Regulation of Dishevelled and β-catenin in rat skeletal muscle: an alternative exercise-induced GSK-3β signaling pathway

2006 ◽  
Vol 291 (1) ◽  
pp. E152-E158 ◽  
Author(s):  
William G. Aschenbach ◽  
Richard C. Ho ◽  
Kei Sakamoto ◽  
Nobuharu Fujii ◽  
Yangfeng Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Treadmill Running ◽  
Glycogen Depletion ◽  
Multifunctional Protein ◽  
Highly Correlated ◽  
Gsk 3Β

β-catenin is a multifunctional protein involved in cell-cell adhesion and the Wnt signaling pathway. β-Catenin is activated upon its dephosphorylation, an event triggered by Dishevelled (Dvl)-mediated phosphorylation and deactivation of glycogen synthase kinase-3β (GSK-3β). In skeletal muscle, both insulin and exercise decrease GSK-3β activity, and we tested the hypothesis that these two stimuli regulate β-catenin. Immunoblotting demonstrated that Dvl, Axin, GSK-3β, and β-catenin proteins are expressed in rat red and white gastrocnemius muscles. Treadmill running exercise in vivo significantly decreased β-catenin phosphorylation in both muscle types, with complete dephosphorylation being elicited by maximal exercise. β-Catenin dephosphorylation was intensity dependent, as dephosphorylation was highly correlated with muscle glycogen depletion during exercise ( r2 = 0.84, P < 0.001). β-Catenin dephosphorylation was accompanied by increases in GSK-3β Ser9 phosphorylation and Dvl-GSK-3β association. In contrast to exercise, maximal insulin treatment (1 U/kg body wt) had no effect on skeletal muscle β-catenin phosphorylation or Dvl-GSK-3β interaction. In conclusion, exercise in vivo, but not insulin, increases the association between Dvl and GSK-3β in skeletal muscle, an event paralleled by β-catenin dephosphorylation.

Wnt/β-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy

2005 ◽  
Vol 289 (4) ◽  
pp. C853-C859 ◽  
Author(s):  
Dustin D. Armstrong ◽  
Karyn A. Esser
Keyword(s):  
Skeletal Muscle ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Muscle Hypertrophy ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Growth Control ◽  
Skeletal Muscle Hypertrophy ◽  
Study Results ◽  
Gsk 3Β

β-Catenin is a transcriptional activator shown to regulate the embryonic, postnatal, and oncogenic growth of many tissues. In most research to date, β-catenin activation has been the unique downstream function of the Wnt signaling pathway. However, in the heart, a Wnt-independent mechanism involving Akt-mediated phosphorylation of glycogen synthase kinase (GSK)-3β was recently shown to activate β-catenin and regulate cardiomyocyte growth. In this study, results have identified the activation of the Wnt/β-catenin pathway during hypertrophy of mechanically overloaded skeletal muscle. Significant increases in β-catenin were determined during skeletal muscle hypertrophy. In addition, the Wnt receptor, mFrizzled (mFzd)-1, the signaling mediator disheveled-1, and the transcriptional co-activator, lymphocyte enhancement factor (Lef)-1, are all increased during hypertrophy of the overloaded mouse plantaris muscle. Experiments also determined an increased association between GSK-3β and the inhibitory frequently rearranged in advanced T cell-1 protein with no increase in GSK-3β phosphorylation (Ser9). Finally, skeletal muscle overload resulted in increased nuclear β-catenin/Lef-1 expression and induction of the transcriptional targets c-Myc, cyclin D1, and paired-like homeodomain transcription factor 2. Thus this study provides the first evidence that the Wnt signaling pathway induces β-catenin/Lef-1 activation of growth-control genes during overload induced skeletal muscle hypertrophy.

scholarly journals RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Jikui Sun ◽  
Quanfeng Ma ◽  
Banban Li ◽  
Chen Wang ◽  
Lidong Mo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Inhibitory Effect ◽  
Who Grade ◽  
Pathway Network ◽  
Mechanistic Investigation ◽  
Signaling Axis ◽  
Gsk 3Β

Abstract Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

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

1999 ◽  
Vol 277 (2) ◽  
pp. E299-E307 ◽  
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.

