scholarly journals mTORC1 controls glycogen synthase kinase 3β nuclear localization and function

2018 ◽  
Author(s):  
Stephen J. Bautista ◽  
Ivan Boras ◽  
Adriano Vissa ◽  
Noa Mecica ◽  
Christopher M. Yip ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nuclear Localization ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Transcriptional Networks ◽  
Dependent Manner ◽  
Glycogen Synthase Kinase 3Β ◽  
Wide Range ◽  
Metabolic Conditions ◽  
And Function

AbstractGlycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of rapamycin (mTORC1) led to partial redistribution of GSK3β from the cytosol to the nucleus, and GSK3β-dependent reduction of the expression of c-myc and snail. mTORC1 is controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance. Indeed AMPK activation or amino acid deprivation promoted GSK3β nuclear localization in an mTORC1-dependent manner. GSK3β was detected in several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through perturbation of Rab7 resulted in loss of GSK3β from lysosomes, and enhanced GSK3β nuclear localization as well as GSK3β-dependent reduction of c-myc levels. This indicates that GSK3β nuclear localization and function is suppressed by mTORC1, and suggests a new link between metabolic conditions sensed by mTORC1 and GSK3β-dependent regulation of transcriptional networks controlling biomass production.Summary statement (15-30 words)GSK3β nuclear localization and function is negatively regulated by the metabolic and mitogenic sensor mTORC1. mTORC1 control of GSK3β localization requires Rab7 and lysosomal membrane traffic.

scholarly journals Mitogenic and Metabolic signals regulate mTOR complex 1 function to control GSK3β nuclear program

2021 ◽  
Author(s):  
Stephen James Bautista
Keyword(s):  
Plasma Membrane ◽  
Amino Acid ◽  
Nuclear Localization ◽  
Glycogen Synthase ◽  
Transcriptional Networks ◽  
Nucleocytoplasmic Shuttling ◽  
Metabolic Signalling ◽  
Wide Range ◽  
Amino Acid Sensing ◽  
Mtor Complex 1

Mitogenic and metabolic signalling are two cell pathways that control different aspects of cellular physiology including, growth, proliferation, metabolism, and transcription. Mitogenic signalling involves mitogens and growth factors to stimulate various receptor signalling pathways such as epidermal growth factor receptor (EGFR), while metabolic signalling involves proteins that sense changes in abundance of specific nutrients or metabolites such as amino acids and ATP. Here, I have uncovered that EGFR signalling is controlled by clathrin nanodomains at the plasma membrane, yet this requirement for clathrin does not reflect a role for receptor internalization in EGFR signalling. Specifically, I found that clathrin is required for activation of the key signaling intermediate Akt by EGFR upon EGF stimulation. Furthermore, I have also resolved a series of signals including Phospholipase C γ1 (PLCγ1) that may control EGF stimulated Akt activation by modulating the assembly of clathrin into plasma membrane nanodomains. These findings suggest that clathrin nanodomains at the plasma membrane are important for controlling EGFR signalling, thus impacting mitogenic signaling. A downstream signalling pathway controlled by Akt is the Glycogen synthase kinase 3 (GSK3) pathway. GSK3 phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3 substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3 function is controlled through regulation of its nuclear localization. I found that perturbations in mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3 from the cytosol to the nucleus and to a GSK3 dependent reduction of the levels of both c-Myc and Snail. In addition to conditional nuclear localization, GSK3 was also detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of various aspects of the function and regulation late endosomes/lysosomes resulted in perturbation of GSK3 nucleocytoplasmic shuttling and activity. Furthermore, I found that DEPDC5, a subunit of the lysosomal amino-acid sensing GATOR1 complex, controls amino acid sensing mechanisms to regulate GSK3 nucleocytoplasmic shuttling. These findings uncover a new signalling axis that is controlled by specific aspects of both mitogenic and metabolic signalling, which may interface with the nucleus to reprogram transcriptional cellular networks for growth and proliferation. Understanding how mTORC1- GSK3 signalling impacts transcriptional networks may be an important target for different therapies and treatments against diverse forms of cancer.

scholarly journals mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β

2018 ◽  
Vol 293 (38) ◽  
pp. 14723-14739 ◽  
Author(s):  
Stephen J. Bautista ◽  
Ivan Boras ◽  
Adriano Vissa ◽  
Noa Mecica ◽  
Christopher M. Yip ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
And Function ◽  
Mtor Complex 1

scholarly journals Mitogenic and Metabolic signals regulate mTOR complex 1 function to control GSK3β nuclear program

2021 ◽  
Author(s):  
Stephen James Bautista
Keyword(s):  
Plasma Membrane ◽  
Amino Acid ◽  
Nuclear Localization ◽  
Glycogen Synthase ◽  
Transcriptional Networks ◽  
Nucleocytoplasmic Shuttling ◽  
Metabolic Signalling ◽  
Wide Range ◽  
Amino Acid Sensing ◽  
Mtor Complex 1

