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The Journal of Neuroscience, January 17, 2007, 27(3):574-581; doi:10.1523/JNEUROSCI.5094-06.2007

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Neurobiology of Disease
Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Ji-Wu Wang, Yuzuru Imai, and Bingwei Lu

Department of Pathology, Stanford University School of Medicine, and Geriatric Research, Education, and Clinical Center/Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304

Correspondence should be addressed to Bingwei Lu at the above address. Email: bingwei{at}stanford.edu

Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human ß-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.

Key words: Alzheimer's disease; APP; Drosophila; LKB1; MARK/PAR-1; neurodegeneration; tau phosphorylation; stress

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Received Aug. 24, 2006; accepted Dec. 2, 2006.

Correspondence should be addressed to Bingwei Lu at the above address. Email: bingwei{at}stanford.edu

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