Role Of GSK-3β Research Articles

GSK3β: A ray of hope for the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3β (glycogen synthase kinase 3β), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3β participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3β in DKD and its damage mechanism in different intrinsic renal cells. GSK3β is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3β inhibitors on DKD are also discussed.

Ferroptosis, a Regulated Form of Cell Death, as a Target for the Development of Novel Drugs Preventing Ischemia/Reperfusion of Cardiac Injury, Cardiomyopathy and Stress-Induced Cardiac Injury.

The hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is about 6% and has not decreased in recent years. The leading cause of death of these patients is ischemia/reperfusion (I/R) cardiac injury. It is quite obvious that there is an urgent need to create new drugs for the treatment of STEMI based on knowledge about the pathogenesis of I/R cardiac injury, in particular, based on knowledge about the molecular mechanism of ferroptosis. In this study, it was demonstrated that ferroptosis is involved in the development of I/R cardiac injury, antitumor drug-induced cardiomyopathy, diabetic cardiomyopathy, septic cardiomyopathy, and inflammation. There is indirect evidence that ferroptosis participates in stress-induced cardiac injury. The activation of AMPK, PKC, ERK1/2, PI3K, and Akt prevents myocardial ferroptosis. The inhibition of HO-1 alleviates myocardial ferroptosis. The roles of GSK-3β and NOS in the regulation of ferroptosis require further study. The stimulation of Nrf2, STAT3 prevents ferroptosis. The activation of TLR4 and NF-κB promotes ferroptosis of cardiomyocytes. MiR-450b-5p and miR-210-3p can increase the tolerance of cardiomyocytes to hypoxia/reoxygenation through the inhibition of ferroptosis. Circ_0091761 RNA, miR-214-3p, miR-199a-5p, miR-208a/b, miR-375-3p, miR-26b-5p and miR-15a-5p can aggravate myocardial ferroptosis.

The role of GSK3β in DNA repair mechanisms and resistance in PDAC

The role of GSK3β in DNA repair mechanisms and resistance in PDAC

GSK3β-driven SOX2 overexpression is a targetable vulnerability in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest forms of human malignancy that currently lacks approved targeted therapeutics. Accumulating evidence suggests that SOX2 overexpression is a key driving factor for ESCC and various squamous cell carcinoma. Here, through screening a small-molecule kinase inhibitor library, we identified GSK3β as a kinase that is critically required for robust SOX2 expression in ESCC cells. GSK3β did not promote SOX2 transcriptionally but was required for SOX2 protein stability. We demonstrated that GSK3β interacts with and phosphorylates SOX2 at residue S251, which blocks SOX2 from ubiquitination and proteasome-dependent degradation instigated by ubiquitin E3 ligase CUL4ADET1-COP1. Pharmacological inhibition or knockdown of GSK3β by RNA interference selectively impaired SOX2-positive ESCC cell proliferation, cancer stemness, and tumor growth in mouse xenograft model, suggesting that GSK3β promotes ESCC tumorigenesis primarily by driving SOX2 overexpression. GSK3β was found to be frequently overexpressed in clinical esophageal tumors, and there was a positive correlation between GSK3β and SOX2 protein levels. Notably, we found that SOX2 enhanced GSK3β expression transcriptionally, suggesting the existence of a vicious cycle that drives a coordinated GSK3β and SOX2 overexpression in ESCC cells. Finally, we demonstrated in tumor xenograft model that GSK3β inhibitor AR-A014418 was effective in suppressing SOX2-positive ESCC tumor progression and inhibited tumor progression cooperatively with chemotherapeutic agent carboplatin. In conclusion, we uncovered a novel role for GSK3β in driving SOX2 overexpression and tumorigenesis and provided evidence that targeting GSK3β may hold promise for the treatment of recalcitrant ESCCs.

Glycogen synthesis kinase-3β involves in the analgesic effect of liraglutide on diabetic neuropathic pain

AimsExplore whether Glycogen synthesis kinase-3β (GSK3β) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP). MethodsDNP was induced by streptozocin (STZ) in WT and GSK3β(S9A) mice, which carried a constitutively active form of GSK3β. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ injection. The behavior of neuropathic pain was evaluated 2 h after drugs administration. The microglial activation and the expression of NOD-like receptor protein 3 (NLRP3) in microglia in cortex were evaluated. The role of GSK3β in the inhibitory effect of liraglutide on the NLRP3 inflammasome was explored in BV2 microglia. ResultsIntracerebroventricular administration of liraglutide significantly relieved neuropathic pain and inhibited the activation of cortical microglia in WT mice with DNP. But the effect of liraglutide disappeared in GSK3β(S9A) mice. In BV2 microglia, GSK3β inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3β through GSK3β(S9A) lentivirus significantly blocked the inhibitory effect of liraglutide on NLRP3 inflammasome in BV2 microglia. Intracerebroventricular administration of liraglutide significantly inhibited the expression of NLRP3 in cortex microglia of DNP group in WT mice but failed in GSK3β(S9A) mice. ConclusionGSK3β involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.

