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MBC in Press, published online ahead of print September 21, 2005
Mol. Biol. Cell 10.1091/mbc.E05-04-0294

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Submitted on April 8, 2005
Revised on August 31, 2005
Accepted on September 11, 2005

Ras Mutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

James M. Mullin,* James M. Leatherman,* Mary Carmen Valenzano,* Erika Rendon Huerta,* Jon Verrechio,{dagger} David M. Smith,{dagger} Karen Snetselaar,{ddagger} Mantao Liu,* Mary Kay Francis,{sect} and Christian Sell*

*The Lankenau Institute for Medical Research, Wynnewood, PA 19096; {dagger}Division of Gastroenterology, Lankenau Hospital, Wynnewood, PA 19096; {ddagger}Department of Biology, St. Joseph’s University, Philadelphia, PA 19131; {sect}Department of Biology, Villanova University, Villanova, PA 19085

Monitoring Editor: Asma Nusrat

Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of D-mannitol increases sixfold but transepithelial electrical resistance increases over 40%. This indicates decreased paracellular permeability to Na+Cl-, yet increased permeability to nonelectrolytes. Permeability increases to D-mannitol (182 mw), polyethylene glycol (4000 mw) and 10,000 mw methylated dextran, but not 2000,000 mw methylated dextran. This implies a ‘ceiling’ on the size of solutes that can cross a ras-mutated epithelial barrier, and therefore that the increased permeability is not due to loss of cells or junctions. While the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins 3 and 5 remained unchanged. An increase in ERK-2 phosphorylation suggests that the down-stream effects on the tight junction may be due to changes in the MAP kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.

Address correspondence to: James M. Mullin (mullinj{at}mlhs.org)




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