GSK-3β (Glycogen Synthase Kinase-3 beta) is a serine/threonine kinase central to Alzheimer's disease, Parkinson's disease, and related tauopathies. It phosphorylates tau at multiple sites, interacts with APP processing, and is regulated by the PI3K/Akt and Wnt/β-catenin pathways.
Glycogen Synthase Kinase-3 beta (GSK-3β) is a serine/threonine kinase that plays a central role in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders[1][2]. Originally identified as a key regulator of glycogen metabolism, GSK-3β has emerged as a critical enzyme in multiple pathological processes including tau hyperphosphorylation, amyloid-beta production, synaptic dysfunction, neuroinflammation, and neuronal death[3][4]. The identification of GSK-3β as a hub in Alzheimer's disease pathogenesis has made it an attractive therapeutic target, with numerous inhibitors advancing to clinical trials over the past two decades[5].
GSK-3β is a constitutively active kinase, meaning it is active under basal physiological conditions, unlike many other kinases that require specific activation signals[6]. This unique characteristic positions GSK-3β as a key "rheostat" that integrates multiple cellular signals and regulates diverse cellular processes[7]. The kinase is encoded by the GSK3B gene located on chromosome 3q13.33 in humans and is highly expressed in brain regions critical for memory and cognition, including the hippocampus and prefrontal cortex[8]. Its central position in cellular signaling networks, combined with its involvement in virtually every hallmark of Alzheimer's disease pathology, has made GSK-3β one of the most extensively studied therapeutic targets in neurodegeneration research[9].
GSK-3β is regulated by phosphorylation at Ser9 (inhibitory) via Akt, PKA, and PKC, and by tyrosine autophosphorylation at Tyr216. It interacts with scaffold proteins like axin in the Wnt signaling pathway.
GSK-3β is a 47 kDa protein consisting of 420 amino acids organized into a typical bilobal kinase structure with an N-terminal catalytic domain and a C-terminal regulatory region[10]. The active site of GSK-3β resides in a shallow groove between the two lobes, where ATP binding and substrate phosphorylation occur[11]. Unlike most kinases, GSK-3β exhibits a unique substrate priming requirement: it preferentially phosphorylates substrates that have already been pre-phosphorylated at a position four residues C-terminal to the target serine/threonine, a mechanism mediated by prior phosphorylation by other kinases such as casein kinase 1 (CK1), protein kinase A (PKA), and cyclin-dependent kinases (CDKs)[12].
The three-dimensional structure of GSK-3β reveals several structural features critical for its function and regulation. The activation loop contains a tyrosine residue (Tyr216 in human GSK-3β) that must be phosphorylated for maximal kinase activity[13]. This auto-phosphorylation event occurs during protein synthesis and is catalyzed by an intramolecular mechanism[14]. Additionally, the C-terminal domain contains a nuclear localization signal (NLS) and a nuclear export signal (NES), allowing GSK-3β to shuttle between cellular compartments in response to various stimuli[15].
GSK-3β activity is tightly regulated by multiple mechanisms that allow rapid modulation of its function in response to cellular demands[16]. The most well-characterized regulatory mechanism involves phosphorylation at Ser9, which creates a pseudosubstrate that occupies the substrate-binding groove and inhibits kinase activity[17]. This inhibitory phosphorylation is mediated by several kinases, including Akt/PKB, protein kinase A (PKA), protein kinase C (PKC), S6K1, and p90RSK[18]. Growth factors, insulin, and Wnt ligands all signal through these kinases to inhibit GSK-3β activity, linking extracellular signals to the regulation of downstream substrates[19].
Beyond phosphorylation, GSK-3β activity is modulated by protein-protein interactions, subcellular localization, and proteolytic processing[20]. GSK-3β forms complexes with various regulatory proteins, including the scaffold protein axin, which localizes GSK-3β to the Wnt signaling pathway complex where it phosphorylates β-catenin and other substrates[21]. Additionally, GSK-3β can be sequestered by other binding partners, including FRAT (Frequently Rearranged in Advanced T-cell lymphomas), which prevents access to certain substrates without affecting overall kinase activity[22].
