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J. Biol. Chem., Vol. 279, Issue 11, 10389-10396, March 12, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/11/10389    most recent M312871200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, J. Y. Articles by Lee, M. G. Search for Related Content PubMed PubMed Citation Articles by Kim, J. Y. Articles by Lee, M. G. Social Bookmarking                      What's this?

Inhibitory Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Anion-transporting Activities by Shank2^*

Joo Young Kim, WonSun Han, Wan Namkung, Ji Hyun Lee, Kyung Hwan Kim, Hyewon Shin, Eunjoon Kim, and Min Goo Lee¶

From the Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752 and the Creative Research Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Guseong-dong, Daejeon 305-701, Korea

Accumulating evidence suggests that protein-protein interactions play an important role in transepithelial ion transport. In the present study, we report on the biochemical and functional association between cystic fibrosis transmembrane conductance regulator (CFTR) and a PDZ domain-containing protein Shank2. Exploratory reverse transcription-PCR screening revealed mRNAs for several members of PDZ domain-containing proteins in epithelial cells. Shank2, one of these scaffolding proteins, showed a strong interaction with CFTR by yeast two-hybrid assays. Shank2-CFTR interaction was verified by co-immunoprecipitation experiments in mammalian cells. Notably, this interaction was abolished by mutations in the PDZ domain of Shank2. Protein phosphorylation, transport and Cl^- current by CFTR were measured in NIH 3T3 cells with heterologous expression of Shank2. Of interest, expression of Shank2 suppressed cAMP-induced phosphorylation and activation of CFTR. Importantly, loss of Shank2 by stable transfection of antisense-hShank2 plasmid strongly increased CFTR currents in colonic T84 cells, in which CFTR and Shank2 were natively expressed. Our results indicate that Shank2 negatively regulates CFTR and that this may play a significant role in maintaining epithelial homeostasis under normal and diseased conditions such as those presented by secretory diarrhea.

Received for publication, November 25, 2003 , and in revised form, December 16, 2003.

^* This work was supported by Grant R02-2002-000-00052-0 from the Basic Research Program of the Korea Science & Engineering Foundation and Grant 2001-041-F00110 from the Korea Research Foundation (to M. G. L.), and by the Korean Ministry of Science and Technology (to E. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Korea. Tel.: 82-2-361-5221; Fax: 82-2-313-1894; E-mail: mlee{at}yumc.yonsei.ac.kr.

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