Mitogenic and metabolic signalling are two cell pathways that control different aspects of cellular physiology including, growth, proliferation, metabolism, and transcription. Mitogenic signalling involves mitogens and growth factors to stimulate various receptor signalling pathways such as epidermal growth factor receptor (EGFR), while metabolic signalling involves proteins that sense changes in abundance of specific nutrients or metabolites such as amino acids and ATP. Here, I have uncovered that EGFR signalling is controlled by clathrin nanodomains at the plasma membrane, yet this requirement for clathrin does not reflect a role for receptor internalization in EGFR signalling. Specifically, I found that clathrin is required for activation of the key signaling intermediate Akt by EGFR upon EGF stimulation. Furthermore, I have also resolved a series of signals including Phospholipase C γ1 (PLCγ1) that may control EGF stimulated Akt activation by modulating the assembly of clathrin into plasma membrane nanodomains. These findings suggest that clathrin nanodomains at the plasma membrane are important for controlling EGFR signalling, thus impacting mitogenic signaling. A downstream signalling pathway controlled by Akt is the Glycogen synthase kinase 3 (GSK3) pathway. GSK3 phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3 substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3 function is controlled through regulation of its nuclear localization. I found that perturbations in mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3 from the cytosol to the nucleus and to a GSK3 dependent reduction of the levels of both c-Myc and Snail. In addition to conditional nuclear localization, GSK3 was also detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of various aspects of the function and regulation late endosomes/lysosomes resulted in perturbation of GSK3 nucleocytoplasmic shuttling and activity. Furthermore, I found that DEPDC5, a subunit of the lysosomal amino-acid sensing GATOR1 complex, controls amino acid sensing mechanisms to regulate GSK3 nucleocytoplasmic shuttling. These findings uncover a new signalling axis that is controlled by specific aspects of both mitogenic and metabolic signalling, which may interface with the nucleus to reprogram transcriptional cellular networks for growth and proliferation. Understanding how mTORC1- GSK3 signalling impacts transcriptional networks may be an important target for different therapies and treatments against diverse forms of cancer.

scholarly journals The nuclear localization of glycogen synthase kinase 3β is required its putative PY-nuclear localization sequences

2012 ◽  
Vol 34 (4) ◽  
pp. 375-382 ◽  
Author(s):  
Sung Hwa Shin ◽  
Eun Jeoung Lee ◽  
Jaesun Chun ◽  
Sunghee Hyun ◽  
Youg Il Kim ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Nuclear Localization Sequences

scholarly journals The role of glycogen synthase kinase-3β in glioma cell apoptosis induced by remifentanil

2013 ◽  
Vol 18 (4) ◽  
Author(s):  
Jing Xu ◽  
Pengjuan Xu ◽  
Zhigui Li ◽  
Lu Xiao ◽  
Zhuo Yang
Keyword(s):  
Flow Cytometry ◽  
Nmda Receptor ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Dependent Manner ◽  
Glycogen Synthase Kinase 3Β ◽  
Hoechst 33342 ◽  
Gsk 3Β

AbstractThe aim of malignant glioma treatment is to inhibit tumor cell proliferation and induce tumor cell apoptosis. Remifentanil is a clinical anesthetic drug that can activate the N-methyl-D-aspartate (NMDA) receptor. NMDA receptor signaling activates glycogen synthase kinase-3β (GSK-3β). Discovered some 32 years ago, GSK-3β was only recently considered as a therapeutic target in cancer treatment. The purpose of this study was to assess whether remifentanil can induce the apoptosis of C6 cells through GSK-3β activation. 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was used to detect cell viability. Hoechst 33342 staining and flow cytometry were used to detect cell apoptosis. The effect of GSK-3β activation was detected using a GSK-3β activation assay kit and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a potent and selective small molecule inhibitor of GSK-3β. The MTT assay indicated that remifentanil induced C6 cell death in a concentration- and time-dependent manner. Hoechst 33342 staining and flow cytometry showed that remifentanil significantly induced C6 cell apoptosis. The measurement of GSK-3β activation showed that remifentanil increased the cellular level of GSK-3β. All of these toxic effects can be attenuated by treatment with TDZD-8. These results suggest that remifentanil is able to induce C6 cell apoptosis through GSK-3β activation, which provides a basis for its potential use in the treatment of malignant gliomas.

scholarly journals KLHL1/MRP2 Mediates Neurite Outgrowth in a Glycogen Synthase Kinase 3β-Dependent Manner

2006 ◽  
Vol 26 (22) ◽  
pp. 8371-8384 ◽  
Author(s):  
Seyha Seng ◽  
Hava Karsenty Avraham ◽  
Shuxian Jiang ◽  
Saritha Venkatesh ◽  
Shalom Avraham
Keyword(s):  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Growth Cones ◽  
Glycogen Synthase Kinase ◽  
Actin Binding ◽  
Dependent Manner ◽  
Glycogen Synthase Kinase 3Β ◽  
Expression Levels

ABSTRACT The actin-based cytoskeleton is essential for the generation and maintenance of cell polarity, cellular motility, and the formation of neural cell processes. MRP2 is an actin-binding protein of the kelch-related protein family. While MRP2 has been shown to be expressed specifically in brain, its function is still unknown. Here, we report that in neuronal growth factor (NGF)-induced PC12 cells, MRP2 was expressed along the neurite processes and colocalized with Talin at the growth cones. MRP2 mRNA and protein levels were up-regulated in PC12 cells following NGF stimulation. Moreover, treatment of PC12 cells with interfering RNAs for MRP2 and glycogen synthase kinase 3β (GSK3β) resulted in the inhibition of neurite outgrowth. A significant decrease in MRP2 expression levels was observed following GSK3β inhibition, which was correlated with the inhibited neurite outgrowth, while GSK3β overexpression was found to increase MRP2 expression levels. MRP2 interacted with GSK3β through its NH2 terminus containing the BTB domain, and these molecules colocalized along neurite processes and growth cones in differentiated PC12 cells and rat primary hippocampal neurons. Additionally, increased associations of MRP2 with GSK3β and MRP2 with actin were observed in the NGF-treated PC12 cells. Thus, this study provides, for the first time, insights into the involvement of MRP2 in neurite outgrowth, which occurs in a GSK3β-dependent manner.

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