Subcellular localization represents another critical layer of GSK-3β regulation. While GSK-3β is predominantly cytoplasmic, it can translocate to the nucleus and mitochondria under specific conditions[23]. Nuclear GSK-3β phosphorylates transcription factors including CREB, NF-κB, and p53, thereby influencing gene expression programs relevant to neuronal survival and plasticity[24]. Mitochondrial GSK-3β has been implicated in the regulation of mitochondrial permeability transition pore opening and apoptosis[25].
GSK-3β is a key component of the β-catenin destruction complex in Wnt signaling. When Wnt ligands activate Frizzled and LRP5/6 receptors, GSK-3β is inhibited, allowing β-catenin accumulation and TCF/LEF-mediated transcription.
GSK-3β serves as a critical component of the destruction complex that regulates β-catenin degradation in the absence of Wnt signaling[26]. In this canonical pathway, GSK-3β phosphorylates β-catenin at specific serine and threonine residues (Ser33, Ser37, Thr41), targeting it for ubiquitination and proteasomal degradation[27]. When Wnt ligands bind to their receptors (Frizzled and LRP5/6), the destruction complex is disassembled, allowing β-catenin to accumulate and translocate to the nucleus where it activates TCF/LEF-mediated transcription of pro-survival genes[28].
Dysregulation of Wnt signaling has been implicated in Alzheimer's disease pathogenesis, with evidence suggesting both reduced canonical Wnt activity and aberrant GSK-3β-mediated phosphorylation events[29]. The interplay between GSK-3β and the Wnt pathway extends beyond β-catenin regulation, as GSK-3β also phosphorylates other components of the pathway including axin, APC, and disheveled[30]. This complex regulatory network positions GSK-3β as both a downstream target and a modulator of Wnt signaling, with implications for synaptic plasticity, neurogenesis, and neuronal survival[31].
The PI3K/Akt pathway inhibits GSK-3β via Ser9 phosphorylation. This pathway is impaired in type 3 diabetes (brain insulin resistance), contributing to increased GSK-3β activity in Alzheimer's disease.
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway represents a major signaling cascade that regulates GSK-3β activity in response to growth factors and insulin[32]. Following receptor tyrosine kinase activation, PI3K generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits Akt to the plasma membrane where it becomes activated by PDK1-mediated phosphorylation[33]. Activated Akt then phosphorylates GSK-3β at Ser9, inhibiting its kinase activity[34].
This pathway plays crucial roles in neuronal survival, metabolism, and synaptic plasticity. Insulin signaling through this cascade promotes glucose metabolism, protein synthesis, and dendritic spine formation[35]. Importantly, impaired insulin signaling and reduced Akt activity have been documented in Alzheimer's disease brains, potentially contributing to increased GSK-3β activity[36]. The concept of "type 3 diabetes" or brain-specific insulin resistance has gained traction as a framework for understanding how metabolic dysfunction contributes to neurodegeneration[37].
GSK-3β interacts with mitogen-activated protein kinase (MAPK) pathways in complex ways that influence cellular outcomes[^38]. While some MAPK pathways (such as ERK) can indirectly inhibit GSK-3β through p90RSK-mediated Ser9 phosphorylation, others (like p38 and JNK) can activate GSK-3β or modulate its substrate specificity[^39]. JNK-mediated phosphorylation of GSK-3β at Thr43 has been shown to promote its nuclear translocation and enhance phosphorylation of specific substrates[^40].
These MAPK pathways respond to cellular stress, inflammatory cytokines, and oxidative stress—all factors implicated in neurodegenerative processes[^41]. The cross-talk between GSK-3β and stress-activated kinases creates a network where multiple pathological stimuli can converge to dysregulate GSK-3β activity, potentially explaining its central role in neurodegeneration[^42].
GSK-3β is one of the principal kinases hyperphosphorylating tau at sites including Thr181, Ser199, Ser202, Thr231, Ser396, and Ser404, promoting neurofibrillary tangle formation in Alzheimer's disease and related tauopathies.
