Pathway Map Details

wtCFTR and delta508 traffic / Clathrin coated vesicles formation (norm and CF)



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Object list (links open in MetaCore):

CFTR, AP complex 2, AP180, HIP12, SNX9, HIP1, Actin cytoskeletal, Clathrin heavy chain, Myosin VI, Eps15, Epsin 1, DAB2, Actin, Dynamin-2, Endophilin B1, BIN1 (Amphiphysin II), Clathrin, PICALM, Myosin I

Description:

wtCFTR and delta508 traffic/ Clathrin coated vesicles formation (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 internalizated from plasma membrane in a Clathrin -dependent manner. The classical key components of Clathrin-dependent endocytosis of CFTR are Adaptor-related protein complex 2 ( AP complex 2 ) [6], [7] and Disabled homolog 2 mitogen-responsive phosphoprotein ( Dab2 ) [8]. In addition, some cargo-unspecified adaptors may participate in this process [9], [10], [11].

After the Clathrin lattice is formed, dynamins (e.g., Dynamin-2 ), endophilin (e.g., Endophilin B1 ), epsins and amphiphysin (e.g., BIN1 ) are involved in membrane invagination and Clathrin rearrangements. The plus-end motor Myosin I pulls the Dynamin-2 ring in the direction of the cell surface, while the minus-end motor Myosin VI pulls the coated bud into the cytosol. The resulting strain could then severe the constricted stalk beneath the dynamin ring [8], [12].

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

References:

  1. Kogan I, Ramjeesingh M, Li C, Kidd JF, Wang Y, Leslie EM, Cole SP, Bear CE
    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
    Endocytic trafficking of CFTR in health and disease. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2007 Jan;6(1):1-14
  6. Weixel KM, Bradbury NA
    The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator binds to AP-2 clathrin adaptors. The Journal of biological chemistry 2000 Feb 4;275(5):3655-60
  7. Weixel KM, Bradbury NA
    Mu 2 binding directs the cystic fibrosis transmembrane conductance regulator to the clathrin-mediated endocytic pathway. The Journal of biological chemistry 2001 Dec 7;276(49):46251-9
  8. Swiatecka-Urban A, Boyd C, Coutermarsh B, Karlson KH, Barnaby R, Aschenbrenner L, Langford GM, Hasson T, Stanton BA
    Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2004 Sep 3;279(36):38025-31
  9. Wendland B
    Epsins: adaptors in endocytosis? Nature reviews. Molecular cell biology 2002 Dec;3(12):971-7
  10. Szymkiewicz I, Shupliakov O, Dikic I
    Cargo- and compartment-selective endocytic scaffold proteins. The Biochemical journal 2004 Oct 1;383(Pt 1):1-11
  11. Edeling MA, Smith C, Owen D
    Life of a clathrin coat: insights from clathrin and AP structures. Nature reviews. Molecular cell biology 2006 Jan;7(1):32-44
  12. Ungewickell EJ, Hinrichsen L
    Endocytosis: clathrin-mediated membrane budding. Current opinion in cell biology 2007 Aug;19(4):417-25