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J. Biol. Chem., Vol. 280, Issue 25, 24072-24084, June 24, 2005

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Spatial and Functional Heterogeneity of Sphingolipid-rich Membrane Domains^*

Etsuko Kiyokawa¶, Takeshi Baba||, Naomi Otsuka, Asami Makino, Shinichi Ohno||, and Toshihide Kobayashi**

From the RIKEN, Wako, Saitama 351-0198, Japan, Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, ^||Department of Anatomy, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan, and ^**INSERM U585, Institut National des Sciences Appliquées-Lyon, 69621 Villeurbanne, France

Little is known about the organization of lipids in biomembranes. Lipid rafts are defined as sphingolipid- and cholesterol-rich clusters in the membrane. Details of the lipid distribution of lipid rafts are not well characterized mainly because of a lack of appropriate probes. Ganglioside GM1-specific protein, cholera toxin, has long been the only lipid probe of lipid rafts. Recently it was shown that earthworm toxin, lysenin, specifically recognizes sphingomyelin-rich membrane domains. Binding of lysenin to sphingomyelin is accompanied by the oligomerization of the toxin that leads to pore formation in the target membrane. In this study, we generated a truncated lysenin mutant that does not oligomerize and thus is non-toxic. Using this mutant lysenin, we showed that plasma membrane sphingomyelin-rich domains are spatially distinct from ganglioside GM1-rich membrane domains in Jurkat T cells. Like T cell receptor activation and cross-linking of GM1, cross-linking of sphingomyelin induced calcium influx and ERK phosphorylation in the cell. However, unlike CD3 or GM1, cross-linking of sphingomyelin did not induce significant protein tyrosine phosphorylation. Combination of lysenin and sphingomyelinase treatment suggested the involvement of G-protein-coupled receptor in sphingomyelin-mediated signal transduction. These results thus suggest that the sphingomyelin-rich domain provides a functional signal cascade platform that is distinct from those provided by T cell receptor or GM1. Our study therefore elucidates the spatial and functional heterogeneity of lipid rafts.

Received for publication, February 28, 2005 , and in revised form, April 18, 2005.

^* This work was supported by grants from the RIKEN Frontier Research System (to T. K.), the Bioarchitect Research Project of RIKEN (to T. K.), the RIKEN presidential research grant for intersystem collaboration (to E. K. and T. K.), grants from the Ministry of Education, Science, Sports and Culture of Japan (Grants 13770119 (to E. K.), 15590157 (to T. B.), and 14370753 and 16044247 (to T. K.)), the RIKEN presidential research grant for innovative tool development (to E. K.), the Hayashi Memorial Foundation for Female Natural Scientists (to E. K.), the Novartis Foundation (Japan) for the Promotion of Science (to E. K.), and the Ara Parseghian Medical Research Foundation (to T. K.). 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.

^¶ To whom correspondence may be addressed: Dept. of Tumor Virology, Research Inst. for Microbial Diseases, Osaka University, 3-1, Yamada-oka, Suita-shi, Osaka 565-0871, Japan. E-mail: kiyokawa{at}biken.osaka-u.ac.jp.

To whom correspondence may be addressed: RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel.: 81-48-467-9612; Fax: 81-48-467-8693; E-mail: kobayasi{at}riken.jp.

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