DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity

P. R. Wu, P. I. Tsai, G. C. Chen, H. J. Chou, Y. P. Huang, Y. H. Chen, M. Y. Lin, A. Kimchi, C. T. Chien, R. H. Chen

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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.

Original languageEnglish
Pages (from-to)1507-1520
Number of pages14
JournalCell Death and Differentiation
Volume18
Issue number9
DOIs
Publication statusPublished - 2011 Sep 1

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Keywords

  • DAPK
  • MARK/PAR-1
  • microtubules
  • neurodegeneration
  • tau phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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. (2011). DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity. Cell Death and Differentiation, 18(9), 1507-1520. https://doi.org/10.1038/cdd.2011.2