Tau-tubulin kinase

Ikezu, Seiko; Ikezu, Tsuneya

doi:10.3389/fnmol.2014.00033

Cited by 60 publications

(69 citation statements)

References 86 publications

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“…From evolutionary perspective, TTBK2 is a member of casein kinase 1 (CK1) superfamily, its kinase domain shows 38% identity with CK1δ (30,31). Apart from TTBK2, additional kinase MARK4 has been implicated in cilium initiation and assembly, although it seems to control the processes via SDA rather than DA of mother centriole (32).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Bernatík

Pejšková

Vysloužil

et al. 2019

Preprint

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Primary cilia (PC) are organelles necessary for proper implementation of developmental and homeostasis processes. To initiate their assembly, coordinated actions of multiple proteins are needed. Tau tubulin kinase 2 (TTBK2) is a key player in the cilium assembly pathway, controlling final step of cilia initiation. The function of TTBK2 in ciliogenesisis is critically dependent on its kinase activity, however, precise mechanism of TTBK2 action is so far incompletely understood, due to very limited information about its relevant substrates. In this study we identify CEP83, CEP89, CCDC92, Rabin8 and DVL3 as substrates of TTBK2 kinase activity. Further, we characterise a set of phosphosites of the newly identified substrates and CEP164, induced by TTBK2 in vitro and in vivo. Intriguingly, we further show that identified TTBK2 phosphosites and consensus sequence delineated from those are distinct from motifs previously assigned to TTBK2. Finally, we address functional relevance of selected phosphorylations of CEP164 and provide evidence that the examined TTBK2-induced phosphorylations of CEP164 are relevant for the process of cilia formation. In summary, our work provides important insight into substrates-TTBK2 kinase relationship and suggests that phosphorylation of substrates on multiple sites by TTBK2 is probably involved in the control of ciliogenesis in human cells.

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Section: Introductionmentioning

confidence: 99%

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Bernatík

Pejšková

Vysloužil

et al. 2019

Preprint

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“…Recent work has shown that TTBK1 is co-localized with pS422 + pTau in neuronal cell soma containing pre-tangles but not in neuropil threads or neurofibrillary tangles [8]. Since TTBK1 can directly phosphorylate tau at S422, this data suggest its role in pS422 + pTau accumulation in pre-tangle + neurons [6,43].…”

Section: Discussionmentioning

confidence: 88%

Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

Ikezu

Dixie

Koro

et al. 2019

Preprint

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The accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer's disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppresses the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ synergistically induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.This work was funded in part by NIH

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“…Using computational algorithms for microRNA target prediction 18 on all known tau kinases (i.e. Cdk5, GSK3, MARK, PKA, AMPK) 17,19,20 revealed only three kinases are predicted targets for miR-219 and highly conserved in both humans and rodents (mouse and rat), Tau tubulin kinase 1 (TTBK1), Calcium/calmodulin-dependent protein kinase 2 gamma subunit (CAMK2) and Glycogen synthase kinase 3 beta (GSK3) ( Supplementary Figure 1), which are all implicated in the generation and/or accumulation of abnormal hyperphosphorylated tau [21][22][23][24][25] . Importantly, miR-219 is not predicted to bind to the 3'UTR and repress expression of any known tau phosphatases 26 .…”

Section: Resultsmentioning

confidence: 99%

MiR-219 deficiency in Alzheimer’s disease contributes to neurodegeneration and memory dysfunction through post-transcriptional regulation of tau-kinase network

Arnés

et al. 2019

Preprint

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Intracellular accumulation of hyperphosphorylated misfolded tau proteins is one of the main neuropathological hallmarks in Alzheimer's disease (AD) and related tauopathies. Hence, knowledge and understanding of disease mechanisms altering tau proteostasis and inducing cytotoxicity is critical.MicroRNAs (miRNAs) are capable of binding to and silencing many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. Therefore, observed abnormalities in their expression patterns in neurodegeneration suggest alterations of microRNA-target networks as drivers of cellular dysfunction in the disease. Strikingly, here we have found in autopsy brain tissue that miRNA miR-219 expression levels are decreased in a brain region early affected in AD patients, the entorhinal cortex. Our bioinformatics analysis indicates miR-219 is predicted to target Calcium/calmodulin-dependent protein kinase 2 gamma subunit (CAMK2), Tau tubulin kinase 1 (TTBK1) and Glycogen synthase kinase 3 beta (GSK3), which are all implicated in the generation of abnormal hyperphosphorylated tau. We reveal human proteomic data supporting dysregulation in the levels of predicted miR-219 targets in the entorhinal cortex. In mammalian cellular models, we found that downregulation of miR-219 de-repress synthesis of three tau kinases, CAMK2, TTBK1 and GSK3 on the post-transcriptional level resulting in tau phosphorylation and cell toxicity. Finally, we show that deficiency of miR-219 in vivo promotes age dependent neurodegeneration in the adult brain, with enhanced alterations in tau proteostasis, presynaptic terminals and memory impairment. Taken together, our data implicate miRNA dysregulation central to AD etiopathogenesis and suggest potential targets for the treatment of AD and related tauopathies.

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Tau-tubulin kinase

Cited by 60 publications

References 86 publications

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

MiR-219 deficiency in Alzheimer’s disease contributes to neurodegeneration and memory dysfunction through post-transcriptional regulation of tau-kinase network

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