Tau protein is a microtubule-associated protein primarily expressed in neurons, where it stabilizes axonal microtubules and regulates axonal transport[^43]. In Alzheimer's disease and related tauopathies, tau becomes abnormally hyperphosphorylated, leading to its dissociation from microtubules, microtubule destabilization, and eventually the formation of neurofibrillary tangles (NFTs)[^44]. GSK-3β is one of the principal kinases responsible for tau hyperphosphorylation, capable of phosphorylating tau at over 30 distinct sites that have been identified in Alzheimer's disease brain[^45].
The tau protein contains multiple GSK-3β recognition motifs characterized by the SXXXS sequence, where the first serine is pre-phosphorylated by a "priming kinase" before GSK-3β phosphorylates the second site[^46]. Key tau sites phosphorylated by GSK-3β include Thr181, Ser199, Ser202, Thr231, Ser396, and Ser404—all sites commonly found hyperphosphorylated in Alzheimer's disease[^47]. Phosphorylation at these sites reduces tau's affinity for microtubules and promotes the aggregation of tau into oligomers and fibrils that form NFTs[^48].
Transgenic mouse models have provided critical evidence for the role of GSK-3β in tau pathology in vivo[^49]. Overexpression of GSK-3β in neurons leads to tau hyperphosphorylation, microtubule instability, and behavioral deficits reminiscent of Alzheimer's disease[^50]. Conversely, genetic reduction of GSK-3β levels or activity attenuates tau pathology in mouse models of tauopathy[^51]. These studies have established a causal relationship between GSK-3β dysregulation and tau pathology, though the precise mechanisms may vary depending on disease stage and cellular context[^52].
Human post-mortem studies have reinforced the relevance of GSK-3β to tau pathology in Alzheimer's disease. Active, phosphorylated GSK-3β has been colocalized with neurofibrillary tangles in Alzheimer's disease brain, suggesting that GSK-3β-mediated tau phosphorylation contributes to tangle formation in humans[^53]. Furthermore, studies examining GSK-3β polymorphisms and activity have identified associations between GSK-3β genetic variants and Alzheimer's disease risk, though these findings have not been universally replicated[^54].
The consequences of GSK-3β-mediated tau hyperphosphorylation extend beyond microtubule destabilization to affect multiple cellular processes[^55]. Hyperphosphorylated tau can sequester normal tau and other microtubule-associated proteins, further disrupting microtubule organization[^56]. Tau pathology also impairs axonal transport, leading to deficits in mitochondrial trafficking, neurotransmitter vesicle dynamics, and organelle distribution[^57]. These transport deficits contribute to synaptic dysfunction, energy depletion, and eventually neuronal death[^58].
Additionally, abnormal tau can spread between neurons in a prion-like fashion, propagating pathology from affected to unaffected brain regions[^59]. GSK-3β has been implicated in this spread, as it can phosphorylate tau in ways that enhance its aggregation propensity and release from neurons[^60]. The contribution of GSK-3β to tau pathology thus affects not only the affected neurons but may also drive disease progression through intercellular propagation[^61].
GSK-3β regulates amyloid precursor protein (APP) processing and BACE1 expression, influencing amyloid-beta production in Alzheimer's disease. It creates a feed-forward loop with Aβ, as amyloid activates GSK-3β, which then promotes tau pathology.
Amyloid-beta (Aβ) peptides, the principal components of amyloid plaques in Alzheimer's disease, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase[^62]. GSK-3β influences APP processing through multiple mechanisms, including direct phosphorylation of APP and regulation of the expression and activity of secretases[^63]. GSK-3β phosphorylation of APP at Thr668 has been shown to affect APP trafficking and processing, potentially favoring amyloidogenic cleavage[^64].
Beyond direct effects on APP, GSK-3β potently regulates the transcription of BACE1, the rate-limiting enzyme in Aβ production[^65]. GSK-3β phosphorylates and activates the transcription factor CREB, while also promoting the nuclear localization and activity of NF-κB, both of which can drive BACE1 expression[^66]. In animal models, GSK-3β overexpression or activation leads to increased Aβ production and accumulation, while GSK-3β inhibition reduces amyloid pathology[^67].
