Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1.
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 beta-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.
Wang
Ji-Wu
JW
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, USA.
Imai
Yuzuru
Y
Lu
Bingwei
B
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D024801:Tauopathies / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D038362:Glycogen Synthase Kinase 3; C472496:Par-1 protein, Drosophila; D000091162:AMP-Activated Protein Kinase Kinases