Microtubule-associated protein tau is essential for long-term depression in the hippocampus

The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro , an effect that was replicated by RNAi knockdown of tau in vitro . We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.

Download Full-text

GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽

10.3390/biology10070610 ◽

2021 ◽

Vol 10 (7) ◽

pp. 610

Author(s):

Robin Park ◽

Andrew L. Coveler ◽

Ludimila Cavalcante ◽

Anwaar Saeed

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Potential ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

In Vivo Models ◽

Gsk 3Β ◽

Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Download Full-text

Sites of phosphorylation in tau and factors affecting their regulation

Biochemical Society Symposium ◽

10.1042/bss0670073 ◽

2001 ◽

Vol 67 ◽

pp. 73-80 ◽

Cited By ~ 60

Author(s):

Brian H. Anderton ◽

Joanna Betts ◽

Walter P. Blackstock ◽

Jean-Pierre Brion ◽

Sara Chapman ◽

...

Keyword(s):

Glycogen Synthase ◽

Principal Component ◽

Paired Helical Filaments ◽

Glycogen Synthase Kinase 3 ◽

P38 Kinase ◽

Factors Affecting ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Tau Mutation

The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases. In vitro, glycogen synthase kinase-3 (GSK-3), extracellular signal-related kinase-1 and -2, and mitogen-activated protein kinases, p38 kinase and c-jun N-terminal kinase, all phosphorylate many of these sites, although with different efficiencies for particular sites. Phosphorylation studies in transfected cells and neurons show that GSK-3 phosphorylates tau more extensively than do these other proline-directed kinases. Mutations in tau have been shown to affect in vitro phosphorylation of tau by GSK-3. The Arg406-->Trp (R406W) tau mutation also affects tau phosphorylation in cells.

Download Full-text

The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase

Biochemical Journal ◽

10.1042/bj3550609 ◽

2001 ◽

Vol 355 (3) ◽

pp. 609-615 ◽

Cited By ~ 184

Author(s):

Yvonne L. WOODS ◽

Philip COHEN ◽

Walter BECKER ◽

Ross JAKES ◽

Michel GOEDERT ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Kinases ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Initiation Factor ◽

Glycogen Synthase Kinase 3 ◽

General Role ◽

Protein Tau ◽

Microtubule Associated Protein Tau ◽

Protein Synthesis Initiation

The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535in vitro and that eIF2Bε is highly phosphorylated at Ser539in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.

Download Full-text

Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau

FEBS Letters ◽

10.1016/0014-5793(92)81496-9 ◽

1992 ◽

Vol 314 (3) ◽

pp. 315-321 ◽

Cited By ~ 337

Author(s):

E.-M. Mandelkow ◽

G. Drewes ◽

J. Biernat ◽

N. Gustke ◽

J. Van Lint ◽

...

Keyword(s):

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Protein Tau ◽

Microtubule Associated Protein Tau

Download Full-text

Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3

Molecular and Cellular Biology ◽

10.1128/mcb.00232-06 ◽

2006 ◽

Vol 26 (15) ◽

pp. 5784-5796 ◽

Cited By ~ 60

Author(s):

Alexander Hergovich ◽

Joanna Lisztwan ◽

Claudio R. Thoma ◽

Christiane Wirbelauer ◽

Robert E. Barry ◽

...

Keyword(s):

Tumor Suppressor ◽

Glycogen Synthase ◽

Human Cancer ◽

Suppressor Gene ◽

Binding Activity ◽

Glycogen Synthase Kinase ◽

Normal Operation ◽

Glycogen Synthase Kinase 3

ABSTRACT Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is linked to the development of tumors of the eyes, kidneys, and central nervous system. VHL encodes two gene products, pVHL30 and pVHL19, of which one, pVHL30, associates functionally with microtubules (MTs) to regulate their stability. Here we report that pVHL30 is a novel substrate of glycogen synthase kinase 3 (GSK3) in vitro and in vivo. Phosphorylation of pVHL on serine 68 (S68) by GSK3 requires a priming phosphorylation event at serine 72 (S72) mediated in vitro by casein kinase I. Functional analysis of pVHL species carrying nonphosphorylatable or phosphomimicking mutations at S68 and/or S72 reveals a central role for these phosphorylation events in the regulation of pVHL's MT stabilization (but not binding) activity. Taken together, our results identify pVHL as a novel priming-dependent substrate of GSK3 and suggest a dual-kinase mechanism in the control of pVHL's MT stabilization function. Since GSK3 is a component of multiple signaling pathways that are altered in human cancer, our results further imply that normal operation of the GSK3-pVHL axis may be a critical aspect of pVHL's tumor suppressor mechanism through the regulation of MT dynamics.

Download Full-text

Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo

ACS Chemical Neuroscience ◽

10.1021/cn300110c ◽

2012 ◽

Vol 3 (11) ◽

pp. 963-971 ◽

Cited By ~ 80

Author(s):

Jose A. Morales-Garcia ◽

Rosario Luna-Medina ◽

Sandra Alonso-Gil ◽

Marina Sanz-SanCristobal ◽

Valle Palomo ◽

...

