusion event is regulated by a member of RAS oncogene family Rab-5A, Early endosome antigen 1 ( EEA1 ) [7], [8] and Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) [9], [10].

At this phase, quality control at early endosome may eliminate deltaF508-CFTR as well. Components of the Ub-dependent endosomal sorting machinery Hepatocyte growth factor-regulated tyrosine kinase substrate ( Hrs ), Signal transducing adaptor molecule 2 ( STAM2 ), Tumor susceptibility gene 101 ( TSG101 ), Vacuolar protein sorting 25 homolog ( Vps25 ) and Chromatin modifying protein 4B ( CHMP4B ) are selectively bound to deltaF508-CFTR and stimulate lysosomal degradation of the misfolded CFTR [11].

The maturation of sorting endosomes to late endosomes is realized with participation of a member of the RAS oncogene family Rab7 via unknown mechanism [12], [13], [8].


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