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J. Biol. Chem., Vol. 279, Issue 16, 15938-15945, April 16, 2004

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Casein Kinase 1 Delta Phosphorylates Tau and Disrupts Its Binding to Microtubules^*

Guibin Li, Haishan Yin, and Jeff Kuret¶||

From the Center for Molecular Neurobiology, Ohio State Biochemistry Program, and the ^¶Department of Molecular and Cellular Biochemistry, Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210

Tau hyperphosphorylation precedes neuritic lesion formation in Alzheimer's disease, suggesting it participates in the tau fibrillization reaction pathway. Candidate tau protein kinases include members of the casein kinase 1 (CK1) family of phosphotransferases, which are highly overexpressed in Alzheimer's disease brain and colocalize with neuritic and granulovacuolar lesions. Here we characterized the contribution of one CK1 isoform, Cki, to the phosphorylation of tau at residues Ser²⁰²/Thr²⁰⁵ and Ser³⁹⁶/Ser⁴⁰⁴ in human embryonic kidney 293 cells using immunodetection and fluorescence microscopy. Treatment of cells with membrane permeable CK1 inhibitor 3-[(2,3,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261) lowered occupancy of Ser³⁹⁶/Ser⁴⁰⁴ phosphorylation sites by >70% at saturation, suggesting that endogenous CK1 was the major source of basal phosphorylation activity at these sites. Overexpression of Cki increased CK1 enzyme activity and further raised tau phosphorylation at residues Ser²⁰²/Thr²⁰⁵ and Ser³⁹⁶/Ser⁴⁰⁴ in situ. Inhibitor IC261 reversed tau hyperphosphorylation induced by Cki overexpression. Co-immunoprecipitation assays showed direct association of tau and Cki in situ, consistent with tau being a Cki substrate. Cki overexpression also produced a decrease in the fraction of bulk tau bound to detergent-insoluble microtubules. These results suggest that Cki phosphorylates tau at sites that modulate tau/microtubule binding, and that the expression pattern of Cki in Alzheimer's disease is consistent with it playing an important role in tau aggregation.

Received for publication, December 23, 2003 , and in revised form, January 26, 2004.

^* This work was supported by National Institutes of Health Grant AG14452 (to J. 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: Center for Neurobiotechnology, 1060 Carmack Rd., Columbus, OH 43210. Tel.: 614-688-5899; Fax: 614-292-5379; E-mail: kuret.3{at}osu.edu.

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