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Molecular and Cellular Biology, July 2000, p. 4680-4690, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Distinct Pathways of Cell Migration and Antiapoptotic Response to Epithelial Injury: Structure-Function Analysis of Human Intestinal Trefoil Factor

Koichi Kinoshita, Douglas R. Taupin,dagger Hiroshi Itoh,Dagger and Daniel K. Podolsky*

Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Received 22 October 1999/Returned for modification 1 December 1999/Accepted 23 March 2000

The trefoil peptide intestinal trefoil factor (ITF) plays a critical role in the protection of colonic mucosa and is essential to restitution after epithelial damage. These functional properties are accomplished through coordinated promotion of cell migration and inhibition of apoptosis. ITF contains a unique three-looped trefoil motif formed by intrachain disulfide bonds among six conserved cysteine residues, which is thought to contribute to its marked protease resistance. ITF also has a seventh cysteine residue, which permits homodimer formation. A series of cysteine-to-serine substitutions and a C-terminally truncated ITF were made by PCR site-directed mutagenesis. Any alteration of the trefoil motif or truncation resulted in loss of protease resistance. However, neither an intact trefoil domain nor dimerization was required to promote cell migration. This pro-restitution activity correlated with the ability of the ITF mutants to activate mitogen-activated protein (MAP) kinase independent of phosphorylation of the epidermal growth factor (EGF) receptor. In contrast, only intact ITF retained both phosphatidylinositol 3-kinase and the EGF receptor-dependent antiapoptotic effect in HCT116 and IEC-6 cells. The inability to block apoptosis correlated with a loss of trefoil peptide-induced transactivation of the EGF receptor or Akt kinase in HT-29 cells. In addition to defining structural requirements for the functional properties of ITF, these findings demonstrate that distinct intracellular signaling pathways mediate the effects of ITF on cell migration and apoptosis.

* Corresponding author. Mailing address: Massachusetts General Hospital, GI Unit, 55 Fruit St., GRJ-719, Boston, MA 02114-2696. Phone: (617) 726-7411. Fax: (617) 724-2136. E-mail: Podolsky.Daniel{at}mgh.harvard.edu.

dagger Present address: Signal Transduction Group, Trescowthick Research Laboratories, Peter MacCallum Cancer Center, Melbourne 3014, Victoria, Australia.

Dagger Present address: 2nd Department of Pathology, Miyazaki Medical College, Miyazaki 889-16, Japan.

Molecular and Cellular Biology, July 2000, p. 4680-4690, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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