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Vol. 16, Issue 12, 5538-5550, December 2005

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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 , David M. Smith , Karen Snetselaar , Mantao Liu ^*, Mary Kay Francis , and Christian Sell ^*

^* The Lankenau Institute for Medical Research, Wynnewood, PA 19096; Division of Gastroenterology, Lankenau Hospital, Wynnewood, PA 19096; Department of Biology, St. Joseph's University, Philadelphia, PA 19131; and Department of Biology, Villanova University, Villanova, PA 19085

Submitted April 8, 2005; Revised August 31, 2005; Accepted September 11, 2005
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 >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to D-mannitol (M_r 182), polyethylene glycol (M_r 4000), and 10,000-M_r methylated dextran but not to 2,000,000-M_r 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. Although 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 extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein 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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