Pathway Map Details

wtCFTR and delta508-CFTR traffic / Generic schema (norm and CF)

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SNAP-23, Syntaxin 1A, PIST (CAL), Filamin B (TABP), PKA-reg (cAMP-dependent), Syntaxin 6, CFTR, CFTR, COPII, CFTR, Myosin Vb, DAB2, Syntaxin 12, VIL2 (ezrin), Clathrin, HCO(,3)('-) extracellular region, CFTR, SNAP-25, Rab-11A, CFTR, CFTR, AP complex 2, ATP cytosol, Clathrin heavy chain, glutathione = glutathione, Chloride ion extracellular region, PKA-cat (cAMP-dependent), Glutathione extracellular region, HCO(,3)('-) = HCO(,3)('-), VAMP8, TSG101, VTI1B, Vps25, EBP50, Rab-9, Glutathione cytoplasm, CHMP4B, E3KARP (NHERF2), CFTR, CFTR, PKC-epsilon, VAMP2, Coatomer, Rab-5A, Rab-27A, CFTR, Rab-7, CFTR, Rab-4, Filamin A, STAM2, COMMD1 (MURR1), Chloride ion cytosol, TC10, Hrs, Ubiquitin, HCO(,3)('-), Syntaxin 8, Cl(-) = Cl(-)


wtCFTR and delta508-CFTR traffic/ Generic schema (norm and CF)

The cystic fibrosis transmembrane conductance regulator ( CFTR ) is a member of the ATP-binding cassette transporter superfamily and 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 loss of a Phe residue at position 508 ( deltaF508 -CFTR ). It 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].

Export of CFTR from ER to the Golgi may be realized in Coat protein complex-II ( COPII )-dependent manner [7], [8]. It is supposed, that binding of COPII to deltaF508 -CFTR is disrupted, thus preventing membrane expression of deltaF508 -CFTR [9].

A G olgi associated PDZ and coiled-coil motif containing ( PIST ) regulates CFTR trafficking. PIST causes a reduction in the number of CFTR channels in the plasma membrane and facilitates trafficking of CFTR to lysosomes [10], [11], [12]. PIST action is activated by Syntaxin 6 [13], (Cheng et al., The 21st annual north American cystic fibrosis conference, California, 2007 ) and is inhibited by R as homolog gene family, member Q ( TC10 ) [14].

CFTR modified in ER and/or Golgi may be delivered from the Golgi to the apical membrane, possibly, with participation of coat protein complex Coatomer [15]. CFTR stabilization in plasma membrane depends on participation of different proteins. For example, S olute carrier family 9 member 3 regulator 1 ( EBP50 ) [16], Copper metabolism domain containing 1 ( COMMD1 ) (Drevillion, L et al., The 21st annual north American cystic fibrosis conference, California, 2007), Protein kinase C epsilon ( PKC-epsilon ) [17] Filamin A and Filamin B [18] and cAMP-dependent protein kinase ( PKA ) stabilize CFTR [19]. Syntaxin 1A/ Synaptosomal-associated protein 23kDa ( SNAP-23 ) have negative influence on CFTR membrane expression [19], [20].

CFTR may be internalizated from plasma membrane in Clathrin -dependent manner. The classical key components of Clathrin-dependent endocytosis of CFTR are Adaptor-related protein complex 2 ( AP complex 2 ) [21], [22] and D isabled homolog 2 mitogen-responsive phosphoprotein ( Dab2 ) [23]. In addition, some cargo-unspecified adaptors may participate in this process [24], [25], [26].

Next phase is the fusion of coated-pit-derived primary endocytic vesicles with sorting endosomes. It is regulated,for example,. by a member of RAS oncogene family Rab-5A [27], [28] and Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) [29], [30].

At this phase quality control at early endosome may eliminate deltaF508 -CFTR too. 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 [31].

The maturation of sorting endosomes to late endosomes is facilitated by a member of the RAS oncogene family Rab7 via an unknown mechanism [32], [33], [28].

Late endosomes may participate in fusion with the other late endosomes or lysosome via SNARE-mediated mechanism [34], [35], [30]. In addition, Rab7 is directly involved in the aggregation and fusion of late endocytic structures/lysosomes [36], [37].

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 internal or cytosolic CFTR pool [38], [39].

Moreover, CFTR may be delivered to the cell surface via the shot pathway from endosomes via different recycling endosomes [29], [5]. It is realized mainly via Rab-4 and/or Rab-11A -dependent mechanisms [39].

Endogenous Rab-11A, a member of RAS oncogene family, forms a complex with Myosin Vb which facilitates recycling of CFTR from recycling endosomes to the apical plasma membrane in polarized epithelial cells [40], [41], [42]. Rab-4 protein group 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 [43].

It was shown that regulation of expression or activity of some member CFTR traffic pathway may lead to the membrane expression of deltaF508 -CFTR. For example, over-regulation of Rab-11A [28], EBP50 [44] and down-regulation Rab-5A, Rab-7 [28] and Syntaxin 6 (Cheng et al., The 21st annual north American cystic fibrosis conference, California, 2007 ) have this effect.


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