scholarly journals A divergent canonical WNT-signaling pathway regulates microtubule dynamics

2004 ◽  
Vol 164 (2) ◽  
pp. 243-253 ◽  
Author(s):  
Lorenza Ciani ◽  
Olga Krylova ◽  
Matthew J. Smalley ◽  
Trevor C. Dale ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Canonical Wnt Signaling ◽  
Microtubule Stability ◽  
Gsk 3Β ◽  
Canonical Wnt

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

scholarly journals ROLE OF GSK-3 IN Wnt/β-CATENIN SIGNALING PATHWAY IN OBESITY

2021 ◽  
Vol 23 (4) ◽  
pp. 775-780
Author(s):  
A. S. Kulakova ◽  
I. A. Snimshchikova ◽  
M. O. Plotnikova
Keyword(s):  
Serum Level ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Obese Patients ◽  
Healthy Individuals ◽  
Gsk 3Β ◽  
The Impact

The complexity of the adipogenesis mechanism results from the impact of multiple cues, among which an important place is held by the components of the Wnt signaling pathway. The search for potential markers of the development of diseases related to obesity aroused an interest in the study of GSK-3 (glycogen synthase kinase), β-catenin. GSK-3β is an intracellular serine / threonine kinase found in the cytoplasm, nucleus, mitochondria, synthesized in all body tissues and involved in regulating metabolic processes, cell proliferation, apoptosis etc. The first of the discovered functions of GSK-3β was the regulation of glycogen synthesis. Active GSK-3β phosphorylates and thereby inhibits glycogen synthase. As a result of the insulin binding to the cell receptor via inositol-3-phosphate, protein kinase B (Akt1) is activated, which, in turn, phosphorylates and inhibits GSK-3β. In addition, GSK-3β is involved in the regulating glucose metabolism. The most important function of GSK-3β is the inhibition of the β-catenin protein. In a resting cell, GSK-3β in complex with the APC and Axin proteins binds and phosphorylates the β-catenin transcription factor, which leads to its ubiquitination and degradation. When Wnt proteins act on the cell, the Dvl protein is activated, which, by binding to GSK-3β, releases β-catenin, preventing its degradation, however, the role of GSK3α/β in the adipocyte inflammatory response has not yet been fully investigated, therefore it seems promising to study the role of GSK-3 in the Wnt/β-catenin signaling pathway in obesityThe aim of the study was to assess the activity of the components of the Wnt signaling pathway in obese patients by measuring the serum level of GSK-3 and β-catenin. There were enrolled 32 patients with progressive forms of I-III degree obesity in the absence of diabetes mellitus. The concentration of serum GSK-3α, GSK-3β, and β-catenin was measured by enzyme-linked immunoassay. Data are presented as absolute and relative (%) number of patients; arithmetic mean; medians, 1 and 3 quartiles – Ме (Q0.25-Q0.75). Obese patients contained a 7.5-fold increased serum level of GSK-3α (785 (371-1317.5) pg/ml) compared to healthy individuals 105 (102.5-110) pg/ml, (p < 0.001), paralleled with increased amount of GSK-3β, which level in obese patients was 295 (190-695) pg/ml, which is by 18.3% higher than those in healthy individuals 241 (218.75-287.5) pg/ml, p = 0.111. Amount of GSK-3 depending on the degree of obesity tended to increase, most often coupled to decreased β-catenin level which is consistent with the literature data and can be considered as a prognostic criterion for the course of pathological processes in obesity. 

scholarly journals Integrin-linked kinase is a key signal factor involved in Nogo-66-induced inhibition of neurite outgrowth

2020 ◽  
Author(s):  
Ya-ping Yu ◽  
Qiang-ping Wang ◽  
Jian-Ying Shen ◽  
Nan-xiang Xiong ◽  
Hua Yu ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Glycogen Synthase ◽  
Growth Inhibitor ◽  
Neural Regeneration ◽  
Integrin Linked Kinase ◽  
Gsk 3Β

