INTESTINAL TREFOIL FACTOR INDUCES INACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED PROTEIN-KINASE IN INTESTINAL EPITHELIAL-CELLS

Intestinal trefoil factor (ITF), a small, compact protease-resistant p eptide, is abundantly expressed in goblet cells of large and small int estine, Although several biological activities of ITF have been identi fied, including promotion of wound healing, stimulation of epithelial cell migration, and protection of intestinal epithelial barrier, littl e is known about signaling events through which ITF mediates its physi ological function, In this study, the effects of exogenous ITF on mito gen-activated protein kinase (MAPK) signaling cascades were examined i n IEC-6 cells, a nontransformed intestinal epithelial cell line that d oes not express endogenous trefoil peptides, Stimulation with ITF resu lted in rapid decrease in extracellular signal-related protein kinase (ERK) activity and concomitant reduced ERK tyrosine phosphorylation. I TF also decreased activation of ERK activity induced by either transfo rming growth factor-alpha, which links extracellular stimuli to the Ra s/Raf/MEK/ERK pathway via the epidermal growth factor receptor, or pho rbol 12-myristate 13-acetate, which activates Raf through protein kina se C. ITF-induced inhibition of ERK activity was blocked by an inhibit or of tyrosine and dual-specific phosphatases, sodium orthovanadate, I n summary, ITF leads to inhibition of ERK and the MAPK pathway through activation of tyrosine or dual-specific phosphatase.