Dapk Activates Mark1/2 to Regulate Microtubule Assembly, Neuronal Differentiation, and Tau Toxicity
Resource
CELL DEATH AND DIFFERENTIATION v.18 n.9 SP. ISS. S pp.1507-1520
Journal
Cell Death and Differentiation
Pages
1507-1520
Date Issued
2011
Date
2011
Author(s)
Wu, P-R
Tsai, P-I
Chen, G-C
Chou, H-J
Huang, Y-P
Chen, Y-H
Lin, M-Y
Kimchi, A
Chien, C-T
Chen, R-H
Abstract
Death-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.
Subjects
DAPK
MARK/PAR-1
tau phosphorylation
neurodegeneration
microtubules
SDGs
Other Subjects
actin; 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; Mus