AbstractNogo-66, the extracellular domain of Nogo-A, has been identified as the most important myelin-associated neuronal growth inhibitor. Evidence suggested that Nogo-66 exert its neurite inhibition effect via a Nogo-66/Protein kinase B (PKB)/Glycogen synthase kinase-3β (GSK-3β)/tau signaling pathway. Integrin-linked kinase (ILK) is a serine/threonine kinase mediating axon upstream growth of PKB and GSK-3β. However, the contribution of ILK to the Nogo-66-induced inhibition of neurite, is not clear. In this study, we set out to reveal the role of ILK on Nogo-66 signaling in vitro and in vivo. To deteremine this directly, Recombinant adenoviruses were constructed to upregulate or downregulate the expresioon of ILK in Neuro 2a (N2a)and analysis the change of downstream molecule and neurite length. The results showed that Nogo-66 inhibited the phosphorylation of ILK, while ILK regulated the phosphorylation of PKB and GSK-3β, and the expression of tau in Nogo-66-treated N2a cells. ILK overexpression through lentivirus vector transfection reduced the inhibitory effect of neurite outgrowth induced by Nogo-66 in cortical neurons. The Tau expression in the complete spinal cord transection rat model was promoted by the overexpression of ILK. Our findings indicated that ILK is a key signal factor involved in Nogo-66-induced inhibition of neurite outgrowth. The mechanism of Nogo-66 signaling pathway was further explained and a proper target for the promotion of neural regeneration was also provided by this study.

scholarly journals RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis

2020 ◽  
Vol 318 (2) ◽  
pp. G352-G360 ◽  
Author(s):  
Yongan Fu ◽  
Yilin Chen ◽  
Jinghua Huang ◽  
Zongda Cai ◽  
Yangqiang Wang
Keyword(s):  
Gastric Cancer ◽  
Liver Metastasis ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model ◽  
Highly Correlated

Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC. NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.

scholarly journals Protein Breakdown in Muscle from Burned Rats Is Blocked by Insulin-Like Growth Factor I and Glycogen Synthase Kinase-3β Inhibitors

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3141-3149 ◽  
Author(s):  
Cheng-Hui Fang ◽  
Bing-Guo Li ◽  
J. Howard James ◽  
Jy-Kung King ◽  
Amy R. Evenson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Signaling Pathway ◽  
Lithium Chloride ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Breakdown ◽  
Igf I ◽  
Gsk 3Β

Abstract We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3β (GSK-3β) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3β. In addition, the GSK-3β inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3β-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3β and Foxo transcription factors.

scholarly journals Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ann Jeffers ◽  
Wenyi Qin ◽  
Shuzi Owens ◽  
Kathleen B. Koenig ◽  
Satoshi Komatsu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Alveolar Epithelial Cell ◽  
Lung Fibroblasts ◽  
Myofibroblast Differentiation ◽  
Gsk 3Β

AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 3 years after diagnosis. Although the etiology of IPF is unknown, it is characterized by extensive alveolar epithelial cell apoptosis and proliferation of myofibroblasts in the lungs. While the origins of these myofibroblast appear to be diverse, fibroblast differentiation contributes to expansion of myofibroblasts and to disease progression. We found that agents that contribute to neomatrix formation and remodeling in pulmonary fibrosis (PF); TGF-β, Factor Xa, thrombin, plasmin and uPA all induced fibroblast/myofibroblast differentiation. These same mediators enhanced GSK-3β activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3β signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; α-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In in vivo studies, the progression of TGF-β and bleomycin mediated PF was significantly attenuated by 9-ING-41 administered at 7 and 14 days respectively after the establishment of injury. Specifically, 9-ING-41 treatment significantly improved lung function (compliance and lung volumes; p < 0.05) of TGF-β adenovirus treated mice compared to controls. Similar results were found in mice with bleomycin-induced PF. These studies clearly show that activation of the GSK-3β signaling pathway is critical for the induction of myofibroblast differentiation in lung fibroblasts ex vivo and pulmonary fibrosis in vivo. The results offer a strong premise supporting the continued investigation of the GSK-3β signaling pathway in the control of fibroblast-myofibroblast differentiation and fibrosing lung injury. These data provide a strong rationale for extension of clinical trials of 9-ING-41 to patients with IPF.

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

Biology ◽  
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.

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