Perhaps most importantly, GSK-3β contributes to a pathogenic feed-forward loop between amyloid and tau pathologies[^68]. Aβ can activate GSK-3β through various mechanisms, including NMDA receptor-mediated calcium influx, oxidative stress, and inflammatory signaling[^69]. Activated GSK-3β then promotes tau hyperphosphorylation and neurodegeneration[^70]. This synergistic interaction helps explain why both amyloid and tau pathologies are required for the full clinical manifestation of Alzheimer's disease[^71].
Animal models have demonstrated that removing tau rescues memory deficits caused by Aβ accumulation, suggesting that tau mediates Aβ toxicity downstream of GSK-3β[^72]. Similarly, reducing GSK-3β activity protects against Aβ-induced synaptic dysfunction and memory impairment in multiple experimental systems[^73]. These findings highlight GSK-3β as a potential therapeutic target that could address multiple aspects of Alzheimer's disease pathogenesis[^74].
GSK-3β regulates synaptic plasticity, affecting AMPA and NMDA receptor trafficking, and impacts cholinergic, dopaminergic, serotonergic, and GABAergic signaling.
Synaptic dysfunction represents one of the earliest and most robust correlates of cognitive decline in Alzheimer's disease[^75]. GSK-3β is a key regulator of synaptic plasticity, the cellular basis of learning and memory, with both inhibitory and excitatory effects depending on its subcellular localization and substrate context[^76]. In the hippocampus, GSK-3β activity is required for the depotentiation of previously strengthened synapses, suggesting a role in memory flexibility and updating[^77].
GSK-3β phosphorylates several synaptic proteins directly, including Synapsin I, which is essential for synaptic vesicle mobilization and neurotransmitter release[^78]. GSK-3β also regulates the surface expression and trafficking of glutamate receptors, particularly AMPA and NMDA receptors, which mediate excitatory synaptic transmission[^79]. Excessive GSK-3β activity can lead to synaptic depression, impaired long-term potentiation (LTP), and enhanced long-term depression (LTD)—patterns consistent with memory impairment[^80].
Beyond direct effects on synaptic structure, GSK-3β influences neurotransmitter systems implicated in Alzheimer's disease and other neurodegenerative disorders[^81]. Cholinergic neurons, which degenerate early in Alzheimer's disease, express high levels of GSK-3β, and GSK-3β dysregulation contributes to cholinergic dysfunction through effects on acetylcholine synthesis and release[^82]. GSK-3β also modulates dopaminergic, serotonergic, and GABAergic signaling through phosphorylation of receptors, transporters, and transcription factors controlling neurotransmitter expression[^83].
These effects on neurotransmitter systems may contribute to non-cognitive symptoms of Alzheimer's disease, including depression, anxiety, and agitation, which significantly impact patient quality of life[^84]. The broad influence of GSK-3β on synaptic function and neurochemistry reflects its central position in neuronal signaling networks and underscores why its dysregulation has such pervasive consequences for brain function[^85].
GSK-3β regulates microglial activation and cytokine production via NF-κB and NLRP3 inflammasome, creating bidirectional inflammation-neurodegeneration loops in Alzheimer's and Parkinson's disease.
Neuroinflammation is a consistent feature of Alzheimer's disease and other neurodegenerative conditions, with activated microglia and astrocytes surrounding amyloid plaques and neurofibrillary tangles[^86]. GSK-3β plays a critical role in regulating the inflammatory response of glial cells, with context-dependent effects on cytokine production and phagocytosis[^87]. In resting microglia, GSK-3β activity maintains an anti-inflammatory state, while inhibition of GSK-3β promotes pro-inflammatory gene expression in response to immune challenges[^88].
However, in the context of Alzheimer's disease pathology, GSK-3β activity can drive chronic neuroinflammation that contributes to neurodegeneration[^89]. GSK-3β phosphorylates and activates the transcription factor NF-κB, a master regulator of inflammatory gene expression, while also regulating the NLRP3 inflammasome and STAT signaling pathways[^90]. Pro-inflammatory cytokines released from activated glia, including IL-1β, TNF-α, and IL-6, can in turn activate GSK-3β in neurons, creating a vicious cycle of inflammation and dysfunction[^91].
