scholarly journals Reciprocal regulation of TORC signaling and tRNA modifications by Elongator enforces nutrient-dependent cell fate

2019 ◽  
Vol 5 (6) ◽  
pp. eaav0184 ◽  
Author(s):  
Julie Candiracci ◽  
Valerie Migeot ◽  
Yok-Hian Chionh ◽  
Fanelie Bauer ◽  
Thomas Brochier ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Growth ◽  
Cell Fate ◽  
Glycogen Synthase ◽  
Yeast Cells ◽  
Glycogen Synthase Kinase 3 ◽  
Trna Modification ◽  
Reciprocal Regulation ◽  
Trna Modifications ◽  
Dependent Cell

Nutrient availability has a profound impact on cell fate. Upon nitrogen starvation, wild-type fission yeast cells uncouple cell growth from cell division to generate small, round-shaped cells that are competent for sexual differentiation. The TORC1 (TOR complex 1) and TORC2 complexes exert opposite controls on cell growth and cell differentiation, but little is known about how their activity is coordinated. We show that transfer RNA (tRNA) modifications by Elongator are critical for this regulation by promoting the translation of both key components of TORC2 and repressors of TORC1. We further identified the TORC2 pathway as an activator of Elongator by down-regulating a Gsk3 (glycogen synthase kinase 3)–dependent inhibitory phosphorylation of Elongator. Therefore, a feedback control is operating between TOR complex (TORC) signaling and tRNA modification by Elongator to enforce the advancement of mitosis that precedes cell differentiation.

scholarly journals Schizosaccharomyces pombe skp1+ encodes a protein kinase related to mammalian glycogen synthase kinase 3 and complements a cdc14 cytokinesis mutant.

1996 ◽  
Vol 16 (1) ◽  
pp. 179-191 ◽  
Author(s):  
S E Plyte ◽  
A Feoktistova ◽  
J D Burke ◽  
J R Woodgett ◽  
K L Gould
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Cell Fate ◽  
Hormonal Regulation ◽  
Glycogen Synthase ◽  
Phosphorylation Site ◽  
Biochemical Properties ◽  
Yeast Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

We report the cloning of the skp1+ gene, a Schizosaccharomyces pombe homolog of the glycogen synthase kinase 3 (GSK-3) family whose members in higher eukaryotes are involved in cell fate determination, nuclear signalling, and hormonal regulation. skp1 is 67% identical to mammalian GSK-3 beta and displays similar biochemical properties in vitro. Like GSK-3 beta, skp1 is phosphorylated on a conserved tyrosine residue, and this phosphorylation is required for efficient activity. skp1 is also phosphorylated at a serine which has been identified as S-335. Phosphorylation at this site is likely to inhibit its function. Unlike the mammalian enzyme, skp1 both tyrosine autophosphorylates in yeast cells and can phosphorylate other proteins on tyrosine in bacteria. The skp1+ gene is not essential. However, cells with deletions in skp1+ are sensitive to heat shock and exhibit defects in sporulation. Overexpression of wild-type skp1+ specifically complements cdc14-118, one of several mutations causing a defect in cytokinesis. In addition, certain phosphorylation site mutants induce a delay or block in cytokinesis when overexpressed. Together, these data identify novel interactions of a fission yeast GSK-3 homolog with elements of the cytokinesis machinery.

scholarly journals A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

2015 ◽  
Vol 89 (18) ◽  
pp. 9232-9241 ◽  
Author(s):  
Crystal Woodard ◽  
Gangling Liao ◽  
C. Rory Goodwin ◽  
Jianfei Hu ◽  
Zhi Xie ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Glycogen Synthase ◽  
Primary Effusion Lymphoma ◽  
Protein Microarrays ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Parp Cleavage ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACTThe Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence forin vivophosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death.IMPORTANCEKSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild-type BC3 PEL cells.

scholarly journals Glycogen synthase kinase 3 regulates cell fate in dictyostelium

Cell ◽  
1995 ◽  
Vol 80 (1) ◽  
pp. 139-148 ◽  
Author(s):  
A.J Harwood ◽  
S.E Plyte ◽  
J Woodgett ◽  
H Strutt ◽  
R.R Kay
Keyword(s):  
Cell Fate ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Regulation of polarized growth initiation and termination cycles by the polarisome and Cdc42 regulators

2004 ◽  
Vol 164 (2) ◽  
pp. 207-218 ◽  
Author(s):  
Scott Bidlingmaier ◽  
Michael Snyder
Keyword(s):  
Cell Differentiation ◽  
Cell Growth ◽  
Fusion Proteins ◽  
Eukaryotic Cell ◽  
Yeast Cells ◽  
Polarized Growth ◽  
High Concentration ◽  
Dynamic Regulation ◽  
Polarized Cell Growth ◽  
Growth Initiation

The dynamic regulation of polarized cell growth allows cells to form structures of defined size and shape. We have studied the regulation of polarized growth using mating yeast as a model. Haploid yeast cells treated with high concentration of pheromone form successive mating projections that initiate and terminate growth with regular periodicity. The mechanisms that control the frequency of growth initiation and termination under these conditions are not well understood. We found that the polarisome components Spa2, Pea2, and Bni1 and the Cdc42 regulators Cdc24 and Bem3 control the timing and frequency of projection formation. Loss of polarisome components and mutation of Cdc24 decrease the frequency of projection formation, while loss of Bem3 increases the frequency of projection formation. We found that polarisome components and the cell fusion proteins Fus1 and Fus2 are important for the termination of projection growth. Our results define the first molecular regulators that control the timing of growth initiation and termination during eukaryotic cell differentiation.

