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RECEPTORS AND SIGNAL TRANSDUCTION

Juxtacrine activation of EGFR regulates claudin expression and increases transepithelial resistance

Departments of ¹Medicine and ²Surgery, Vanderbilt University, Nashville, Tennessee

Submitted 27 June 2007 ; accepted in final form 10 September 2007

Heparin-binding (HB)-EGF, a ligand for EGF receptors, is synthesized as a membrane-anchored precursor that is potentially capable of juxtacrine activation of EGF receptors. However, the physiological importance of such juxtacrine signaling remains poorly described, due to frequent inability to distinguish effects mediated by membrane-anchored HB-EGF vs. mature "secreted HB-EGF." In our studies, using stable expression of a noncleavable, membrane-anchored rat HB-EGF isoform (MDCK^rat5aa cells) in Madin-Darby canine kidney (MDCK) II cells, we observed a significant increase in transepithelial resistance (TER). Similar significant increases in TER were observed on stable expression of an analogous, noncleavable, membrane-anchored human HB-EGF construct (MDCK^human5aa cells). The presence of noncleavable, membrane-anchored HB-EGF led to alterations in the expression of selected claudin family members, including a marked decrease in claudin-2 in MDCK^rat5aa cells compared with the control MDCK cells. Reexpression of claudin-2 in MDCK^rat5aa cells largely prevented the increases in TER. Ion substitution studies indicated decreased paracellular ionic permeability of Na⁺ in MDCK^rat5aa cells, further indicating that the altered claudin-2 expression mediated the increased TER seen in these cells. In a Ca²⁺-switch model, increased phosphorylation of EGF receptor and Akt was observed in MDCK^rat5aa cells compared with the control MDCK cells, and inhibition of these pathways inhibited TER changes specifically in MDCK^rat5aa cells. Therefore, we hypothesize that juxtacrine activation of EGFR by membrane-anchored HB-EGF may play an important role in the regulation of tight junction proteins and TER.

heparin-binding-epidermal growth factor; membrane-anchored; epidermal growth factor receptor

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