Astrocytes, the most abundant glial cell type in the brain, also respond to GSK-3β modulation with altered morphology and function[^92]. GSK-3β activity regulates astrocyte differentiation, reactive gliosis, and the astrocytic response to injury[^93]. In Alzheimer's disease, astrocyte dysfunction contributes to impaired potassium buffering, glutamate homeostasis, and metabolic support for neurons[^94]. Whether GSK-3β inhibition would ameliorate or exacerbate astrocyte dysfunction remains an area of active investigation with implications for therapeutic strategies[^95].
While most extensively studied in Alzheimer's disease, GSK-3β dysregulation has been implicated in multiple other neurodegenerative conditions[^96]. In Parkinson's disease (PD), GSK-3β activity is increased in affected brain regions and contributes to the phosphorylation of α-synuclein, promoting its aggregation into Lewy bodies[^97]. GSK-3β also phosphorylates parkin and LRRK2, proteins genetically linked to familial Parkinson's disease, potentially modulating their function in ways that influence disease pathogenesis[^98].
Experimental models have demonstrated that GSK-3β inhibition protects against dopaminergic neuron loss in toxin-based PD models, though clinical translation has been limited by toxicity concerns with broad-spectrum GSK-3β inhibitors[^99]. The potential for GSK-3β-targeted strategies in PD remains an active area of investigation, particularly with the development of more selective inhibitors and novel delivery approaches[^100].
GSK-3β has been implicated in amyotrophic lateral sclerosis (ALS), where it may contribute to motor neuron dysfunction through effects on TDP-43 pathology and excitotoxicity[^101]. In frontotemporal dementia (FTD), particularly forms linked to tau mutations, GSK-3β-mediated tau phosphorylation drives neurodegeneration in frontal and temporal brain regions[^102]. The diversity of neurodegenerative conditions involving GSK-3β reflects its fundamental role in neuronal homeostasis and the consequences of its dysregulation across multiple pathological substrates[^103].
In Huntington's disease, GSK-3β phosphorylates mutant huntingtin protein and modulates its aggregation and toxicity[^104]. GSK-3β activity is also increased in prion diseases, where it may contribute to the conversion of normal prion protein to its pathogenic form and the resulting neurodegeneration[^105]. These findings suggest that GSK-3β represents a common downstream effector in diverse neurodegenerative processes, potentially explaining why interventions targeting this kinase have broad neuroprotective potential[^106].
Lithium, the prototypical mood stabilizer, was among the first GSK-3β inhibitors identified and remains the best-characterized pharmacological agent targeting this kinase[^107]. Lithium inhibits GSK-3β directly by competing with magnesium ions at the ATP-binding site and indirectly by promoting Ser9 phosphorylation through inhibition of protein phosphatases[^108]. Epidemiological studies have suggested that lithium treatment is associated with reduced risk of dementia, and clinical trials of lithium in Alzheimer's disease have shown promising, though mixed, results[^109].
Beyond lithium, numerous GSK-3β inhibitors have been developed with varying degrees of selectivity and pharmacological properties[^110]. These include ATP-competitive inhibitors (such as CHIR99021, SB-216763, and Tideglusib), substrate-competitive inhibitors (such as L807mts), and allosteric modulators[^111]. Tideglusib, a selective non-ATP-competitive GSK-3β inhibitor, has advanced to clinical trials for Alzheimer's disease and has shown acceptable safety profiles, though efficacy results have been disappointing thus far[^112].
The development of GSK-3β inhibitors for neurodegeneration has faced several significant challenges[^113]. First, GSK-3β is ubiquitously expressed and participates in numerous essential physiological processes, making systemic inhibition likely to produce adverse effects[^114]. Second, GSK-3β has tumor suppressor functions in some contexts, raising concerns about long-term safety in non-cancer populations[^115]. Third, compensatory mechanisms may limit the efficacy of sustained pharmacological inhibition[^116].
