Intestinal trefoil factor induces inactivation of extracellular signal-regulated protein kinase in intestinal epithelial cells (IEC-6 cellymitogen-activated protein kinaseyTGFayPMAyphosphatase)

Intestinal trefoil factor (ITF), a small, com- pact protease-resistant peptide, is abundantly expressed in goblet cells of large and small intestine. Although several biological activities of ITF have been identified, including promotion of wound healing, stimulation of epithelial cell migration, and protection of intestinal epithelial barrier, little is known about signaling events through which ITF mediates its physiological function. In this study, the effects of exoge- nous ITF on mitogen-activated protein kinase (MAPK) sig- naling cascades were examined in IEC-6 cells, a nontrans- formed intestinal epithelial cell line that does not express endogenous trefoil peptides. Stimulation with ITF resulted in rapid decrease in extracellular signal-related protein kinase (ERK) activity and concomitant reduced ERK tyrosine phos- phorylation. ITF also decreased activation of ERK activity induced by either transforming growth factor-a, which links extracellular stimuli to the RasyRafyMEKyERK pathway via the epidermal growth factor receptor, or phorbol 12-myristate 13-acetate, which activates Raf through protein kinase C. ITF-induced inhibition of ERK activity was blocked by an inhibitor of tyrosine and dual-specific phosphatases, sodium orthovanadate. In summary, ITF leads to inhibition of ERK and the MAPK pathway through activation of tyrosine or dual-specific phosphatase.