scholarly journals Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3β and β-Catenin and Inhibits Axis Formation ofXenopus Embryos

1998 ◽  
Vol 18 (5) ◽  
pp. 2867-2875 ◽  
Author(s):  
Hideki Yamamoto ◽  
Shosei Kishida ◽  
Takaaki Uochi ◽  
Satoshi Ikeda ◽  
Shinya Koyama ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Binding Site ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Amino Acid Identity ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Axis Formation ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

ABSTRACT Using a yeast two-hybrid method, we identified a novel protein which interacts with glycogen synthase kinase 3β (GSK-3β). This protein had 44% amino acid identity with Axin, a negative regulator of the Wnt signaling pathway.We designated this protein Axil for Axin like. Like Axin, Axil ventralized Xenopus embryos and inhibited Xwnt8-induced Xenopus axis duplication. Axil was phosphorylated by GSK-3β. Axil bound not only to GSK-3β but also to β-catenin, and the GSK-3β-binding site of Axil was distinct from the β-catenin-binding site. Furthermore, Axil enhanced GSK-3β-dependent phosphorylation of β-catenin. These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3β-dependent phosphorylation of β-catenin, thereby inhibiting axis formation.

scholarly journals Regulation of Glycogen Synthase Kinase 3β and Downstream Wnt Signaling by Axin

1999 ◽  
Vol 19 (10) ◽  
pp. 7147-7157 ◽  
Author(s):  
Chester M. Hedgepeth ◽  
Matthew A. Deardorff ◽  
Kathleen Rankin ◽  
Peter S. Klein
Keyword(s):  
Wnt Signaling ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Axis Formation ◽  
Glycogen Synthase Kinase 3Β ◽  
Adenomatous Polyposis Coli Protein ◽  
Interaction Domain ◽  
Regulatory Domains ◽  
Gsk 3Β

ABSTRACT Axin is a recently identified protein encoded by thefused locus in mice that is required for normal vertebrate axis formation. We have defined a 25-amino-acid sequence in axin that comprises the glycogen synthase kinase 3β (GSK-3β) interaction domain (GID). In contrast to full-length axin, which has been shown to antagonize Wnt signaling, the GID inhibits GSK-3β in vivo and activates Wnt signaling. Similarly, mutants of axin lacking key regulatory domains such as the RGS domain, which is required for interaction with the adenomatous polyposis coli protein, bind and inhibit GSK-3β in vivo, suggesting that these domains are critical for proper regulation of GSK-3β activity. We have identified a novel self-interaction domain in axin and have shown that formation of an axin regulatory complex in vivo is critical for axis formation and GSK-3β activity. Based on these data, we propose that the axin complex may directly regulate GSK-3β enzymatic activity in vivo. These observations also demonstrate that alternative inhibitors of GSK-3β can mimic the effect of lithium in developingXenopus embryos.

scholarly journals Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy

2000 ◽  
Vol 151 (1) ◽  
pp. 117-130 ◽  
Author(s):  
Syed Haq ◽  
Gabriel Choukroun ◽  
Zhao Bin Kang ◽  
Hardeep Ranu ◽  
Takashi Matsui ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Cellular Response ◽  
Glycogen Synthase ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Gsk 3Β

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

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 Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3β and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection

2018 ◽  
Vol 62 (6) ◽  
pp. e02045-17 ◽  
Author(s):  
Chia-Ling Chen ◽  
Miao-Huei Cheng ◽  
Chih-Feng Kuo ◽  
Yi-Lin Cheng ◽  
Ming-Han Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Streptococcal Toxic Shock Syndrome ◽  
Glycogen Synthase Kinase 3Β ◽  
Diphenylene Iodonium ◽  
Group A ◽  
Gsk 3Β

ABSTRACTGroup AStreptococcus(GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phoxand subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3β/NF-κB/NO signaling pathway.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jingjin Li ◽  
Chonglong Shi ◽  
Zhengnian Ding ◽  
Wenjie Jin
Keyword(s):  
Cognitive Dysfunction ◽  
Lithium Chloride ◽  
Glycogen Synthase ◽  
Postoperative Cognitive Dysfunction ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Central Nervous System Complication ◽  
Proinflammatory Mediators ◽  
M1 Polarization ◽  
Gsk 3Β

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.

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