title: DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: P-R
authors.initials: PR
authors.lastname: Wu
authors.forename: P-I
authors.initials: PI
authors.lastname: Tsai
authors.forename: G-C
authors.initials: GC
authors.lastname: Chen
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chou
authors.forename: Y-P
authors.initials: YP
authors.lastname: Huang
authors.forename: Y-H
authors.initials: YH
authors.lastname: Chen
authors.forename: M-Y
authors.initials: MY
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Kimchi
authors.forename: C-T
authors.initials: CT
authors.lastname: Chien
authors.forename: R-H
authors.initials: RH
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D064550:Death-Associated Protein Kinases; D004330:Drosophila; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016875:tau Proteins; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases