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Journal of Biochemistry Advance Access published online on January 3, 2009
Journal of Biochemistry, doi:10.1093/jb/mvn176
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© The authors 2009. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Signaling pathway involving GULP, MAPK, and Rac1 for SR-BI-induced phagocytosis of apoptotic cells

Yoichi Osada1, Toshiro Sunatani1, In-San Kim2, Yoshinobu Nakanishi1 and Akiko Shiratsuchi1,*

1Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan, and 2Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea

*To whom correspondence should be addressed: Akiko Shiratsuchi: Tel: +81 76 234 4424, Fax: +81 76 264 6223, E-mail: shira{at}kenroku.kanazawa-u.ac.jp

Received September 14, 2008; Accepted December 13, 2008


  Abstract

Class B scavenger receptor type I (SR-BI) is a phosphatidylserine (PS)-recognizing receptor of testicular Sertoli cells responsible for the phagocytosis of spermatogenic cells undergoing apoptosis. Here we determined signal mediators that compose a signaling pathway for SR-BI-induced phagocytosis. Results of a yeast two-hybrid analysis and a cell-free binding assay indicated that SR-BI binds to engulfment adapter protein (GULP) using the C-terminal intracellular domain. A co-immunoprecipitation analysis showed the existence of a complex of GULP and SR-BI in cells prior to the activation of SR-BI by PS. A reduction of GULP expression in phagocytes decreased the SR-BI-mediated phagocytosis of apoptotic cells. Administration to phagocytes of PS-containing liposomes increased the levels of the GTP-bound form of Rac1 and the phosphorylated forms of mitogen-activated protein kinases (MAPK) p38 and extracellular signal-related kinase 1 and 2. Finally, lowering the expression of GULP abrogated MAPK phosphorylation, and the presence of MAPK inhibitors reduced the level of GTP-bound Rac1 in PS-activated phagocytes. These results collectively suggested the following signaling pathway for the SR-BI-induced phagocytosis: 1) PS-recognizing SR-BI activates associated GULP; 2) activated GULP induces MAPK phosphorylation; 3) activated MAPK increases GTP-bound Rac1; and 4) activated Rac1 induces a rearrangement of the actin cytoskeleton.

Key Words: apoptosis, phagocytosis, phosphatidylserine, scavenger receptor, small G protein


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