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J. Biol. Chem., Vol. 279, Issue 12, 11616-11625, March 19, 2004

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Ubiquitination-mediated Regulation of Biosynthesis of the Adhesion Receptor SHPS-1 in Response to Endoplasmic Reticulum Stress^*

Reiko Murai-Takebe, Tetsuya Noguchi, Takeshi Ogura, Toshiyuki Mikami¶, Kazunori Yanagi¶, Kenjiro Inagaki, Hiroshi Ohnishi||, Takashi Matozaki||, and Masato Kasuga

From the Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, ^¶Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., 4-2-1 Takatsukasa, Takarazuka 665-8555, and ^||Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi 371-8512, Japan

Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF^NFB42) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF^NFB42 mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2 induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF^NFB42 regulates SHPS-1 biosynthesis in response to ER stress.

Received for publication, October 20, 2003 , and in revised form, December 18, 2003.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER) (to M. 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 should be addressed: Division of Diabetes and Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel.: 81-78-382-5861; Fax: 81-78-382-2080; E-mail: noguchi{at}med.kobe-u.ac.jp.

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