Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry

  title={Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry},
  author={Eric T Lund and Robert Mckenna and D. B. Evans and Sandeep Savitaprakash Sharma and W. Rodney Mathews},
  journal={Journal of Neurochemistry},
Hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies, and tau protein kinase II is reported to play a role in the pathogenesis of Alzheimer's disease. Recently, we reported that tau protein kinase II (cdk5/p20)‐phosphorylated human tau inhibits microtubule assembly, and tau protein kinase II (cdk5/p20) phosphorylation of microtubule‐associated tau results in dissociation of phosphorylated tau from the microtubules and tubulin… 

Mitotic-like Tau Phosphorylation by p25-Cdk5 Kinase Complex*

The data suggest that p25-Cdk5 is responsible for the mitotic-like phosphoepitopes present in NFT and argue for a critical role of Cdk5 in neurodegenerative mechanisms.

Phosphorylation of FTDP-17 Mutant tau by Cyclin-dependent Kinase 5 Complexed with p35, p25, or p39*

The results indicate that FTDP-17 mutations do not affect the phosphorylatability of tau by Cdk5 complexed with p35, p25, or p39 and may explain part of the discrepancy reported previously between in vivo and in vitro phosphorylation of FT DP-17 tau mutants.

Casein Kinase 1 Delta Phosphorylates Tau and Disrupts Its Binding to Microtubules*

The results suggest that Ckiδ phosphorylates tau at sites that modulate tau/microtubule binding, and that the expression pattern of CKIδ in Alzheimer's disease is consistent with it playing an important role in tau aggregation.

Global analysis of phosphorylation of tau by the checkpoint kinases Chk1 and Chk2 in vitro.

13 sites have been identified to be phosphorylated in AD brains, among which 13 sites are located within the microtubule-binding domain and C-terminal domain, whose phosphorylation has been shown to reduce tau binding to microtubules and/or has been implicated in tau toxicity.

No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

It is concluded that conversion of p35 to p25 does not alter the catalytic efficiency of theCDK5 catalytic subunit by using histone H1 or tau as substrates, and that neurotoxicity associated with CDK5/p25 is unlikely attributable to CDK 5 hyperactivation, as measured in vitro.

Physiological and pathological phosphorylation of tau by Cdk5

This article summarizes the physiological and pathological phosphorylation of tau via Cdk5, a member of the cyclin-dependent kinases, which is activated in post-mitotic neurons via the neuron-specific activator p35 and plays a critical role in brain development and physiological synaptic activity.

p35/Cdk5 pathway mediates soluble amyloid‐β peptide‐induced tau phosphorylation in vitro

Results show that sAβ is a potent activator of the p25/Cdk5 pathway, resulting in promotion of AD‐like tau phosphorylation in vitro, and indicate that dystrophic neurites appear before the formation of neuritic plaques.

Electrochemical investigations into kinase-catalyzed transformations of tau protein.

This study illustrates the validity and the utility of the labeled electrochemical approach for probing the changes in protein film properties, conformation, and orientation as a function of the enzymatically catalyzed modifications.

Tau phosphorylation in neuronal cell function and dysfunction

Identification of the protein kinases that phosphorylate tau in vivo in both physiological and pathological processes could provide potential therapeutic targets for the treatment of AD and other neurodegenerative diseases in which there is tau pathology.



Tau Phosphorylation at Serine 396 and Serine 404 by Human Recombinant Tau Protein Kinase II Inhibits Tau's Ability to Promote Microtubule Assembly*

In vitro phosphorylation of human tau by human recombinant tau protein kinase II severely inhibits the ability of tau to promote microtubule assembly as monitored by tubulin polymerization, and results suggest a possible role for tau Protein Kinase II-mediated tau phosphorylations in initiating the destabilization of microtubules.

Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein.

It is suggested that tau protein kinase II is indirectly involved, at least in part, in the regulation of the phosphorylation state of tau in neuronal cells.

Phosphorylation by Neuronal cdc2-like Protein Kinase Promotes Dimerization of Tau Protein in Vitro *

  • H. Paudel
  • Biology, Chemistry
    The Journal of Biological Chemistry
  • 1997
It is suggested that phosphorylation by NCLK promotes dimerization and formation of disulfide cross-linked tau dimers, which is suggested to be the key step leading to PHF assembly.

The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease.

The results support the view that reactivation of the cell cycle machinery is involved in tau hyperphosphorylation, and identify 17 phosphorylation sites comprising 80-90% of the total phosphate incorporated, except S214 and S262.

Proline-directed phosphorylation of human Tau protein.

τ Protein Kinase II Is Involved in the Regulation of the Normal Phosphorylation State of τ Protein

It is suggested that τ protein kinase II is indirectly involved, at least in part, in the regulation of the phosphorylation state of τ in neuronal cells.

New Phosphorylation Sites Identified in Hyperphosphorylated Tau (Paired Helical Filament‐Tau) from Alzheimer's Disease Brain Using Nanoelectrospray Mass Spectrometry

The solubilisation of PHF‐tau followed by its purification by Mono Q chromatography and reversed‐phase HPLC is described and the combination of the new data with previous reports shows that PHF-tau can be phosphorylated on at least 25 different sites, including five sites not previously identified.