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MBC in Press, published online ahead of print July 19, 2006
Mol. Biol. Cell 10.1091/mbc.E06-02-0129

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Submitted on February 13, 2006
Revised on June 20, 2006
Accepted on July 6, 2006

TIP-1 Has PDZ Scaffold Antagonist Activity

Christine Alewine,* Olav Olsen,* James B. Wade, and Paul A. Welling

Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201

Monitoring Editor: Keith Mostov

PDZ proteins usually contain multiple protein-protein interaction domains, and act as molecular scaffolds that are important for the generation and maintenance of cell polarity and cell signaling. Here, we identify and characterize TIP-1 as an atypical PDZ protein that is composed almost entirely of a single PDZ domain and functions as a negative regulator of PDZ-based scaffolding. We found that TIP-1 competes with the basolateral membrane mLin-7/CASK complex for interaction with the potassium channel Kir 2.3 in model renal epithelia. Consequently, polarized plasma membrane expression of Kir 2.3 is disrupted resulting in pronounced endosomal targeting of the channel, similar to the phenotype observed for mutant Kir 2.3 channels lacking the PDZ binding motif. TIP-1 is ubiquitously expressed, raising the possibility that TIP-1 may play a similar role in regulating the expression of other membrane proteins containing a type I PDZ ligand.


*These authors contributed equally to this work.

Address correspondence to: Paul A. Welling (pwelling{at}umaryland.edu)




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