These challenges have prompted exploration of alternative approaches, including partial inhibition, tissue-selective delivery, and targeting of downstream effectors rather than GSK-3β itself[^117]. Understanding the context-dependent roles of GSK-3β and identifying biomarkers that predict response to inhibition will be essential for developing effective therapeutic strategies[^118].
Given the limitations of direct GSK-3β inhibition, considerable effort has focused on indirect modulation through upstream signaling pathways[^119]. Agents that enhance insulin signaling (such as GLP-1 receptor agonists), activate Wnt signaling (such as small molecule Wnt activators), or inhibit inflammatory pathways can reduce GSK-3β activity through physiological mechanisms[^120]. Some of these agents have shown promise in preclinical models and are being evaluated in clinical trials for Alzheimer's disease and related conditions[^121].
The central role of GSK-3β in Alzheimer's disease pathogenesis has motivated efforts to develop biomarkers that reflect GSK-3β activity in patients[^122]. Cerebrospinal fluid (CSF) levels of phosphorylated tau and other substrates may indirectly indicate GSK-3β activity, though specific markers of GSK-3β itself have been difficult to develop[^123]. Imaging agents that bind to GSK-3β or its phosphorylated substrates could potentially allow monitoring of GSK-3β activity in vivo, though such tools remain in early development[^124].
Genetic variants in the GSK3B gene and its regulatory regions may influence an individual's susceptibility to Alzheimer's disease and rate of progression[^125]. Studies have identified single nucleotide polymorphisms (SNPs) in the GSK3B promoter that affect transcription factor binding and GSK-3β expression levels[^126]. Environmental factors that modulate GSK-3β activity, including diet, exercise, and psychological stress, may also influence neurodegenerative risk through effects on this central kinase[^127].
Future research on GSK-3β in neurodegeneration must address the complexity of its regulation and function in different cellular contexts, disease stages, and individual backgrounds[^128]. Single-cell approaches and advanced imaging techniques are revealing previously unrecognized patterns of GSK-3β localization and activity that may inform more targeted therapeutic strategies[^129]. Understanding how GSK-3β interacts with other kinases and phosphatases to determine net phosphorylation of specific substrates will be crucial for predicting and optimizing therapeutic effects[^130].
The identification of genetic and environmental modifiers of GSK-3β function suggests that personalized approaches to GSK-3β-targeted therapy may be warranted[^131]. Patients with specific genetic backgrounds, disease subtypes, or biomarker profiles may respond differently to GSK-3β modulation, and future clinical trials may need to stratify participants based on these factors[^132]. The integration of systems biology approaches with clinical data may help identify which patients are most likely to benefit from GSK-3β-targeted interventions[^133].
Emerging areas of GSK-3β research relevant to neurodegeneration include its role in circadian rhythm regulation, metabolic dysfunction, and the gut-brain axis[^134]. Disruption of circadian rhythms is increasingly recognized as a risk factor for Alzheimer's disease, and GSK-3β-mediated phosphorylation of circadian clock proteins may link metabolic and circadian dysfunction to neurodegeneration[^135]. Similarly, the gut-brain axis and peripheral inflammatory signals may influence brain GSK-3β activity through mechanisms that remain to be fully elucidated[^136].
GSK-3β occupies a central position in the molecular pathogenesis of Alzheimer's disease and other neurodegenerative disorders. Through its regulation of tau phosphorylation, amyloid processing, synaptic function, inflammation, and neuronal survival, GSK-3β integrates multiple pathological insults into a common downstream effector pathway. While direct GSK-3β inhibition has faced challenges in clinical translation, the fundamental importance of this kinase in neurodegeneration remains clear. Future therapeutic strategies may benefit from indirect modulation, pathway-targeted approaches, or context-specific interventions that account for the complex regulation of GSK-3β in health and disease. As our understanding of GSK-3β biology continues to deepen, so too will our ability to develop effective interventions that slow or prevent the neurodegenerative processes that underlie dementia.
