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

Authors
 Ji Hyun Lee  ;  Wito Richter  ;  Min Goo Lee  ;  Marco Conti  ;  Eunjoon Kim  ;  Kyung Hwan Kim  ;  Wan Namkung 
Citation
 Journal of Biological Chemistry, Vol.282(14) : 10414-10422, 2007 
Journal Title
 Journal of Biological Chemistry 
ISSN
 0021-9258 
Issue Date
2007
Abstract
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.
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DOI
10.1074/jbc.M610857200
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
김경환(Kim, Kyung Hwan)
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
이지현(Lee, Ji Hyun)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/96224
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