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Glucose Regulates Microtubule Disassembly and the Dose of Insulin Secretion via Tau Phosphorylation.
Ho KH, Yang X, Osipovich AB, Cabrera O, Hayashi ML, Magnuson MA, Gu G, Kaverina I
(2020) Diabetes 69: 1936-1947
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclin-Dependent Kinase 5, Glucose, Glycogen Synthase Kinase 3, Insulin Secretion, Insulin-Secreting Cells, Mice, Microtubules, Phosphorylation, Protein Kinase C, tau Proteins
Show Abstract · Added July 2, 2020
The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning over to restrict insulin oversecretion in basal conditions and preserve the insulin pool that can be released following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.
© 2020 by the American Diabetes Association.
2 Communities
3 Members
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12 MeSH Terms
Inhibition of Glycogen Synthase Kinase 3β as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury.
Farr SA, Niehoff ML, Kumar VB, Roby DA, Morley JE
(2019) J Neurotrauma 36: 1869-1875
MeSH Terms: Animals, Brain Injuries, Traumatic, Cognitive Dysfunction, Glycogen Synthase Kinase 3 beta, Maze Learning, Mice, Oligonucleotides, Antisense
Show Abstract · Added March 12, 2019
Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3β (GSK-3β) in its phosphorylated form (p-GSK-3β) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3β (AO) gene. Using a model of closed-head concussive TBI, we subjected mice to TBI and injected AO or a random antisense (AO) 15 min post-injury. One week post-injury, mice were tested in object recognition with 24 h delay. At 4 weeks post- injury, mice were tested with a T-maze foot shock avoidance memory test and a second object recognition test with 24 h delay using different objects. Mice that received AO show improved memory in both object recognition and T-maze compared with AO- treated mice that were subjected to TBI. Next, we verified that AO blocked the surge in phosphorylated GSK-3β post-TBI. Mice were subjected to TBI and injected with antisense 15 min post-TBI with AO or AO. Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3β, p-tyr216GSK-3β, and phospho-tau (p-tau) showed that mice that received a TBI+AO had significantly higher p-ser9GSK-3β, p-tyr216GSK-3β, and p-tau levels than the mice that received TBI+AO and the Sham+AO mice. The current finding suggests that inhibiting GSK-3β increase after TBI with an antisense directed at GSK-3β prevents learning and memory impairments.
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7 MeSH Terms
Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling.
Ng VH, Hang BI, Sawyer LM, Neitzel LR, Crispi EE, Rose KL, Popay TM, Zhong A, Lee LA, Tansey WP, Huppert S, Lee E
(2018) J Cell Sci 131:
MeSH Terms: Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Cell Line, Glycogen Synthase Kinase 3, Humans, Intracellular Signaling Peptides and Proteins, Mitochondrial Proteins, Phosphorylation, Protein Binding, Threonine, Wnt Signaling Pathway, Wnt3A Protein, X-Linked Inhibitor of Apoptosis Protein, Xenopus
Show Abstract · Added July 6, 2018
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in embryos. Although XIAP ubiquitylates TLE3 at wild-type levels , it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.
© 2018. Published by The Company of Biologists Ltd.
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15 MeSH Terms
GSK3β Interactions with Amyloid Genes: An Autopsy Verification and Extension.
Hohman TJ, Chibnik L, Bush WS, Jefferson AL, De Jaeger PL, Thornton-Wells TA, Bennett DA, Schneider JA
(2015) Neurotox Res 28: 232-8
MeSH Terms: Adaptor Proteins, Signal Transducing, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid, Brain, Cognitive Dysfunction, Cohort Studies, Educational Status, Female, Follow-Up Studies, Gene Expression, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Male, Polymorphism, Single Nucleotide, Sex Characteristics, United States
Show Abstract · Added February 22, 2016
Glyocogen synthase kinase 3 (GSK3) plays an important role in the pathophysiology of Alzheimer's disease (AD) through the phosphorylation of tau. Recent work has suggested that GSK3β also plays a role in the amyloid pathway of AD through genetic interactions with APP and APBB2 on in vivo measures of amyloid. This project extends the previously identified genotype interactions to an autopsy measure of amyloid, while also testing the same interactions leveraging gene expression data quantified in the prefrontal cortex. 797 participants (251 cognitively normal, 196 mild cognitive impairment, and 350 Alzheimer's disease) were drawn from the Religious Orders Study and Rush Memory and Aging Project. A mean score of amyloid load was calculated across eight brain regions, gene expression levels from frozen sections of the dorsolateral prefrontal cortex were quantified using RNA amplification, and expression signals were generated using Beadstudio. Three SNPs previously identified in genetic interactions were genotyped using the Illumina 1M genotyping chip. Covariates included age, sex, education, and diagnosis. We were able to evaluate 2 of the 3 previously identified interactions, of which the interaction between GSK3β (rs334543) and APBB2 (rs2585590) was found in this autopsy sample (p = 0.04). We observed a comparable interaction between GSK3β and APBB2 when comparing the highest tertile of gene expression to the lowest tertile, t(1) = -2.03, p = 0.043. These results provide additional evidence of a genetic interaction between GSK3β and APBB2 and further suggest that GSK3β is involved in the pathophysiology of both of the primary neuropathologies of Alzheimer's disease.
