Protein Kinase FA/Glycogen Synthase Kinase‐3α After Heparin Potentiation Phosphorylates τ on Sites Abnormally Phosphorylated in Alzheimer's Disease Brain

  title={Protein Kinase FA/Glycogen Synthase Kinase‐3$\alpha$ After Heparin Potentiation Phosphorylates $\tau$ on Sites Abnormally Phosphorylated in Alzheimer's Disease Brain},
  author={Shiaw‐Der Yang and Jau-Song Yu and Shine-Gwo Shiah and Jun‐Jae Huang},
  journal={Journal of Neurochemistry},
Abstract: Previously, we identified protein kinase FA/glycogen synthase kinase‐3α (GSK‐3α) as a brain microtubule‐associated τ kinase that phosphorylates Ser235 and Ser404 of τ and causes its electrophoretic mobility shift in gels, a unique property characteristic of paired helical filament‐associated pathological τ (PHF‐τ) in Alzheimer's disease brains. In this study, we found that the activity of kinase FA/GSK‐3α towards phosphorylation of brain τ could be stimulated approximately fourfold by… 

Overactivation of glycogen synthase kinase‐3 by inhibition of phosphoinositol‐3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory

It is demonstrated that injection of wortmannin or GF‐109203X into the left ventricle of rat brains leads to overactivation of GSK‐3, hyperphosphorylation of tau and spatial memory impairment resulting from PI3K and PKC inhibition, and in vivo inhibition of phosphoinositol‐3 kinase and protein kinase C results in overactivation.

Tau protein kinase I/GSK-3Β/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brain

Initial evidence is provided that TPKI/GSK-3Β/FA after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau and neuronal degeneration in Alzheimer disease brains.

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.

Phosphorylation Sites on Tau Identified by Nanoelectrospray Mass Spectrometry

The three MAP kinases, p38, ERK2, and GSK3β are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.

GSK‐3 mediates the okadaic acid‐induced modification of collapsin response mediator protein‐2 in human SK‐N‐SH neuroblastoma cells

It is demonstrated for the first time that OA can induce phosphorylation of CRMP‐2 in SK‐N‐SH cells at sites aberrantly phosphorylated in AD brain, and both GSK‐3α and 3β and Ser‐522 kinase(s) are involved in this process.

Selective interaction of protein kinase FA/glycogen synthase kinase-3alpha with membrane phospholipids.

  • J. YuW. ChanS. Yang
  • Biology, Chemistry
    Biochemical and biophysical research communications
  • 1997
It was found that kinase FA/GSK-3alpha can associate with NaOH-extracted brain membranes and selectively interact with several kinds of reconstituted phospholipid vesicles including phosphatidic acid (PA),osphatidyl ethanolamine (PE), phosph atidyl inositol (PI), and phosphatodyl serine (PS) vesicle.

Heat stress induces tyrosine phosphorylation/activation of kinase Fa/GSK‐3α (a human carcinoma dedifferentiation modulator) in A431 cells

Initial evidence is provided that kinase FA/GSK‐3α represents a newly described heat stress–inducible protein subjected to tyrosine phosphorylation/activation, representing a new mode of signal transduction for the regulation of this human carcinoma dedifferentiation modulator and a new modes of heat induction on cascade activation of a protein kinase.



Protein Kinase FA/GSK‐3 Phosphorylates on Ser235‐Pro and Ser404‐Pro that Are Abnormally Phosphorylated in Alzheimer's Disease Brain

Results provide initial evidence that protein kinase FA/GSK‐3 may represent one of the Ser‐Pro motif‐directed kinases involved in the abnormal phosphorylation of pathological PHF‐ in Alzheimer's disease brain.

Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state.

It is proposed that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.

Phosphorylation of microtubule‐associated protein tau: identification of the site for Ca2(+)‐calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles.

It is shown that a single phosphorylation site is responsible for the pronounced shift in electrophoretic mobility characteristic for tau from Alzheimer neurofibrillary tangles, located at Ser 405 in the C‐terminal tail of the protein outside the region of internal repeats.

Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain

The findings suggest that the hyperph phosphorylation of τ in Alzheimer disease brain could result from a protein dephosphorylation defect in vivo, and the decrease in the phosphatase activities in Alzheimer diseased brains might also be involved in the formation of β‐amyloid by augmenting the amyloidogenic pathway processing of β-amyloids precursor protein.

Molecular cloning and expression of glycogen synthase kinase‐3/factor A.

The physiological importance of these two proteins in cellular signal transduction is discussed, and partial purification of GSK‐3 activity from bovine brain results in the isolation of active alpha and beta proteins.

Identification of the ATP·Mg-dependent protein phosphatase activator (Fa) as a synapsin I kinase that inhibits cross-linking of synapsin I with brain microtubules

The results suggest the possible involvement of factorFa as a synapsin I kinase in the regulation of axonal transport process of synaptic vesicles via the promotion of vesicle motility during neurotransmission.