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J. Biol. Chem., Vol. 283, Issue 4, 2454-2464, January 25, 2008

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Glycogen Synthase Kinase 3β Interacts with and Phosphorylates the Spindle-associated Protein Astrin^*

Tai-Shan Cheng, Yun-Ling Hsiao, Ching-Chih Lin^¶, Chang-Tze Ricky Yu^||, Ching-Mei Hsu, Mau-Sun Chang^**, Chu-I Lee, Chi-Ying F. Huang, Shen-Long Howng^¶¶, and Yi-Ren Hong¹

From the Graduate Institute of Biochemistry and Graduate Institute of Medicine, Kaohsiung Medical University and ^¶Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 807, Taiwan, ^||Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou 545, Taiwan, ^**Department of Medical Research, Mackay Memorial Hospital, Taipei 104, Taiwan, Department of Medical Technology, Fooyin University, Kaohsiung 831, Taiwan, Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan, and ^¶¶Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan

Emerging evidence shows that glycogen synthase kinase 3β (GSK3β) is involved in mitotic division and that inhibiting of GSK3β kinase activity causes defects in spindle microtubule length and chromosome alignment. However, the purpose of GSK3β involvement in spindle microtubule assembly and accurate chromosome segregation remains obscure. Here, we report that GSK3β interacts with the spindle-associated protein Astrin both in vitro and in vivo. Additionally, Astrin acts as a substrate for GSK3β and is phosphorylated at Thr-111, Thr-937 ((S/T)P motif) and Ser-974/Thr-978 ((S/T)XXX(S/T)-p motif; p is a phosphorylatable residue). Inhibition of GSK3β impairs spindle and kinetochore accumulation of Astrin and spindle formation at mitosis, suggesting that Astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by GSK3β. Conversely, depletion of Astrin by small interfering RNA has no detectable influence on the localization of GSK3β. Interestingly, in vitro assays demonstrated that Astrin enhances GSK3β-mediated phosphorylation of other substrates. Moreover, we showed that coexpression of Astrin and GSK3β differentially increases GSK3β-mediated Tau phosphorylation on an unprimed site. Collectively, these data indicate that GSK3β interacts with and phosphorylates the spindle-associated protein Astrin, resulting in targeting Astrin to the spindle microtubules and kinetochores. In turn, the GSK3β-Astrin complex may also facilitate further physiological and pathological phosphorylation.

Received for publication, August 15, 2007 , and in revised form, November 30, 2007.

^* This work was supported by NSC 95-2320-B-037-012 (Taiwan) (to Y.-R. H.) and NSC 95-2314-B-037-050 (to S.-L. H.). 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.

¹ To whom correspondence should be addressed: Graduate Institute of Biochemistry Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd., Kaohsiung 807 Taiwan. Tel.: 886-7-3121101 (ext. 5386); Fax: 886-7-3218309; E-mail: m835016{at}cc.kmu.edu.tw.

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