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19 MeSH Terms
Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis.
Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W
(2015) Gut 64: 1028-39
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Growth Inhibitors, Immunohistochemistry, Mice, Mice, Knockout, Peptides, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, Stomach Neoplasms, Transcriptional Activation, Trefoil Factor-1, beta Catenin
Show Abstract · Added February 19, 2015
OBJECTIVE - In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis.
DESIGN - Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway.
RESULTS - Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis.
CONCLUSIONS - Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
0 Communities
2 Members
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17 MeSH Terms
Liver, but not muscle, has an entrainable metabolic memory.
Chen SS, Otero YF, Mulligan KX, Lundblad TM, Williams PE, McGuinness OP
(2014) PLoS One 9: e86164
MeSH Terms: AMP-Activated Protein Kinases, Animals, Blood Glucose, Dogs, Energy Metabolism, Female, Glucagon, Glycogen, Glycogen Synthase, Insulin, Lactic Acid, Lipid Metabolism, Liver, Male, Muscle, Skeletal, Oxidation-Reduction, Protein-Serine-Threonine Kinases, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Pyruvic Acid
Show Abstract · Added July 21, 2014
Hyperglycemia in the hospitalized setting is common, especially in patients that receive nutritional support either continuously or intermittently. As the liver and muscle are the major sites of glucose disposal, we hypothesized their metabolic adaptations are sensitive to the pattern of nutrient delivery. Chronically catheterized, well-controlled depancreatized dogs were placed on one of three isocaloric diets: regular chow diet once daily (Chow) or a simple nutrient diet (ND) that was given either once daily (ND-4) or infused continuously (ND-C). Intraportal insulin was infused to maintain euglycemia. After 5 days net hepatic (NHGU) and muscle (MGU) glucose uptake and oxidation were assessed at euglycemia (120 mg/dl) and hyperglycemia (200 mg/dl) in the presence of basal insulin. While hyperglycemia increased both NHGU and MGU in Chow, NHGU was amplified in both groups receiving ND. The increase was associated with enhanced activation of glycogen synthase, glucose oxidation and suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Accelerated glucose-dependent muscle glucose uptake was only evident with ND-C. This was associated with a decrease in PDK-4 expression and an increase in AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, ND-C markedly increased hepatic FGF-21 expression. Thus, augmentation of carbohydrate disposal in the liver, as opposed to the muscle, is not dependent on the pattern of nutrient delivery.
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19 MeSH Terms
Interactions between GSK3β and amyloid genes explain variance in amyloid burden.
Hohman TJ, Koran ME, Thornton-Wells TA, Alzheimer's Neuroimaging Initiative
(2014) Neurobiol Aging 35: 460-5
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Female, Gene Expression Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Linear Models, Male, Middle Aged, Plaque, Amyloid, Polymorphism, Single Nucleotide, Risk, tau Proteins
Show Abstract · Added December 10, 2014
The driving theoretical framework of Alzheimer's disease (AD) has been built around the amyloid-β (Aβ) cascade in which amyloid pathology precedes and drives tau pathology. Other evidence has suggested that tau and amyloid pathology may arise independently. Both lines of research suggest that there may be epistatic relationships between genes involved in amyloid and tau pathophysiology. In the current study, we hypothesized that genes coding glycogen synthase kinase 3 (GSK-3) and comparable tau kinases would modify genetic risk for amyloid plaque pathology. Quantitative amyloid positron emission tomography data from the Alzheimer's Disease Neuroimaging Initiative served as the quantitative outcome in regression analyses, covarying for age, gender, and diagnosis. Three interactions reached statistical significance, all involving the GSK3β single nucleotide polymorphism rs334543-2 with APBB2 (rs2585590, rs3098914) and 1 with APP (rs457581). These interactions explained 1.2%, 1.5%, and 1.5% of the variance in amyloid deposition respectively. Our results add to a growing literature on the role of GSK-3 activity in amyloid processing and suggest that combined variation in GSK3β and APP-related genes may result in increased amyloid burden.
