CFTR (cystic fibrosis transmembrane conductance regulator) is expressed in the apical membrane of epithelial cells. Cell-surface CFTR levels are regulated by endocytosis and recycling. A number of adaptor proteins including AP-2 (μ2 subunit) and Dab2 (Disabled-2) have been proposed to modulate CFTR internalization. In the present study we have used siRNA (small interfering RNA)-mediated silencing of these adaptors to test their roles in the regulation of CFTR cell-surface trafficking and stability in human airway epithelial cells. The results indicate that μ2 and Dab2 performed partially overlapping, but divergent, functions. While μ2 depletion dramatically decreased CFTR endocytosis with little effect on the half-life of the CFTR protein, Dab2 depletion increased the CFTR half-life ~3-fold, in addition to inhibiting CFTR endocytosis. Furthermore, Dab2 depletion inhibited CFTR trafficking from the sorting endosome to the recycling compartment, as well as delivery of CFTR to the late endosome, thus providing a mechanistic explanation for increased CFTR expression and half-life. To test whether two E3 ligases were required for the endocytosis and/or down-regulation of surface CFTR, we siRNA-depleted CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and c-Cbl (casitas B-lineage lymphoma). We demonstrate that CHIP and c-Cbl depletion have no effect on CFTR endocytosis, but c-Cbl depletion modestly enhanced the half-life of CFTR. The results of the present study define a significant role for Dab2 both in the endocytosis and post-endocytic fate of CFTR.
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Research Article|
December 21 2011
Dab2 is a key regulator of endocytosis and post-endocytic trafficking of the cystic fibrosis transmembrane conductance regulator
Lianwu Fu;
Lianwu Fu
1
*Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
1Correspondence may be addressed to either of these authors (email lianwufu@uab.edu or jcollawn@uab.edu).
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Andras Rab;
Andras Rab
*Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Li Ping Tang;
Li Ping Tang
†Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Steven M. Rowe;
Steven M. Rowe
†Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
‡Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Zsuzsa Bebok;
Zsuzsa Bebok
*Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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James F. Collawn
James F. Collawn
1
*Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
1Correspondence may be addressed to either of these authors (email lianwufu@uab.edu or jcollawn@uab.edu).
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Publisher: Portland Press Ltd
Received:
August 29 2011
Revision Received:
September 30 2011
Accepted:
October 13 2011
Accepted Manuscript online:
October 13 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (2): 633–643.
Article history
Received:
August 29 2011
Revision Received:
September 30 2011
Accepted:
October 13 2011
Accepted Manuscript online:
October 13 2011
Citation
Lianwu Fu, Andras Rab, Li Ping Tang, Steven M. Rowe, Zsuzsa Bebok, James F. Collawn; Dab2 is a key regulator of endocytosis and post-endocytic trafficking of the cystic fibrosis transmembrane conductance regulator. Biochem J 15 January 2012; 441 (2): 633–643. doi: https://doi.org/10.1042/BJ20111566
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