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J. Biol. Chem., Vol. 280, Issue 36, 31714-31721, September 9, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/36/31714    most recent M506225200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harada, Y. Articles by Fukada, Y. Search for Related Content PubMed PubMed Citation Articles by Harada, Y. Articles by Fukada, Y. Social Bookmarking                      What's this?

Ser-557-phosphorylated mCRY2 Is Degraded upon Synergistic Phosphorylation by Glycogen Synthase Kinase-3^*

Yuko Harada, Mihoko Sakai, Nobuhiro Kurabayashi, Tsuyoshi Hirota, and Yoshitaka Fukada

From the Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-Ku, Tokyo 113-0033, Japan

Cryptochrome 1 and 2 act as essential components of the central and peripheral circadian clocks for generation of circadian rhythms in mammals. Here we show that mouse cryptochrome 2 (mCRY2) is phosphorylated at Ser-557 in the liver, a well characterized peripheral clock tissue. The Ser-557-phosphorylated form accumulates in the liver during the night in parallel with mCRY2 protein, and the phosphorylated form reaches its maximal level at late night, preceding the peak-time of the protein abundance by 4 h in both light-dark cycle and constant dark conditions. The Ser-557-phosphorylated form of mCRY2 is localized in the nucleus, whereas mCRY2 protein is located in both the cytoplasm and nucleus. Importantly, phosphorylation of mCRY2 at Ser-557 allows subsequent phosphorylation at Ser-553 by glycogen synthase kinase-3 (GSK-3), resulting in efficient degradation of mCRY2 by a proteasome pathway. As assessed by phosphorylation of GSK-3 at Ser-9, which negatively regulates the kinase activity, GSK-3 exhibits a circadian rhythm in its activity with a peak from late night to early morning when Ser-557 of mCRY2 is highly phosphorylated. Altogether, the present study demonstrates an important role of sequential phosphorylation at Ser-557/Ser-553 for destabilization of mCRY2 and illustrates a model that the circadian regulation of mCRY2 phosphorylation contributes to rhythmic degradation of mCRY2 protein.

Received for publication, June 8, 2005

^* This work was supported in part by grant-in-aid for Scientific Research 14104003 from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1S.

Present address: Division of Neuroscience, Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115.

To whom correspondence should be addressed. Tel.: 81-3-5841-4381; Fax: 81-3-5802-8871; E-mail: sfukada{at}mail.ecc.u-tokyo.ac.jp.

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