Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms

Liu, Gong‐Ping; Zhang, Yao; Yao, Xiu-Qing; Zhang, Change; Fang, Jiang; Wang, Qun; Wang, Jian‐Zhi

doi:10.1016/j.neurobiolaging.2007.03.012

Cited by 70 publications

(47 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, coimmunoprecipitation experiments clearly suggest a physical association of I 2 PP2A with GSK-3␤ in contrast with CAMKII. Consistent with our finding, Liu et al (72) showed that overactivation of GSK-3␤ inhibits PP2A through up-regulation of I 2 PP2A , indicating a positive correlation between I 2 PP2A and GSK-3␤ activity. We further confirmed the in vivo association of GSK-3␤ with I 2 PP2A in AD brain, where both are co-localized in the neuronal cytoplasm.…”

Section: Pp2asupporting

confidence: 93%

“…Additionally, we noticed a significant activation of GSK-3␤, as detected by a decrease in inhibitory phosphorylation at Ser 9 . Our current finding is consistent with previous reports that showed that accumulation of I 2 PP2A or overexpression of the C-terminal cleaved fragment of I 2 PP2A , I 2CTF , results in an increase in GSK-3␤ activity (32,72). Co-treatment with LiCl (GSK-3␤ inhibitor) and KN-93 (CAMKII inhibitor) significantly reduced the I 2 PP2A -induced Tau hyperphosphorylation.…”

Section: Pp2asupporting

confidence: 93%

See 1 more Smart Citation

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

Arif

Wei

Zhang

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: In Alzheimer brain, I 2 PP2A is translocated from the neuronal nucleus to the cytoplasm and promotes abnormal hyperphosphorylation of Tau. Results: Inactivation of nuclear localization signal (NLS) causes retention of I 2 PP2A in the cell cytoplasm, where it promotes Tau hyperphosphorylation by affecting PP2A signaling. Conclusion: Retention of I 2 PP2A in cell cytoplasm results in Tau hyperphosphorylation. Significance: The study provides potential tools for investigating Tau-based therapeutics.

show abstract

Section: Pp2asupporting

confidence: 93%

Section: Pp2asupporting

confidence: 93%

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

Arif

Wei

Zhang

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…PP-2A activity is regulated by endogenous protein inhibitors. PP-2A is considered a major tau phosphatase because it binds to tau and directly or indirectly regulates its phosphorylation by regulating GSK-3 activity [48][49][50][51][52][53] . In the human brain, PP-2A accounts for 70% of the tau phosphatase activity and in the AD brain this enzyme activity is reduced [47] .…”

Section: Tau Phosphatases Phosphatases Counterbalancementioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

show abstract

“…Hence, loss of phosphorylation by ceramide-mediated inactivation of GSK-3β and enhanced dephosphorylation by ceramideactivated PP2a should act synergistically on promoting the stability of microtubules. Interestingly, GSK-3β can also phosphorylate and inactivate PP2a [333]. Therefore, ceramide can activate PP2a in two ways: by direct binding to PP2a and by inactivating GSK-3β (via aPKC).…”

Section: Ceramide and S1p: Close Relatives But Conditional Antagonistsmentioning

confidence: 99%

Ceramide signaling in cancer and stem cells

Bieberich

2008

Future Lipidology

View full text Add to dashboard Cite

Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/ sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells. Keywordsapoptosis; cancer; cell polarity; ceramide; ES cells; lipid rafts; sphingomyelin; sphingosine-1-phosphate Ceramide & its derivatives: from metabolism to cell signalingThe structural core of ceramide is the sphingoid base sphingosine (Figure 1), a lipid that is synthesized from the amino acid serine and the activated fatty acid palmitoyl-CoA (Figure 2). Sphingosine (or sphingenine) was first isolated and characterized by the German pathologist and 'father of neurochemistry ' Johann Ludwig Wilhelm Thudichum (1829-1901 [1,2]. He coined the term sphingolipids, which is derived from 'sphingos', the genitive of Sphinx. In Greek, 'sphingo' means 'to strangle'. According to the legend, a fate of death was meant for everyone who could not solve the riddles posed by the Sphinx. Quite ironically, this is how many sphingolipid researchers may feel when faced with analyzing the function of ceramide. The riddle of ceramide, its function and how it acts as signaling lipid, is far from being solved. To ease our fears when confronted with the Sphinx in sphingolipid biochemistry, a related Greek word, 'sphingein', meaning 'to bind tight', alludes to the possibility of solving the enigma of ceramide by identifying its binding proteins.In addition to ceramide, more than a hundred different sphingolipids are known. The most comprehensive collection of sphingolipids, with respect to their characteristics and structures, can be found at [401], a Webpage supported by the National Institutes of General Medical Sciences [3,4]. Sphingolipids are essential components of cellular membranes and have been (Figure 3) . Among these, their roles as pro-or anti-apoptotic and pro-or anti-proliferative signaling lipids are the most important. Most recently, our group has found that establishment of cell polarity during embryonic development is another biological process regulated by sphingolipids [28]. To define a profile of functions for individual sphingolipids is difficult because of their rapid metabolic interconversion. To add to this predicament, several derivatives of ceramide have functions similar to ceramide itself. Hence, novel techniques are need...

show abstract

Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms

Cited by 70 publications

References 51 publications

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

Tau-induced neurodegeneration: mechanisms and targets

Ceramide signaling in cancer and stem cells

Contact Info

Product

Resources

About