Keyword(s):

Glycogen Synthase ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3

Download Full-text

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416196112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1196-1201 ◽

Cited By ~ 56

Author(s):

Adam G. Walker ◽

Cody J. Wenthur ◽

Zixiu Xiang ◽

Jerri M. Rook ◽

Kyle A. Emmitte ◽

...

Keyword(s):

Prefrontal Cortex ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Fear Extinction ◽

Long Term Depression ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 3

Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.

Download Full-text

Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis.

Molecular and Cellular Biology ◽

10.1128/mcb.14.8.5510 ◽

1994 ◽

Vol 14 (8) ◽

pp. 5510-5522 ◽

Cited By ~ 152

Author(s):

B Lutterbach ◽

S R Hann

Keyword(s):

Glycogen Synthase ◽

Mitogen Activated Protein Kinase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Terminal Domain ◽

In Vivo Experiments ◽

Phosphopeptide Mapping ◽

Hierarchical Phosphorylation

The N-terminal domain of the c-Myc protein has been reported to be critical for both the transactivation and biological functions of the c-Myc proteins. Through detailed phosphopeptide mapping analyses, we demonstrate that there is a cluster of four regulated and complex phosphorylation events on the N-terminal domain of Myc proteins, including Thr-58, Ser-62, and Ser-71. An apparent enhancement of Ser-62 phosphorylation occurs on v-Myc proteins having a mutation at Thr-58 which has previously been correlated with increased transforming ability. In contrast, phosphorylation of Thr-58 in cells is dependent on a prior phosphorylation of Ser-62. Hierarchical phosphorylation of c-Myc is also observed in vitro with a specific glycogen synthase kinase 3 alpha, unlike the promiscuous phosphorylation observed with other glycogen synthase kinase 3 alpha and 3 beta preparations. Although both p42 mitogen-activated protein kinase and cdc2 kinase specifically phosphorylate Ser-62 in vitro and cellular phosphorylation of Thr-58/Ser-62 is stimulated by mitogens, other in vivo experiments do not support a role for these kinases in the phosphorylation of Myc proteins. Unexpectedly, both the Thr-58 and Ser-62 phosphorylation events, but not other N-terminal phosphorylation events, can occur in the cytoplasm, suggesting that translocation of the c-Myc proteins to the nucleus is not required for phosphorylation at these sites. In addition, there appears to be an unusual block to the phosphorylation of Ser-62 during mitosis. Finally, although the enhanced transforming properties of Myc proteins correlates with the loss of phosphorylation at Thr-58 and an enhancement of Ser-62 phosphorylation, these phosphorylation events do not alter the ability of c-Myc to transactivate through the CACGTG Myc/Max binding site.

Download Full-text

In vivo regulation of protein-serine kinases by insulin in skeletal muscle of fructose-hypertensive rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.2.e299 ◽

1999 ◽

Vol 277 (2) ◽

pp. E299-E307 ◽

Cited By ~ 2

Author(s):

Sanjay Bhanot ◽

Baljinder S. Salh ◽

Subodh Verma ◽

John H. McNeill ◽

Steven L. Pelech

Keyword(s):

Skeletal Muscle ◽

Glycogen Synthase ◽

Insulin Injection ◽

Glycogen Synthase Kinase 3 ◽

Phosphatidylinositol 3 Kinase ◽

S6 Kinase ◽

Serine Kinases ◽

Gsk 3Β

The effects of tail-vein insulin injection (2 U/kg) on the regulation of protein-serine kinases in hindlimb skeletal muscle were investigated in hyperinsulinemic hypertensive fructose-fed (FF) animals that had been fasted overnight. Basal protein kinase B (PKB) activity was elevated about twofold in FF rats and was not further stimulated by insulin. Phosphatidylinositol 3-kinase (PI3K), which lies upstream of PKB, was increased ∼3.5-fold within 2–5 min by insulin in control rats. Basal and insulin-activated PI3K activities were further enhanced up to 2-fold and 1.3-fold, respectively, in FF rats. The 70-kDa S6 kinase (S6K) was stimulated about twofold by insulin in control rats. Both basal and insulin-stimulated S6K activity was further enhanced up to 1.5-fold and 3.5-fold, respectively, in FF rats. In control rats, insulin caused a 40–50% reduction of the phosphotransferase activity of the β-isoform of glycogen synthase kinase 3 (GSK-3β), which is a PKB target in vitro. Basal GSK-3β activity was decreased by ∼40% in FF rats and remained unchanged after insulin treatment. In summary, 1) the PI3K → PKB → S6K pathway was upregulated under basal conditions, and 2) insulin stimulation of PI3K and S6K activities was enhanced, but both PKB and GSK-3 were refractory to the effects of insulin in FF rats.

Download Full-text