GSK-3β and its Inhibitors in Alzheimer's Disease: A Recent Update

Alzheimer's disease (AD) is an emerging major health and socioeconomic burden worldwide. It is characterized by neuronal loss, memory loss and cognitive impairment in the aging population. Despite several scientific advancements over the past five decades, the underlying molecular mechanism of the disease progression is yet unknown. Glycogen synthase kinase-3β (GSK-3β) has huge implications on the brain function, causing molecular pathologies, neuronal damage and impairment of brain performance in AD. It is one of the key players in signaling pathways for normal brain functioning and a critical molecular link between amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs). GSK-3β activation is driven by phosphorylation of tau(τ) protein which results in disruption of neuronal synaptic activities and the formation of neuronal plaques. Although the accumulation of Aβ plaques and intracellular tangles of hyperphosphorylated tau protein has been well established as neuropathological hallmarks of the disease, the molecular mechanism has not been unraveled. This review focuses on the role of GSK-3β in the molecular mechanisms participating in the manifestation and progression of AD. The review also suggests that GSK-3β inhibitors can be used as potential therapeutic targets for amelioration of AD.

Characterization and functional analysis of GSK3β from Epinephelus coioides in Singapore grouper iridovirus infection

Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, is a crucial regulator of several signaling pathways and plays a vital role in cell proliferation, growth, apoptosis, and immune responses. However, the role of GSK3β during viral infection in teleosts remains largely unknown. In the present study, a GSK3β homologue from Epinephelus coioides (EcGSK3β) was cloned and characterized. The open reading frame of EcGSK3β consists of 1323 bp, encoding a 440 amino acid protein, with a predicted molecular mass of 48.23 kDa. Similar to its mammalian counterpart, EcGSK3β contains an S_TKc domain. EcGSK3β shares 99.77% homology with the giant grouper (Epinephelus lanceolatus). Quantitative real-time PCR analysis indicated that EcGSK3β mRNA was broadly expressed in all tested tissues, with abundant expression in the skin, blood, and intestines. Additionally, the expression of EcGSK3β increased after Singapore grouper iridovirus (SGIV) infection in grouper spleen (GS) cells. Intracellular localization analysis demonstrated that EcGSK3β is mainly distributed in the cytoplasm. EcGSK3β overexpression promoted SGIV replication during viral infection in vitro. In contrast, silencing of EcGSK3β inhibited SGIV replication. EcGSK3β significantly downregulated the activities of interferon-β, interferon-sensitive response element, and NF-κB. Taken together, these findings are important for a better understanding of the function of GSK3β in fish and reveal its involvement in the host response to viral immune challenge.

Glycogen Synthase Kinase 3β (GSK3β) Regulates Myogenic Differentiation in Skeletal Muscle Satellite Cells of Sheep.

Simple SummaryIn this study, we investigated the function of GSK3β in the skeletal muscle satellite cells (SMSCs) of sheep. The overexpression of GSK3β inhibited myotube formation and the expression of MyoD, MyoG, MyHC1, and MyHC2a genes in sheep SMSCs. Additionally, inhibiting the activity of GSK3β significantly promoted myotube formation as well as MyoD, MyoG, MyHC1, and MyHC2a genes at mRNA levels. The present study provides evidence for studying the mechanisms involved in the regulation of sheep SMSCs differentiation by GSK3β.Glycogen synthase kinase 3β (GSK3β) has a vital role in the regulation of many cellular processes. However, the role of GSK3β in muscle cell differentiation in sheep remains unknown. In this study, we investigated the function of GSK3β in skeletal muscle satellite cells (SMSCs) of sheep. An overexpression of GSK3β significantly inhibited myotube formation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a) in sheep SMSCs. SB216763 treatment had a time-course effect on the phosphorylation levels of sheep GSK3β. In addition, reducing the activity of GSK3β lead to the promotion of sheep SMSCs differentiation as well as the mRNA levels of myogenic genes (MyoD, MyoG, MyHC1, and MyHC2a). This study illustrated the function of GSK3β to inhibit myogenesis in sheep SMSCs, which provided evidence for studying the mechanisms involved in the regulation of sheep SMSCs differentiation by GSK3β.

