Phosphorylation of tau protein by recombinant GSK‐3β: pronounced phosphorylation at select Ser/Thr‐Pro motifs but no phosphorylation at Ser262 in the repeat domain

Godemann, Robert; Biernat, Jacek; Mandelkow, E.; Mandelkow, Eckhard

doi:10.1016/s0014-5793(99)00741-3

Cited by 97 publications

(103 citation statements)

References 60 publications

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“…This inhibition is not due to a direct effect of Dvl on GSK3b, as Dvl and GSK3b do not interact (Li et al 1999), and therefore other interacting proteins must be involved. Further, in the Mudher et al (2001) study tau phosphorylation at the 12E8 epitope (pSer262/356) was decreased by Dvl expression, despite the fact that the 12E8 epitope is not a GSK3b site (Godemann et al 1999). This suggests that Dvl may decrease tau phosphorylation by inhibiting the activity of some other protein kinase(s) and/or by increasing the activity of protein phosphatases, in concert with its effects on GSK3b mediated phosphorylation events.…”

Section: Discussionmentioning

confidence: 92%

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Stoothoff¹,

Bailey²,

Mi³

et al. 2002

Journal of Neurochemistry

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Glycogen synthase kinase 3b (GSK3b) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3b is the microtubuleassociated protein tau. Phosphorylation of tau by GSK3b decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3b is a downstream regulator of the wnt signaling pathway, which maintains the levels of b-catenin. Axin plays a central role in regulating b-catenin levels by bringing together GSK3b and b-catenin and facilitating the phosphorylation of b-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of b-catenin, its effects on the phosphorylation of other GSK3b substrates are unclear.Therefore in this study the effects of axin on GSK3b-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3b. This negative regulation of GSK3b-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3b but not tau and thus sequesters GSK3b away from tau, as an axin mutant that does not bind GSK3b did not inhibit tau phosphorylation by GSK3b. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3b substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

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Section: Discussionmentioning

confidence: 92%

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Stoothoff¹,

Bailey²,

Mi³

et al. 2002

Journal of Neurochemistry

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“…This lead us to focus on GSK3␤, which is also of great interest in the context of AD because it phosphorylates Tau efficiently at Ser/Thr-Pro motifs that are elevated in AD (31,32). In addition, we could show that MARK and GSK3␤ copurified through several steps of purification (11,33).…”

Section: Gsk3␤ Phosphorylates Mark2 At Serine 212 and Reduces Itsmentioning

confidence: 90%

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

Timm¹,

Balusamy²,

et al. 2008

Journal of Biological Chemistry

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MARK/Par-1, a kinase family with diverse functions particularly in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain and cause their detachment from microtubules, and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of the Tau protein in Alzheimer disease, we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3␤ serves the role of the inhibitory kinase. Because GSK3␤ can also phosphorylate Tau at sites outside the repeat domain, the activation of GSK3␤, and concomitant inactivation of MARK can shift the pattern of pathological phosphorylation of Tau protein in Alzheimer disease.

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“…Total RNA was extracted from the cultures as described previously (Godemann et al, 1999). Total RNA was subjected to DnaseI treatment (Roche, Hertforshire, UK) and 2 g of total RNA/sample were used for cDNA synthesis using Superscript II (Invitrogen, San Diego, CA) and an oligodT primer.…”

Section: Methodsmentioning

confidence: 99%

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

Caricasole¹,

Copani²,

Caraci³

et al. 2004

J. Neurosci.

352

334

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We used primary cultures of cortical neurons to examine the relationship between ␤-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to ␤-amyloid peptide (␤AP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3␤. DKK1 was induced at late times after ␤AP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in ␤AP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by ␤-amyloid and is critically involved in the process of tau phosphorylation.

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Phosphorylation of tau protein by recombinant GSK‐3β: pronounced phosphorylation at select Ser/Thr‐Pro motifs but no phosphorylation at Ser262 in the repeat domain

Cited by 97 publications

References 60 publications

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

Glycogen Synthase Kinase (GSK) 3β Directly Phosphorylates Serine 212 in the Regulatory Loop and Inhibits Microtubule Affinity-regulating Kinase (MARK) 2

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

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