Hernández F, Borrell J, Guaza C, Avila J, Lucas JJ. Spatial learning deficit in transgenic mice that conditionally over-express GSK-3β in the brain but do not form tau filaments. 2002. ↩︎
Hooper C, Killick R, Lovestone S. The GSK-3 hypothesis of Alzheimer's disease. 2008. ↩︎
Beurel E, Grieco SF, Jope RS. 'Glycogen synthase kinase-3 (GSK-3): regulation, actions, and diseases'. 2015. ↩︎
Ferrer I, Gomez-Isla T, Puig B, et al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. 2005. ↩︎
Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer's disease. 2015. ↩︎
Woodgett JR. Molecular cloning and expression of glycogen synthase kinase-3/Factor A. 1990. ↩︎
Cohen P, Frame S. The renaissance of GSK-3. 2001. ↩︎
Yao HB, Shaw PC, Wong CC, Wan DC. Expression of glycogen synthase kinase-3 isoforms in mouse tissues and their transcription in the brain. 2002. ↩︎
Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. 2004. ↩︎
ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. Structure of GSK-3beta reveals a primed phosphorylation mechanism. 2001. ↩︎
Dajani R, Fraser E, Roe SM, et al. 'Crystal structure of glycogen synthase kinase-3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition'. 2001. ↩︎
Fiol CJ, Mahrenholz AM, Wang Y, Roeske RW, Roach PJ. 'Formation of protein kinase recognition sites by covalent modification of the substrate: molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase-3'. 1987. ↩︎
Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. 1993. ↩︎
Lochhead PA, Kinstrie R, Sibbet G, Savej K, Cleghon V. A chaperone-dependent GSK3beta transitional intermediate mediates activation-loop autophosphorylation. 2006. ↩︎
Meares GP, Jope RS. 'Resolution of the nuclear import mechanism for GSK-3beta: nuclear localization signal (NLS) sequences, transport factors, and signaling'. 2007. ↩︎
Sutherland C. What Are the Bona Fide GSK-3 Substrates? Int J Alzheimers Dis. 2011. ↩︎
Stambolic V, Woodgett JR. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. 1994. ↩︎
Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK-3 and its inactivation by phosphorylation. 2001. ↩︎
Doble BW, Woodgett JR. 'GSK-3: tricks of the trade for a multi-tasking kinase'. 2003. ↩︎
Jope RS, Cheng YS, Lowell JA, Worthen LM, Song L, Beals KL. The cytoplasmic and nuclear functions of the phospho-protein DREAM. 2007. ↩︎
Kim L, Liu J, Kimmel AR. The novel tyrosine kinase regulators of the Wnt pathway. 2009. ↩︎
Fraser E, Young N, Dajani R, et al. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. 2002. ↩︎
Bijur GN, Jope RS. Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. 2003. ↩︎
Grimes CA, Jope RS. The multifaceted roles of glycogen synthase kinase-3beta in cellular signaling. 2001. ↩︎
Nishihara M, Miura T, Miki T, et al. Modulation of the mitochondrial permeability transition pore by GSK-3beta. 2007. ↩︎
Clevers H, Nusse R. Wnt/β-catenin signaling and disease. 2012. ↩︎
Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. 2002. ↩︎
MacDonald BT, Tamai K, He X. 'Wnt/beta-catenin signaling: components, mechanisms, and diseases'. 2009. ↩︎
Inestrosa NC, Varela-Nallar L. Wnt signaling in the nervous system. 2014. ↩︎
Metcalfe C, Bienz M. Inhibition of GSK-3 by Wnt signaling—two contrasting models. 2011. ↩︎
Inestrosa NC, Arenas E. Emerging roles of Wnts in the adult nervous system. 2010. ↩︎
Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. 'PI3K/Akt and apoptosis: size matters'. 2003. ↩︎
Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. 1997. ↩︎
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 1995. ↩︎
Lee CC, Kuo YM. Emerging roles of brain insulin resistance in cognitive decline and Alzheimer's disease. 2019. ↩︎
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. 2012. ↩︎
de la Monte SM, Wands JR. Alzheimer's disease is type. ↩︎