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

Wu, Pei-Shan; Tsai, Pei-I; Chen, G. C.; Chou, He-Yen; Huang, Yuan; Chen, Y. H.; Lin, Meng-Hsuan; Kimchi, Adi; Chien, Ching‐Te; Chen, R. H.

doi:10.1038/cdd.2011.2

Cited by 70 publications

(64 citation statements)

References 40 publications

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“…MAP1B is a key target of DAPK1 (46). DAPK1 also plays a key role in the regulation of cell morphology by bridging membrane proteins with the cytoskeleton (46,(70)(71)(72). Finally, unbiased loss-of-function studies have shown that DAPK1 is required specifically for proper subcellular localization of late/recycling endosomes (72), the vesicular compartment expanded in the apex of maturing ZCs, as described above.…”

Section: Discussionmentioning

confidence: 94%

The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation

Capoccia¹,

Jin²,

Kong³

et al. 2013

J. Clin. Invest.

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After cell fate specification, differentiating cells must amplify the specific subcellular features required for their specialized function. How cells regulate such subcellular scaling is a fundamental unanswered question. Here, we show that the E3 ubiquitin ligase Mindbomb 1 (MIB1) is required for the apical secretory apparatus established by gastric zymogenic cells as they differentiate from their progenitors. When Mib1 was deleted, death-associated protein kinase-1 (DAPK1) was rerouted to the cell base, microtubule-associated protein 1B (MAP1B) was dephosphorylated, and the apical vesicles that normally support mature secretory granules were dispersed. Consequently, secretory granules did not mature. The transcription factor MIST1 bound the first intron of Mib1 and regulated its expression. We further showed that loss of MIB1 and dismantling of the apical secretory apparatus was the earliest quantifiable aberration in zymogenic cells undergoing transition to a precancerous metaplastic state in mouse and human stomach. Our results reveal a mechanistic pathway by which cells can scale up a specific, specialized subcellular compartment to alter function during differentiation and scale it down during disease.

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Section: Discussionmentioning

confidence: 94%

The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation

Capoccia¹,

Jin²,

Kong³

et al. 2013

J. Clin. Invest.

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“…It is not clear for MARK1 and its close relatives what might be the second target analogous to septins. One intriguing possibility is death-associated protein kinase, which has been reported to relieve autoinhibition of MARK1 and MARK2 by binding to the ‘linker’ region [48] to modulate microtubule assembly and neuronal differentiation, and may do so in concert with KA1 domain engagement by anionic membrane surfaces.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase

Emptage

Lemmon

Ferguson

2017

Biochemical Journal

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Protein kinases are frequently regulated by intramolecular autoinhibitory interactions between protein modules that are reversed when these modules bind other ‘activating’ protein or membrane-bound targets. One group of kinases, the MAP/microtubule affinity-regulating kinases (MARKs) contain a poorly understood regulatory module, the KA1 (kinase associated-1) domain, at their C-terminus. KA1 domains from MARK1 and several related kinases from yeast to humans have been shown to bind membranes containing anionic phospholipids, and peptide ligands have also been reported. Deleting or mutating the C-terminal KA1 domain has been reported to activate the kinase in which it is found — also suggesting an intramolecular autoinhibitory role. Here, we show that the KA1 domain of human MARK1 interacts with, and inhibits, the MARK1 kinase domain. Using site-directed mutagenesis, we identify residues in the KA1 domain required for this auto-inhibitory activity, and find that residues involved in autoinhibition and in anionic phospholipid binding are the same. We also demonstrate that a ‘mini’ MARK1 becomes activated upon association with vesicles containing anionic phospholipids, but only if the protein is targeted to these vesicles by a second signal. These studies provide a mechanistic basis for understanding how MARK1 and its relatives may require more than one signal at the membrane surface to control their activation at the correct location and time. MARK family kinases have been implicated in a plethora of disease states including Alzheimer’s, cancer, and autism, so advancing our understanding of their regulatory mechanisms may ultimately have therapeutic value.

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“…Death-associated protein kinase (DAPK) inhibits microtubule assembly by activating MARK2. The death-associated protein kinase death domain but not catalytic activity is responsible for this activation by binding to the MARK2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK2 (35). PAK5, a neuronal member of the p21-activated kinase family, suppresses the activity of MARK2 (36).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409

Deng

Wang

et al. 2015

Journal of Biological Chemistry

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Background: MARK2 and PKA are both involved in the regulation of microtubule stability. Results: PKA significantly inhibits MARK2 by phosphorylating serine 409 and rescues MARK2-induced microtubule instability and neurite disruption. Conclusion: PKA functions as an upstream inhibitor of MARK2 by directly interacting and phosphorylating it. Significance: The results identify a novel interaction between PKA and MARK2, providing new insight into the signal networks of both.

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

Cited by 70 publications

References 40 publications

The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation

The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation

Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase

Protein Kinase A Rescues Microtubule Affinity-regulating Kinase 2-induced Microtubule Instability and Neurite Disruption by Phosphorylating Serine 409

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