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J. Biol. Chem. 277 (16): 13583-13588

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of a Soluble Form Phospholipase A2 Receptor as a Circulating Endogenous Inhibitor for Secretory Phospholipase A2*

Ken-ichi Higashino, Yasunori Yokota, Takashi Ono, Shigeki Kamitani, Hitoshi Arita, and Kohji HanasakiDagger

From the Shionogi Research Laboratories, Shionogi & Co., Ltd. 12-4 Sagisu, 5-Chome, Fukushima-ku, Osaka 553-0002, Japan

Venomous snakes have various types of phospholipase A2 inhibitory proteins (PLIs) in their circulatory system to protect them from attack by their own phospholipase A2s (PLA2s). Here we show the first evidence for the existence of circulating PLI against secretory PLA2s (sPLA2s) in mammals. In mouse serum, we detected specific binding activities of group IB and X sPLA2s, which was in contrast with the absence of binding activities in serum prepared from mice deficient in PLA2 receptor (PLA2R), a type I transmembrane glycoprotein related to the C-type animal lectin family. Western blot analysis after partial purification with group IB sPLA2 affinity column confirmed the identity of serum sPLA2-binding protein as a soluble form of PLA2R (sPLA2R) that retained all of the extracellular domains of the membrane-bound receptor. Both purified sPLA2R and the recombinant soluble receptor having all of the extracellular portions blocked the biological functions of group X sPLA2, including its potent enzymatic activity and its binding to the membrane-bound receptor. Protease inhibitor tests with PLA2R-overexpressing Chinese hamster ovary cells suggested that sPLA2R is produced by cleavage of the membrane-bound receptor by metalloproteinases. Thus, sPLA2R is the first example of circulating PLI that acts as an endogenous inhibitor for enzymatic activities and receptor-mediated functions of sPLA2s in mice.

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

Dagger To whom correspondence should be addressed. Tel.: 81-6-6455-2104; Fax: 81-6-6458-0987; E-mail: kohji.hanasaki@shionogi.co.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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