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J. Biol. Chem., Vol. 281, Issue 28, 19588-19599, July 14, 2006

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Annexin I Regulates SKCO-15 Cell Invasion by Signaling through Formyl Peptide Receptors^*

Brian A. Babbin¹, Winston Y. Lee, Charles A. Parkos, L. Matthew Winfree, Adil Akyildiz, Mauro Perretti, and Asma Nusrat

From the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322 and The William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom

Annexin 1 (AnxA1) is a multifunctional phospholipid-binding protein associated with the development of metastasis in some invasive epithelial malignancies. However, the role of AnxA1 in the migration/invasion of epithelial cells is not known. In this study, experiments were performed to investigate the role of AnxA1 in the invasion of a model epithelial cell line, SKCO-15, derived from colorectal adenocarcinoma. Small interfering RNA-mediated knockdown of AnxA1 expression resulted in a significant reduction in invasion through Matrigel-coated filters. Localization studies revealed a translocation of AnxA1 to the cell surface upon the induction of cell migration, and functional inhibition of cell surface AnxA1 using antiserum (LCO1) significantly reduced cell invasion. Conversely, SKCO-15 cell invasion was increased by 2-fold in the presence of recombinant full-length AnxA1 and the AnxA1 N-terminal-derived peptide mimetic, Ac2-26. Because extracellular AnxA1 has been shown to regulate leukocyte migratory events through interactions with n-formyl peptide receptors (nFPRs), we examined the expression of FPR-1, FPRL-1, and FPRL-2 in SKCO-15 cells by reverse transcriptase-PCR and identified expression of all three receptors in this cell line. Treatment of SKCO-15 cells with AnxA1, Ac2-26, and the classical nFPR agonist, formylmethionylleucylphenylalanine, induced intracellular calcium release consistent with nFPR activation. Furthermore, the nFPR antagonist, Boc2, abrogated the AnxA1 and Ac2-26-induced intracellular calcium release and increase in SKCO-15 cell invasion. Together, these results support an autocrine/paracrine role for membrane AnxA1 in stimulating SKCO-15 cell migration through nFPR activation. The findings in this study suggest that activation of nFPRs stimulates epithelial cell motility important in the development of metastasis as well as wound healing.

Received for publication, December 6, 2005 , and in revised form, April 27, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Epithelial Pathobiology Research Unit, Dept. of Pathology and Laboratory Medicine, Emory University, Whitehead Biomedical Bldg. 115, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-8542; Fax: 404-727-5838; E-mail: bbabbin{at}emory.edu.

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