Copyright © 2014 Elsevier Inc. All rights reserved.
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2 Members
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16 MeSH Terms
Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis.
von Wilamowitz-Moellendorff A, Hunter RW, García-Rocha M, Kang L, López-Soldado I, Lantier L, Patel K, Peggie MW, Martínez-Pons C, Voss M, Calbó J, Cohen PT, Wasserman DH, Guinovart JJ, Sakamoto K
(2013) Diabetes 62: 4070-82
MeSH Terms: Animals, Blood Glucose, Glucose, Glucose-6-Phosphate, Glycogen Synthase, Hepatocytes, Homeostasis, Insulin, Liver, Liver Glycogen, Mice, Mice, Transgenic, Muscle, Skeletal, Phosphorylation
Show Abstract · Added April 17, 2014
The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.
2 Communities
1 Members
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14 MeSH Terms
Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet.
Coate KC, Smith MS, Shiota M, Irimia JM, Roach PJ, Farmer B, Williams PE, Moore MC
(2013) Diabetes 62: 753-61
MeSH Terms: Animals, Diabetes, Gestational, Diet, High-Fat, Disease Models, Animal, Dogs, Down-Regulation, Female, Fructose, Glucokinase, Glucose, Glucose Intolerance, Glycogen Phosphorylase, Liver Form, Glycogen Synthase, Hyperglycemia, Insulin Resistance, Liver, Liver Glycogen, Maternal Nutritional Physiological Phenomena, Postprandial Period, Pregnancy
Show Abstract · Added June 2, 2014
Net hepatic glucose uptake (NHGU) is an important contributor to postprandial glycemic control. We hypothesized that NHGU is reduced during normal pregnancy and in a pregnant diet-induced model of impaired glucose intolerance/gestational diabetes mellitus (IGT/GDM). Dogs (n = 7 per group) that were nonpregnant (N), normal pregnant (P), or pregnant with IGT/GDM (pregnant dogs fed a high-fat and -fructose diet [P-HFF]) underwent a hyperinsulinemic-hyperglycemic clamp with intraportal glucose infusion. Clamp period insulin, glucagon, and glucose concentrations and hepatic glucose loads did not differ among groups. The N dogs reached near-maximal NHGU rates within 30 min; mean ± SEM NHGU was 105 ± 9 µmol·100 g liver⁻¹·min⁻¹. The P and P-HFF dogs reached maximal NHGU in 90-120 min; their NHGU was blunted (68 ± 9 and 16 ± 17 µmol·100 g liver⁻¹·min⁻¹, respectively). Hepatic glycogen synthesis was reduced 20% in P versus N and 40% in P-HFF versus P dogs. This was associated with a reduction (>70%) in glycogen synthase activity in P-HFF versus P and increased glycogen phosphorylase (GP) activity in both P (1.7-fold greater than N) and P-HFF (1.8-fold greater than P) dogs. Thus, NHGU under conditions mimicking the postprandial state is delayed and suppressed in normal pregnancy, with concomitant reduction in glycogen storage. NHGU is further blunted in IGT/GDM. This likely contributes to postprandial hyperglycemia during pregnancy, with potential adverse outcomes for the fetus and mother.
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20 MeSH Terms
AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
Wang HY, Ducommun S, Quan C, Xie B, Li M, Wasserman DH, Sakamoto K, Mackintosh C, Chen S
(2013) Biochem J 449: 479-89
MeSH Terms: Adipocytes, Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Cells, Cultured, Female, GTPase-Activating Proteins, Glucose, Glucose Tolerance Test, Glucose Transporter Type 4, Glycogen Synthase Kinase 3, Humans, Hypoglycemic Agents, In Vitro Techniques, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Knockout, Muscle, Skeletal, Phosphoenolpyruvate Carboxykinase (GTP), Phosphorylation
Show Abstract · Added July 21, 2014
AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
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24 MeSH Terms