360 688

Cited 79 times in

Dynamic regulation of cystic fibrosis transmembrane conductance regulator by competitive interactions of molecular adaptors

 Ji Hyun Lee  ;  Wito Richter  ;  Min Goo Lee  ;  Marco Conti  ;  Eunjoon Kim  ;  Kyung Hwan Kim  ;  Wan Namkung 
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.282(14) : 10414-10422, 2007 
Journal Title
Issue Date
3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Adaptor Proteins, Signal Transducing/metabolism* ; Animals ; Brain/cytology ; Brain/metabolism* ; CHO Cells ; COS Cells ; Cercopithecus aethiops ; Cricetinae ; Cricetulus ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cystic Fibrosis/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism* ; Diarrhea/metabolism ; Disks Large Homolog 4 Protein ; Epithelial Cells/cytology ; Epithelial Cells/metabolism* ; Guanylate Kinases ; Homeostasis/physiology ; Intracellular Signaling Peptides and Proteins/metabolism* ; Ion Transport/physiology ; Membrane Proteins/metabolism* ; Mice ; NIH 3T3 Cells ; Nerve Tissue Proteins/metabolism* ; Phosphoproteins/metabolism* ; Protein Binding/physiology ; Sodium-Hydrogen Exchangers/metabolism*
Disorganized ion transport caused by hypo- or hyperfunctioning of the cystic fibrosis transmembrane conductance regulator (CFTR) can be detrimental and may result in life-threatening diseases such as cystic fibrosis or secretory diarrhea. Thus, CFTR is controlled by elaborate positive and negative regulations for an efficient homeostasis. It has been shown that expression and activity of CFTR can be regulated either positively or negatively by PDZ (PSD-95/discs large/ZO-1) domain-based adaptors. Although a positive regulation by PDZ domain-based adaptors such as EBP50/NHERF1 is established, the mechanisms for negative regulation of the CFTR by Shank2, as well as the effects of multiple adaptor interactions, are not known. Here we demonstrate a physical and physiological competition between EBP50-CFTR and Shank2-CFTR associations and the dynamic regulation of CFTR activity by these positive and negative interactions using the surface plasmon resonance assays and consecutive patch clamp experiments. Furthermore whereas EBP50 recruits a cAMP-dependent protein kinase (PKA) complex to CFTR, Shank2 was found to be physically and functionally associated with the cyclic nucleotide phosphodiesterase PDE4D that precludes cAMP/PKA signals in epithelial cells and mouse brains. These findings strongly suggest that balanced interactions between the membrane transporter and multiple PDZ-based adaptors play a critical role in the homeostatic regulation of epithelial transport and possibly the membrane transport in other tissues.
Files in This Item:
T200700334.pdf Download
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Ji Hyun(이지현)
사서에게 알리기


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.