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Am J Physiol Gastrointest Liver Physiol 294: G441-G451, 2008. First published November 21, 2007; doi:10.1152/ajpgi.00303.2007
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MUCOSAL BIOLOGY

EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells

Jacques Q. van der Merwe,1 Morley D. Hollenberg,2 and Wallace K. MacNaughton1

Inflammation Research Network, Departments of 1Physiology and Biophysics and 2Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

Submitted 5 July 2007 ; accepted in final form 15 November 2007

We examined the stimulus-secretion pathways whereby proteinase-activated receptor 2 (PAR-2) stimulates Cl– secretion in intestinal epithelial cells. SCBN and T84 epithelial monolayers grown on Snapwell supports and mounted in modified Ussing chambers were activated by the PAR-2-activating peptides SLIGRL-NH2 and 2-furoyl-LIGRLO-NH2. Short-circuit current (Isc) was used as a measure of net electrogenic ion transport. Basolateral, but not apical, application of SLIGRL-NH2 or 2-furoyl-LIGRLO-NH2 caused a concentration-dependent change in Isc that was significantly reduced in Cl–-free buffer and by the intracellular Ca2+ blockers thapsigargin and BAPTA-AM, but not by the Ca2+ channel blocker verapamil. Inhibitors of PKA (H-89) and CFTR (glibenclamide) also significantly reduced PAR-2-stimulated Cl– transport. PAR-2 activation was associated with increases in cAMP and intracellular Ca2+. Immunoblot analysis revealed increases in phosphorylation of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase, Src, Pyk2, cRaf, and ERK1/2 in response to PAR-2 activation. Pretreatment with inhibitors of cyclooxygenases (indomethacin), tyrosine kinases (genistein), EGFR (PD-153035), MEK (PD-98059 or U-0126), and Src (PP1) inhibited SLIGRL-NH2-induced increases in Isc. Inhibition of Src, but not matrix metalloproteinases, reduced EGFR phosphorylation. Reduced EGFR phosphorylation paralleled the reduction in PAR-2-stimulated Isc. We conclude that activation of basolateral, but not apical, PAR-2 induces epithelial Cl– secretion via cAMP- and Ca2+-dependent mechanisms. The secretory effect involves EGFR transactivation by Src, leading to subsequent ERK1/2 activation and increased cyclooxygenase activity.

ion transport; proteinases; signal transduction; protein kinase; cyclooxygenase; mitogen-activated protein kinase; extracellular signal-regulated kinase 1/2


Address for reprint requests and other correspondence: W. K. MacNaughton, Dept. of Physiology and Biophysics, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, AB, Canada T2N 4N1 (e-mail: wmacnaug{at}ucalgary.ca)




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