Site-specific Phosphorylation Protects Glycogen Synthase Kinase-3β from Calpain-mediated Truncation of Its N and C Termini

Ma, Shanshan; Liu, Shaojun; Huang, Qiaoying; Xie, Bo; Lai, Bingquan; Wang, Chong; Song, Bin; Li, Mingtao

doi:10.1074/jbc.m111.321349

Cited by 28 publications

(45 citation statements)

References 41 publications

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“…N-terminal truncation eliminates the regulatory domain that inhibits the catalytic activity (Goni-Oliver et al, 2007;Ma et al, 2012). Thus, the present results seem to propose that during excitotoxicity processes there is an increase in GSK3 activity.…”

Section: Discussionmentioning

confidence: 51%

“…However, the calpain inhibitor calpeptin inhibits GSK3 truncation in cultured neurons and hippocampal slices suggesting that GSK3 is substrate only of calpain. In fact, it has been reported that the caspase-3 inhibitor Z-VAD-FMK does not prevent the generation of GSK3 truncated fragments in rat cerebellar granule neurons (Ma et al, 2012). In addition, in the same KA injected rat model, caspases are not involved in GSK3 decreased levels (Araujo et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have shown that GSK3 can undergo a limited proteolysis in cultured neurons (Crespo-Biel et al, 2010b;Czogalla and Sikorski, 2005;Feng et al, 2013;Goni-Oliver et al, 2007;Ma et al, 2012Ma et al, , 2009). However, it has been unclear whether this truncation of GSK3 occurs in vivo.…”

Section: Discussionmentioning

confidence: 97%

“…1). GSK3β is truncated at its N-and C-terminal ends at residues Thr-38-Thr-39 and Ile-384-Gln-385 (Ma et al, 2012). Thus, an antibody which recognizes the epitope around Ala22 does not recognize N-terminal truncated fragment generated indicating that the enzyme is N-terminal truncated.…”

Section: 2mentioning

confidence: 91%

“…Recently, a novel mechanism of regulation has been described: cleavage of GSK3 by calpain (Goni-Oliver et al, 2007;Ma et al, 2012). Cultured cortical neurons exposed to ionomycin, glutamate or N-methyl-D-aspartate (NMDA) led to the truncation of GSK3 (Goni-Oliver et al, 2007;Ma et al, 2009) as well as hippocampal cells exposed to 3-nitropropionic acid (Crespo-Biel et al, 2010b).…”

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confidence: 99%

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Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

et al. 2015

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In neuronal cultures, glycogen synthase kinase 3(GSK3) is truncated at the N-terminal end by calpain downstream of activated glutamate receptors. However, the in vivo biological significance of that truncation has not been explored. In an attempt to elucidate if GSK3 truncation has a pathophysiological relevance, we have used intraperitoneal injections of kainic acid (KA) in rats and intra-amygdala KA microinjections in mice as in vivo models of excitotoxicity. Spectrin cleavage analyzed by immunohistochemistry was observed in the CA1 hippocampal field in KA-intraperitoneal treated rats while the CA3 region was the hippocampal area affected after intra-amygdala KA microinjections. GSK3β immunofluorescence did not colocalize with truncated spectrin in both treatments using an antibody that recognize the N-terminal end of GSK3β. Thus, those neurons which are spectrin-positive do not show GSK3β immunolabelling. To study GSK3β truncation in vitro, we exposed organotypic hippocampal slices and cultured cortical neurons to KA leading to the truncation of GSK3 and we found that truncation was blocked by the calpain inhibitor calpeptin. These data suggest a relationship between N-terminal GSK3β truncation and excitotoxicity. Overall, our data reinforces the important relationship between glutamate receptors and GSK3 and their role in neurodegenerative processes in which excitotoxicity is involved.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: 2mentioning

confidence: 91%

mentioning

confidence: 99%

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Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

et al. 2015

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C‐terminal truncation of GSK‐3β enhances its dephosphorylation by PP2A

Jin

Wen

et al. 2017

FEBS Letters

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Glycogen synthase kinase-3β (GSK-3β) is the major tau kinase. Its phosphorylation at Ser9 suppresses the activity. In Alzheimer's disease (AD) brain, GSK-3β is truncated at the C terminus by overactivated calpain I, leading to an increase in its activity. However, the effect of truncation on its phosphorylation is unknown. We found here that in AD brain and in cultured cells, C-terminally truncated GSK-3β is less phosphorylated at Ser9 than the full-length enzyme. The truncation promotes GSK-3β nuclear translocation and enhances its interaction with protein phosphatase 2A (PP2A), leading to dephosphorylation. Thus, the truncation of GSK-3β may enhance its activity through Ser9 dephosphorylation by PP2A. Our findings shed new light on the role of calpain-GSK-3β-PP2A in tau pathogenesis of AD.

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Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Mahaman

Huang

Afewerky

et al. 2018

Medicinal Research Reviews

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Alzheimer's disease (AD) is the most common (60% to 80%) age-related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells' life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.

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Site-specific Phosphorylation Protects Glycogen Synthase Kinase-3β from Calpain-mediated Truncation of Its N and C Termini

Cited by 28 publications

References 41 publications

Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

C‐terminal truncation of GSK‐3β enhances its dephosphorylation by PP2A

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

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