Glycogen Synthase Kinase 3β inhibits BMSCs Chondrogenesis in Inflammation via the Cross-Reaction between NF-κB and β-Catenin in the Nucleus.

Inflammation can influence the pluripotency and self-renewal of mesenchymal stem cells (MSCs), thereby altering their cartilage regeneration ability. Sprague-Dawley (SD) rat bone marrow mesenchymal stem cells (BMSCs) were isolated and found to be defective in differentiation potential in the interleukin-1β- (IL-1β-) induced inflammatory microenvironment. Glycogen synthase kinase-3β (GSK-3β) is an evolutionarily conserved serine/threonine kinase that plays a role in numerous cellular processes. The role of GSK-3β in inflammation may be related to the nuclear factor-κB (NF-κB) signaling pathway and the Wnt/β-catenin signaling pathway, whose mechanism remains unclear. In this study, we found that GSK-3β can inhibit chondrogenesis of IL-1β-impaired BMSCs by disrupting metabolic balance and promoting cell apoptosis. By using the inhibitors LiCl and SN50, we demonstrated that GSK-3β regulates the chondrogenesis via the NF-κB and Wnt/β-catenin signaling pathways and possibly mediates the cross-reaction between NF-κB and β-catenin in the nucleus. Given the molecular mechanisms of GSK-3β in chondrogenic differentiation in inflammation, GSK-3β is a crucial target for the treatment of inflammation-induced cartilage disease.

Retraction Note: Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/1741-7015-10-40.

First person – Aadil Qadir Bhat and Mir Owais Ayaz

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Aadil Qadir Bhat and Mir Owais Ayaz are co-first authors on ‘ Identification of a stretch of four discontinuous amino acids involved in regulating kinase activity of IGF1R’, published in JCS. Aadil is a PhD student in the lab of Dr Mohd Jamal Dar at the CSIR-Indian Institute of Integrative Medicine, Jammu, India, investigating membrane receptors and their role in cancers. Mir is a PhD student in the same lab investigating the role of GSK3-β in different types of cancers.

Proteomic characterization of GSK3β knockout shows altered cell adhesion and metabolic pathway utilisation in colorectal cancer cells.

Glycogen-specific kinase (GSK3β) is an integral regulator of the Wnt signalling pathway as well as many other diverse signalling pathways and processes. Dys-regulation of GSK3β is implicated in many different pathologies, including neurodegenerative disorders as well as many different tumour types. In the context of tumour development, GSK3β has been shown to play both oncogenic and tumour suppressor roles, depending upon tissue, signalling environment or disease progression. Although multiple substrates of the GSK3β kinase have been identified, the wider protein networks within which GSK3β participates are not well known, and the consequences of these interactions not well understood. In this study, LC-MS/MS expression analysis was performed using knockout GSK3β colorectal cancer cells and isogenic controls in colorectal cancer cell lines carrying dominant stabilizing mutations of β-catenin. Consistent with the role of GSK3β, we found that β-catenin levels and canonical Wnt activity are unaffected by knockout of GSK3β and therefore used this knockout cell model to identify other processes in which GSK3β is implicated. Quantitative proteomic analysis revealed perturbation of proteins involved in cell-cell adhesion, and we characterized the phenotype and altered proteomic profiles associated with this. We also characterized the perturbation of metabolic pathways resulting from GSK3β knockout and identified defects in glycogen metabolism. In summary, using a precision colorectal cancer cell-line knockout model with constitutively activated β-catenin we identified several of the diverse pathways and processes associated with GSK3β function.