scholarly journals Regulation of Ribosomal S6 Protein Kinase-p90rsk, Glycogen Synthase Kinase 3, and β-Catenin in Early Xenopus Development

1999 ◽  
Vol 19 (2) ◽  
pp. 1427-1437 ◽  
Author(s):  
Monica A. Torres ◽  
Hagit Eldar-Finkelman ◽  
Edwin G. Krebs ◽  
Randall T. Moon
Keyword(s):  
Cell Fate ◽  
Glycogen Synthase ◽  
Dominant Negative ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Fgf Signaling ◽  
Fgf Receptor ◽  
Multifunctional Protein ◽  
Downstream Target ◽  
Cytoplasmic Proteins

ABSTRACT β-Catenin is a multifunctional protein that binds cadherins at the plasma membrane, HMG box transcription factors in the nucleus, and several cytoplasmic proteins that are involved in regulating its stability. In developing embryos and in some human cancers, the accumulation of β-catenin in the cytoplasm and subsequently the nuclei of cells may be regulated by the Wnt-1 signaling cascade and by glycogen synthase kinase 3 (GSK-3). This has increased interest in regulators of both GSK-3 and β-catenin. Searching for kinase activities able to phosphorylate the conserved, inhibitory-regulatory GSK-3 residue serine 9, we found p90 rsk to be a potential upstream regulator of GSK-3. Overexpression of p90 rsk in Xenopus embryos leads to increased steady-state levels of total β-catenin but not of the free soluble protein. Instead, p90 rsk overexpression increases the levels of β-catenin in a cell fraction containing membrane-associated cadherins. Consistent with the lack of elevation of free β-catenin levels, ectopic p90 rsk was unable to rescue dorsal cell fate in embryos ventralized by UV irradiation. We show that p90 rsk is a downstream target of fibroblast growth factor (FGF) signaling during early Xenopus development, since ectopic FGF signaling activates both endogenous and overexpressed p90 rsk . Moreover, overexpression of a dominant negative FGF receptor, which blocks endogenous FGF signaling, leads to decreased p90 rsk kinase activity. Finally, we report that FGF inhibits endogenous GSK-3 activity inXenopus embryos. We hypothesize that FGF and p90 rsk play heretofore unsuspected roles in modulating GSK-3 and β-catenin.

scholarly journals Glycogen Synthase Kinase-3 Is Required for EfficientDictyosteliumChemotaxis

2010 ◽  
Vol 21 (15) ◽  
pp. 2788-2796 ◽  
Author(s):  
Regina Teo ◽  
Kimberley J. Lewis ◽  
Josephine E. Forde ◽  
W. Jonathan Ryves ◽  
Jonathan V. Reddy ◽  
...  
Keyword(s):  
Cell Signaling ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Glycogen Synthase ◽  
Cell Aggregation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cell Fate Determination ◽  
Cell Signaling Pathways

Glycogen synthase kinase-3 (GSK3) is a highly conserved protein kinase that is involved in several important cell signaling pathways and is associated with a range of medical conditions. Previous studies indicated a major role of the Dictyostelium homologue of GSK3 (gskA) in cell fate determination during morphogenesis of the fruiting body; however, transcriptomic and proteomic studies have suggested that GSK3 regulates gene expression much earlier during Dictyostelium development. To investigate a potential earlier role of GskA, we examined the effects of loss of gskA on cell aggregation. We find that cells lacking gskA exhibit poor chemotaxis toward cAMP and folate. Mutants fail to activate two important regulatory signaling pathways, mediated by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and target of rapamycin complex 2 (TORC2), which in combination are required for chemotaxis and cAMP signaling. These results indicate that GskA is required during early stages of Dictyostelium development, in which it is necessary for both chemotaxis and cell signaling.

scholarly journals Mitogen inactivation of glycogen synthase kinase-3β in intact cells via serine 9 phosphorylation

1994 ◽  
Vol 303 (3) ◽  
pp. 701-704 ◽  
Author(s):  
V Stambolic ◽  
J R Woodgett
Keyword(s):  
Cell Fate ◽  
Glycogen Synthase ◽  
Regulatory Proteins ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Serine Kinase ◽  
Intact Cells ◽  
S6 Kinase ◽  
Mitogen Activated Protein

Glycogen synthase kinase-3 (GSK-3), a protein-serine kinase implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors. GSK-3 beta is phosphorylated in vitro at serine 9 by p70 S6 kinase and p90rsk-1, resulting in its inhibition [Sutherland, Leighton, and Cohen (1993) Biochem. J. 296, 15-19]. Using HeLa cells expressing GSK-3 beta or a mutant containing alanine at residue 9, we demonstrate that serine 9 is modified in intact cells and is targeted specifically by p90rsk-1, and that phosphorylation leads to loss of activity. Since p90rsk-1 is directly activated by mitogen-activated protein kinases, agonists of this pathway, such as insulin, repress GSK-3 function.

scholarly journals Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth

2014 ◽  
Vol 15 (5) ◽  
pp. 510-515 ◽  
Author(s):  
Yvette M Carter ◽  
Selvi Kunnimalaiyaan ◽  
Herbert Chen ◽  
T Clark Gamblin ◽  
Muthusamy Kunnimalaiyaan
Keyword(s):  
Cell Growth ◽  
Glycogen Synthase ◽  
Neuroblastoma Cell ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Neuroendocrine Markers
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