A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3α and GSK3β in Regulating Embryonic Stem Cell Fate

Chen, Xi; Wang, Ruizhe; Liu, Xu; Wu, Yongming; Zhou, Tao; Yang, Yujia; Perez, Andrew A.; Chen, Ying-Chu; Hu, Liang; Chadarevian, Jean Paul; Assadieskandar, Amir; Zhang, Chao; Ying, Qi‐Long

doi:10.1016/j.devcel.2017.11.007

Cited by 31 publications

(33 citation statements)

References 48 publications

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“…Vertebrates have two GSK isoforms, and questions remain about the roles they play (or do not) in regulating this pathway. Genetic analysis demonstrated that the two isoforms are largely redundant for Wnt regulation, with single mutants having tissue-specific defects (Doble et al, 2007;Hoeflich et al, 2000), though recent studies with isoform-specific inhibitors suggest possible differences in isoform function in Wnt regulation (Chen et al, 2017).…”

Section: Regulating a Biomolecular Condensate: Wnt Signaling Changes mentioning

confidence: 99%

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

2019

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Wnt/b-Catenin signaling plays key roles in tissue homeostasis and cell fate decisions in embryonic and postembryonic development across the animal kingdom. As a result, pathway mutations are associated with developmental disorders and many human cancers. The multiprotein destruction complex keeps signaling off in the absence of Wnt ligands and needs to be downregulated for pathway activation. We discuss new insights into destruction complex activity and regulation, highlighting parallels to the control of other cell biological processes by biomolecular condensates that form by phase separation to suggest that the destruction complex acts as a biomolecular condensate in Wnt pathway regulation.

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Section: Regulating a Biomolecular Condensate: Wnt Signaling Changes mentioning

confidence: 99%

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

2019

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“…In vertebrates, GSK‐3 is typically encoded by two similar genes, Gsk3a and Gsk3b , which encode the proteins, GSK‐3α and GSK‐3β. The two isoforms share 98% amino acid sequence identity in their catalytic domains and function redundantly in many but not all pathways (e.g., see X. Chen et al, ; Doble, Patel, Wood, Kockeritz, & Woodgett, ; Doble & Woodgett, ; Hoeflich et al, ). Here we will refer to GSK‐3α and GSK‐3β collectively as GSK‐3 unless otherwise specified.…”

Section: What Is Gsk‐3? Backgroundmentioning

confidence: 99%

Glycogen synthase kinase‐3 and alternative splicing

Klein

2018

WIREs RNA

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Glycogen synthase kinase-3 (GSK-3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK-3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK-3 also regulates alternative splicing in response to T-cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK-3-dependent manner. Furthermore, inhibition of GSK-3 alters the splicing of hundreds of mRNAs, indicating a broad role for GSK-3 in the regulation of RNA processing. GSK-3-regulated phosphoproteins include SF3B1, SRSF2, PSF, RBM8A, nucleophosmin 1 (NPM1), and PHF6, many of which are mutated in leukemia and myelodysplasia. As GSK-3 is inhibited by pathways that are pathologically activated in leukemia and loss of Gsk3 in hematopoietic cells causes a severe myelodysplastic neoplasm in mice, these findings strongly implicate GSK-3 as a critical regulator of mRNA processing in normal and malignant hematopoiesis. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

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“…As a consequence, the shown pathways may act both to promote stemness in one setting and differentiation in another, all depending on the microenvironmental context, as well as the subcellular localisation and signalling dynamics of individual pathway components. Note that several of the displayed effectors exist in multiple isoforms and are currently omitted for clarity, although there are cases in which two isoforms may have different or even opposing effects on PSC biology [143].…”

Section: The Specific Pi3k Isoformmentioning

confidence: 99%

PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.

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A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3α and GSK3β in Regulating Embryonic Stem Cell Fate

Cited by 31 publications

References 48 publications

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

Glycogen synthase kinase‐3 and alternative splicing

PI3K in stemness regulation: from development to cancer

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