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J. Biol. Chem., Vol. 281, Issue 24, 16361-16369, June 16, 2006

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Depletion of Hsp90 Induces Multiple Defects in B Cell Receptor Signaling^*

Fumika Shinozaki, Michiko Minami¹, Tomoki Chiba^¶2, Miho Suzuki, Katsuhiko Yoshimatsu, Yoshimasa Ichikawa, Kazuya Terasawa, Yasufumi Emori^||, Ken Matsumoto^**, Tomohiro Kurosaki, Akira Nakai, Keiji Tanaka^¶, and Yasufumi Minami³

From the Department of Biophysics and Biochemistry and Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, Department of Natural and Environmental Science, Faculty of Education, Tokyo Gakugei University, Nukuikitamachi, Tokyo 184-8501, Japan and Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, ^¶Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan, ^||Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, ^**Laboratory of Cellular Biochemistry, RIKEN, Wako, Saitama 351-0198, Japan, Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan, and Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Yamaguchi 775-8505, Japan

Hsp90 participates in many distinct aspects of cellular functions and accomplishes these roles by interacting with multiple client proteins. To gain insight into the interactions between Hsp90 and its clients, here we have reduced the protein level of Hsp90 in avian cells by gene targeting in an attempt to elicit the otherwise undetectable (because of the vast amount of cellular Hsp90) Hsp90-interacting proteins. Hsp90-deficient cells can grow, albeit more slowly than wild-type cells. B cell antigen receptor signaling is multiply impaired in these mutant cells; in particular, the amount of immunoglobulin M heavy chain protein is markedly reduced. Furthermore, serum activation does not promote ERK phosphorylation in Hsp90-deficient cells. These multifaceted depressive effects seem to be provoked independently of each other and possibly recapitulate the proteome-wide in vivo functions of Hsp90. Reintroduction of the Hsp90 gene efficiently restores all of the defects. Unexpectedly, however, introducing the Hsp90 gene is also effective in restoration; thus, these defects might be caused by a reduction in the total expression of Hsp90 rather than by loss of Hsp90-specific function.

Received for publication, January 30, 2006 , and in revised form, April 14, 2006.

^* This work was supported by grants-in-aid for Scientific Research on Priority Areas and Exploratory Research (to Y. M.), Special Coordination Funds for Promoting Science and Technology (to F. S., M. S., K. Y., K. Terasawa, and Y. M.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Research on Health Sciences Focusing on Drug Innovation (to Y. M.) from The Japan Health Sciences Foundation. 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.

² Present address: Doctoral Program in Functional Biosciences, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.

¹ To whom correspondence may be addressed. Tel./Fax: 81-42-329-7435; E-mail: minami{at}u-gakugei.ac.jp. ³ To whom correspondence may be addressed: Dept. of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033. Japan. Tel./Fax: 81-3-5841-3047; E-mail: yminami{at}biochem.s.u-tokyo.ac.jp.

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