Berberine and/or zinc protect against methotrexate-induced intestinal damage: Role of GSK-3β/NRF2 and JAK1/STAT-3 signaling pathways

AimThe present study was undertaken to elucidate the potential protective mechanism of berberine (BBR) and/or zinc (Zn) against methotrexate (MTX)-induced intestinal injury. MethodsFive groups of rats were assigned; normal group (received vehicle), MTX group (20 mg/kg; i.p. single dose), and the other three groups received a single daily oral dose of BBR (50 mg/kg), Zn (5 mg/kg), and BBR plus Zn respectively, for 5 days before MTX and 5 days after. ResultsOur results emphasized the toxic effect of MTX on rat's intestine as shown by disturbance of oxidant/antioxidant status, down-regulation of NRF2, SIRT1, FOXO-3, Akt, and mTOR expressions, along with up-regulation of GSK-3β, JAK1, and STAT-3 expressions. Besides, severe intestinal histopathological changes were also observed. On the contrary, BBR and/or Zn produced marked protection against MTX-induced intestinal toxicity via amelioration of oxidative stress, improving NRF2, SIRT1, FOXO-3, GSK-3β, Akt, mTOR, JAK1, and STAT-3 alterations. Moreover, our treatments significantly restored histopathological abnormalities. Interestingly, combination therapy of BBR plus Zn exhibited higher effectiveness than mono-therapy. SignificanceBBR plus Zn could be used as a novel therapy for the treatment of MTX-induced intestinal damage through modulation of GSK-3β/NRF2, Akt/mTOR, JAK1/STAT-3, and SIRT1/FOXO-3 signaling pathways.

Glycogen Synthase Kinase 3β Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites.

Knowledge of glycogen synthase kinase 3β (GSK3β) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how the intensity of the inflammatory response can be controlled in the course of infections. In recent years many reports have described small molecular weight synthetic and natural compounds, proteins, and interference RNA with the potential to regulate the GSK3β activity and reduce the deleterious effects of the inflammatory response. Our goal in this review is to summarize the most recent advances on the role of GSK3β in the inflammatory response caused by bacteria, bacterial virulence factors (i.e. LPS and others), viruses, and parasites and how the regulation of its activity, mainly its inhibition by different type of molecules, modulates the inflammation.

The Role of GSK3β in SERCA Dysfunction and the Development of Arrhythmogenic Cardiomyopathy

The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump catalyzes the active transport of Ca2+ into the sarcoplasmic reticulum and is responsible for over 70% of Ca2+ turnover after muscle contraction. Phospholamban (PLN) is a well-known SERCA regulator, and impaired SERCA function due to reductions in SERCA and/or enhanced inhibitory PLN action has been linked to the development of various cardiomyopathies. Arrhythmogenic cardiomyopathy (ACM) is an inherited, non-ischemic heart disease presenting with ventricular arrhythmias, hypo/dyskinesia, and fibrotic remodeling. Over 60% of ACM cases are caused by pathogenic variants in genes encoding the cardiac desmosome, where Desmoglein-2 (DSG2) is the second most prevalent desmosomal gene variant in the ACM patient population. Using Dsg2 mutant (Dsg2mut/mut) mice, previous studies showed that the enzyme glycogen synthase kinase-3β (GSK3β), plays a major role in ACM pathogenesis. Inhibiting GSK3β in these mice improved cardiac contractility and ACM pathological phenotypes. We have shown that GSK3β inhibition in cardiomyocytes can also improve SERCA function in wild-type (WT) mice; however, the role of GSK3β activity on SERCA function in Dsg2mut/mut mice is currently unknown. Here, we sought to examine the effects of GSK3β inhibition on SERCA function using a GSK3β-specific inhibitor, SB216763 (SB2), in Dsg2mut/mut mice. At 3 weeks of age, both WT and Dsg2mut/mut mice were treated with SB2 (2.5 mg/kg/day) or equivalent volume/kg/day of vehicle (DMSO) for 13 weeks via intraperitoneal injection. After treatment, mice were sacrificed and hearts were collected and homogenized. Our results show that cardiomyocytes obtained from vehicle treated Dsg2mut/mut mice had significantly lower SERCA2a expression (-52%, p<0.01) compared to vehicle treated WT mice, leading to reduced SERCA2a:PLN (-65%, p=0.04). Maximal SERCA activity was also significantly lower in vehicle treated Dsg2mut/mut mice (-65%, p=0.001). However, in myocardium from SB2 treated Dsg2mut/mut mice, maximal SERCA activity, SERCA2a expression, and SERCA2a:PLN ratio were all restored to near WT levels. We also examined the effects of heterozygous and homozygous GSK3β S9A mutation in the Dsg2mut/mut mice, which prevents phosphorylation and maintains GSK3β in its constitutively active form. When comparing WT with Dsg2mut/mutheterozygous and homozygous GSK3β S9A mutants, we saw a significant but non-progressive decrease in maximal SERCA activity (-60%, p=0.02 and -58%, p=0.03 respectively). In conclusion, these results show that SERCA function is negatively impacted in Dsg2mut/mut cardiomyocytes. Conversely, GSK3β inhibition with SB2 treatment improved SERCA content and activity to healthy WT levels. These results further illuminate the role of GSK3β in ACM pathogenesis and support the use of GSK3β inhibitors in its treatment, as our new promising results indicate this therapeutic strategy can also improve Ca2+ handling.

GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma.

PurposeChordoma is a rare malignant bone tumor transformed from the remnants of notochord. It is characterized as highly aggressive and locally invasive, difficult to be completely removed by surgery, and has a poor clinical prognosis. Glycogen synthase kinase 3 beta (GSK-3β) is involved in many cellular processes. GSK-3β overexpression has been shown to promote the development of many cancers, according to previous studies. However, the role of GSK-3β in chordoma remains unclear.MethodsImmunohistochemistry (IHC) and Western blotting (WB) were performed on clinical specimens to measure GSK-3β expression in chordoma, and immunofluorescence and quantitative real-time polymerase chain reaction (QRT-PCR) were performed to examine the expression of GSK-3β and P21 in cell lines. Cell proliferation was detected by the CCK-8 assay and colony formation analysis, cell migration and invasion checked by Transwell experiments, and cell apoptosis was determined by Annexin V/propidium iodide staining. P21 was predicted as a downstream target gene of GSK-3β using STRING and UNIHI databases. Moreover, we used immunoprecipitation to confirm that GSK-3β and P21 interacted with each other. The double luciferase reporter gene assay showed that GSK-3β could regulate the promoter activity of P21. Finally, the role of the GSK-3β -P21 pathway in chordoma tumorigenesis was analyzed in vivo in nude mice.ResultsOur study showed that GSK-3β was significantly higher in chordoma tissues than in paracancer tissues, and siRNA knockdown of GSK-3β inhibited chordoma cell proliferation and promoted cell apoptosis. Additionally, our research found that GSK-3β bound and downregulated the expression of the P21 gene, and the expression of silencing P21 partially reversed the inhibitory effect of knockdown GSK-3β on chordoma. Furthermore, xenografts showed that knockdown GSK-3β inhibited the formation of chordomas in vivo.ConclusionOur results indicated that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for the clinical treatment of this disorder.

Beneficial role of oleuropein in sepsis-induced myocardial injury. Possible Involvement of GSK-3β/NF-kB pathway.

ABSTRACTPurposeThe present study explored the potential therapeutic role of oleuropein in sepsis-induced heart injury along with the role of GSK-3β/NF-kB signaling pathway.MethodsSepsis-induced myocardial injury was induced by cecal ligation and puncture (CLP) in rats. The cardiac injury was assessed by measuring the levels of cTnI and creatine kinase-MB (CK-MB). Sepsis-induced inflammation was assessed by measuring interleukin-6 (IL-6), IL-10 and HMGB1 levels. The different doses of oleuropein (5, 10, and 20 mg/kg) were given prior to CLP. Oleuropein (20 mg/kg) was administered after 6 hof CLP. The expressions of GSK-3β, p-GSK-3β (Ser9) and nuclear factor-κB (NF-κB) were measured in heart homogenates.ResultsCecal ligation and puncture was associated with myocardial injury, an increase in IL-6, a decrease in IL-10 and an increase in HMGB1. Moreover, it decreased the ratio of p-GSK-3β/GSK-3β and increased the expression of p-NF-kB. Pretreatment with oleuropein attenuated CLP-induced myocardial injury and systemic inflammation in a dose-dependent manner. Administration of oleuropein after the onset of CLP also attenuated cardiac injury and inflammation. It also restored CLP-induced changes in the HMGB1 levels, the ratio of p-GSK-3β/GSK-3β and expression of p- NF-kB.ConclusionsOleuropein attenuates sepsis-induced systemic inflammation and myocardial injury by inhibiting NF-kB and GSK-3β signaling.

Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia.

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.

Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

The Role of GSK3β in T Lymphocytes in the Tumor Microenvironment.

Immunotherapy options for patients with cancer have emerged following decades of research on immune responses against tumors. Most treatments in this category harness T cells with specificity for tumor associated antigens, neoantigens, and cancer-testis antigens. GSK3β is a serine-threonine kinase with the highest number of substrates and multifaceted roles in cell function including immune cells. Importantly, inhibitors of GSK3β are available for clinical and research use. Here, we review the possible role of GSK3β in the immune tumor microenvironment, with goal to guide future research that tests GSK3β inhibition as an immunotherapy adjunct.