分子醫學研究所Wu, P-RP-RWuTsai, P-IP-ITsaiChen, G-CG-CChenChou, H-JH-JChouHuang, Y-PY-PHuangChen, Y-HY-HChenLin, M-YM-YLinKimchi, AAKimchiChien, C-TC-TChienChen, R-HR-HChen2012-07-052018-07-092012-07-052018-07-092011http://ntur.lib.ntu.edu.tw//handle/246246/240673Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer's disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. In this study, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1 /2. Accordingly, DAPK(-/-) mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well- characterized Drosophila model of tauopathy, we show that DAPK exerts an effect in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together , our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology.en-USDAPKMARK/PAR-1tau phosphorylationneurodegenerationmicrotubules[SDGs]SDG3actin; cytoskeleton protein; death associated protein kinase; microtubule associated protein 2; microtubule associated protein 4; mitogen activated protein kinase kinase kinase 1; mitogen activated protein kinase kinase kinase 2; proteinase activated receptor 1; tau protein; Alzheimer disease; animal cell; animal experiment; animal model; animal tissue; article; cell culture; cell death; controlled study; Drosophila; enzyme activation; enzyme binding; enzyme inhibition; microtubule assembly; mouse; nerve cell differentiation; nerve cell lesion; nerve fiber growth; neurotoxicity; nonhuman; photoreceptor; priority journal; protein expression; protein function; protein phosphorylation; rat; tauopathy; Alzheimer Disease; Animals; Apoptosis Regulatory Proteins; Calcium-Calmodulin-Dependent Protein Kinases; Cell Differentiation; Cell Line; Drosophila; Enzyme Activation; Humans; MAP Kinase Signaling System; Mice; Microtubules; Neurons; Phosphorylation; Protein-Serine-Threonine Kinases; tau Proteins; Mus10.1038/cdd.2011.2