scholarly journals Glycogen Synthase Kinase 3 induces multilineage maturation of human pluripotent stem cell-derived lung progenitors in 3D culture

2018 ◽  
Author(s):  
Ana Luisa Rodrigues Toste de Carvalho ◽  
Alexandros Strikoudis ◽  
Tiago J. Dantas ◽  
Ya-Wen Chen ◽  
Hsiao-Yun Liu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Lung Development ◽  
Human Lung ◽  
Glycogen Synthase ◽  
3D Culture ◽  
Alveolar Epithelial Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Type I ◽  
Lung Progenitors

Although strategies for directed differentiation of human pluripotent stem cells (hPSCs) into lung and airway have been established, terminal maturation of the cells remains a vexing problem. We show here that in Collagen I 3D cultures in the absence of glycogen synthase kinase 3 (GSK3) inhibition, hPSC-derived lung progenitors (LPs) undergo multilineage maturation into proximal cells arranged in pseudostratified epithelia, type I alveolar epithelial cells and morphologically mature type II cells. Enhanced cell cycling, one of the signaling outputs of GSK3 inhibition, plays a role in the maturation-inhibiting effect of GSK3 inhibition. Using this model, we show NOTCH signaling induced a distal at the expense of a proximal and ciliated cell fate, while WNT signaling promoted a proximal, club cell fate, thus implicating both signaling pathways in proximodistal specification in human lung development. These findings establish an approach to achieve multilineage maturation of lung and airway cells from hPSCs, demonstrate a pivotal role of GSK3 in the maturation of lung progenitors, and provide novel insight into proximodistal specification during human lung development.

scholarly journals Glycogen synthase kinase 3 induces multilineage maturation of human pluripotent stem cell-derived lung progenitors in 3D culture

Development ◽  
2018 ◽  
Vol 146 (2) ◽  
pp. dev171652 ◽  
Author(s):  
Ana Luisa Rodrigues Toste de Carvalho ◽  
Alexandros Strikoudis ◽  
Hsiao-Yun Liu ◽  
Ya-Wen Chen ◽  
Tiago J. Dantas ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Glycogen Synthase ◽  
3D Culture ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Human Pluripotent Stem Cell ◽  
Lung Progenitors

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 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.

Glycogen synthase kinase-3 (GSK-3) is regulated during Dictyostelium development via the serpentine receptor cAR3

Development ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 325-333 ◽  
Author(s):  
S.E. Plyte ◽  
E. O'Donovan ◽  
J.R. Woodgett ◽  
A.J. Harwood
Keyword(s):  
Cell Fate ◽  
Kinase Activity ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cell Type ◽  
Multicellular Development ◽  
Extracellular Signal ◽  
Camp Receptor ◽  
Extracellular Camp

Glycogen synthase kinase-3 (GSK-3) is required during metazoan development to mediate the effects of the extracellular signal wingless/Wnt-1 and hence is necessary for correct cell type specification. GSK-3 also regulates cell fate during Dictyostelium development, but in this case it appears to mediate the effects of extracellular cAMP. By direct measurement of GSK-3 kinase activity during Dictyostelium development, we find that there is a rise in activity at the initiation of multicellular development which can be induced by cAMP. The timing of the rise correlates with the requirement for the Dictyostelium homologue of GSK-3, GSKA, to specify cell fate. We show that loss of the cAMP receptor cAR3 almost completely abolishes the rise in kinase activity and causes a mis-specification of cell fate that is equivalent to that seen in a gskA- mutant. The phenotype of a cAR3(−) mutant however is less severe than loss of gskA and ultimately gives rise to an apparently wild-type fruiting body. These results indicate that in Dictyostelium extracellular cAMP acts via cAR3 to cause a rise in GSKA kinase activity which regulates cell type patterning during the initial stages of multicellularity.

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.

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