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Molecular and Cellular Biology, September 2008, p. 5288-5298, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.01993-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor-Like Domain Repeat of Stabilin-2 Recognizes Phosphatidylserine during Cell Corpse Clearance{triangledown}

Seung-Yoon Park,2,{dagger} So-Youn Kim,1,{dagger} Mi-Yeon Jung,1,{dagger} Dong-Jun Bae,1 and In-San Kim1*

Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea,1 Department of Biochemistry, School of Medicine, Dongguk University, Kyungju 780-714, Republic of Korea2

Received 6 November 2007/ Returned for modification 3 December 2007/ Accepted 13 June 2008

Exposure of phosphatidylserine (PS) on the cell surface occurs early during apoptosis and serves as a recognition signal for phagocytes. Clearance of apoptotic cells by a membrane PS receptor is one of the critical anti-inflammatory functions of macrophages. However, the PS binding receptors and their recognition mechanisms have not been fully investigated. Recently, we reported that stabilin-2 is a PS receptor that mediates the clearance of apoptotic cells, thus releasing the anti-inflammatory cytokine, transforming growth factor β. In this study, we showed that epidermal growth factor (EGF)-like domain repeats (EGFrp) in stabilin-2 can directly and specifically recognize PS. The EGFrps also competitively impaired apoptotic cell uptake by macrophages in in vivo models. We also showed that calcium ions are required for stabilin-2 to mediate phagocytosis via EGFrp. Interestingly, at least four tandem repeats of EGF-like domains were required to recognize PS, and the second atypical EGF-like domain in EGFrp was critical for calcium-dependent PS recognition. Considering that PS itself is an important target molecule for both apoptotic cells and nonapoptotic cells during various cellular processes, our results should help elucidate the molecular mechanism by which apoptotic cell clearance in the human body occurs and also have implications for targeting PS externalization of nonapoptotic cells.

* Corresponding author. Mailing address: Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea. Phone: 82-53-420-4821. Fax: 82-53-422-1466. E-mail: iskim{at}knu.ac.kr

{triangledown} Published ahead of print on 23 June 2008.

{dagger} S.-Y.P., S.-Y.K., and M.-Y.J. contributed equally to this study.

Molecular and Cellular Biology, September 2008, p. 5288-5298, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.01993-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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