GSK-3: tricks of the trade for a multi-tasking kinase

Doble, Bradley W.; Woodgett, James R.

doi:10.1242/jcs.00384

Cited by 1,898 publications

(1,951 citation statements)

References 161 publications

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“…GSK3β activity is negatively regulated by phosphorylation on Ser9 by Akt, PKA, and PKC (Blomgren et al, 2007). Although the exact role of GSK3β in malignancies is still controversial due to conflicting results from different tumor models (Miyashita et al, 2009), inactivation of GSK3β is thought to contribute to the inhibition of tumor growth via cell cycle and apoptosis regulation (Doble and Woodgett, 2003;Luo, 2009). In this study, caffeine increased GSK3β phosphorylation at Ser9; this regulation was controlled by PKA.…”

Section: Discussionmentioning

confidence: 65%

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Lee

Jeong

et al. 2011

Molecules and Cells

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Section: Discussionmentioning

confidence: 65%

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Lee

Jeong

et al. 2011

Molecules and Cells

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“…GSK-3b, a key player of the Wnt/b-catenin pathway is inhibited by phosphorylation at Ser9 [33]. This in turn prevents b-catenin from degradation and results in increased Wnt/b-catenin signaling [34]. Our immunocytochemistry showed that GSK-3[gr beta] is phosphorylated at Ser9 specifically at the apical surface (Fig.…”

Section: Polarity Protein Expression and Localization In Neural Diffementioning

confidence: 81%

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

Boroviak

Rashbass

2011

Stem Cells

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ESCs undergoing neural differentiation in vitro display an intrinsic heterogeneity with a large subset of the cells forming polarized neural rosettes that maintain the neural progenitor microenvironment. This heterogeneity is not only necessary for normal development but also causes substantial technical challenges for practical applications. Here, we report a novel regulator of early neural progenitors, the apical polarity protein Crb2 (Crumbs homologue 2). Employing monolayer differentiation of mouse ESCs to model neurogenesis in vitro, we find that Crb2 is upregulated with Sox1 and Musashi at the onset of neuroepithelial specification and localizes to the apical side of neural rosettes. Stable Crb2-knockdown (KD) lines die at the onset of neural specification and fail to stabilize several apical polarity proteins. However, these cells are able to proliferate under selfrenewing conditions and can be differentiated into mesodermal and endodermal lineages. Conversely, Crb2 overexpression during neural differentiation results in elevated levels of other apical polarity proteins and increases proliferation. Additionally, sustained overexpression of Crb2 reduces terminal differentiation into TuJ1-positive neurons. Furthermore, we demonstrate that Crb2 overexpression under selfrenewing conditions increases glycogen synthase kinase (GSK)-3b inhibition, correlating with an increase in clonogenicity. To confirm the importance of GSK-3b inhibition downstream of Crb2, we show that Crb2-KD cells can be forced into neural lineages by blocking GSK-3b function and supplementing Epidermal Growth Factor (EGF) and basic Fibroblast Growth Factor (bFGF). Thus, this is the first demonstration that a member of the Crumbs family is essential for survival and differentiation of ESC-derived neural progenitors.

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“…2). LeishH1 was chosen because it 420 possesses the consensus recognition motif for phosphorylation by GSK-3β: S/TXXXS/T(P), where 421 X is any amino-acid (Doble and Woodgett, 2003). LdGSK-3s shows no autophosphorylation when 422 the kinase assay is performed without substrate (Fig.…”

Section: Ldgsk-3 S and Crk3 Inhibitor Screen 389mentioning

confidence: 99%

6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

Xingi

Smirlis

Myrianthopoulos

et al. 2009

International Journal for Parasitology

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Indirubins known to target mammalian cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3) were tested for their antileishmanial activity. 6-Br-indirubin-3'-oxime (6-BIO), 6-Br-indirubin-3'acetoxime and 6-Br-5methylindirubin-3'oxime (5-Me-6-BIO) were the most potent inhibitors of L. donovani promastigote and amastigote growth (IC50 values ≤ 1.2 μM). Since the 6-Br substitution on the indirubin backbone greatly enhances the selectivity for mammalian GSK-3 over CDKs, we identified the leishmanial GSK-3 homologues, a short (LdGSK-3s) and a long one, focusing on LdGSK-3s which is closer to human GSK-3β for further studies. Kinase assays showed that 5-Me-6-BIO inhibited LdGSK-3s more potently than CRK3 (the CDK1 homologue in Leishmania), while 6-BIO was more selective for CRK3. Promastigotes treated with 5-Me-6-BIO accumulated in the S and G2/M cell-cycle phases and underwent apoptosis-like death.Interestingly, these phenotypes were completely reversed in parasites over-expressing LdGSK-3s.This finding strongly supports that LdGSK-3s is a) the intracellular target of 5-Me-6-BIO and b) involved in cell-cycle control and in pathways leading to apoptosis-like death. 6-BIO treatment induced a G2/M arrest, consistent with inhibition of CRK3, and apoptosis-like death. These effects were partially reversed in parasites over-expressing suggesting that in vivo 6-BIO may also target LdGSK-3s. Molecular docking of 5-Me-6-BIO in CRK3 and 6-BIO in human and LdGSK-3s active sites predict the existence of functional/structural differences that are sufficient to explain the observed difference in their affinity. In conclusion, LdGSK-3s is validated as a potential drug target in Leishmania and could be exploited for the development of selective indirubin-based leishmanicidals. AUTHOR AGREEMENT FORMManuscript title: "5-Me-6-BIO targeting the leishmanial GSK-3 short form affects cell-cycle progression and induces apoptosis-like death: exploitation of GSK-3 for treating leishmaniasis" Authors: Evangelia Xingi, Despina Smirlis , Vassilios Myrianthopoulos , Prokopios Magiatis, Karen M. Grant, Laurent Meijer, Emmanuel Mikros, Alexios-Leandros Skaltsounis and Ketty Soteriadou We, the undersigned, acknowledge that we have read the above manuscript and accept responsibility for its contents. We confirm this manuscript has not been published previously and if accepted in the International Journal for Parasitology will not be published elsewhere without the approval of the Editor-in-Chief. We also confirm there are no financial or other relationships that might lead to a conflict of interest.[If a financial or other relationship exists that might lead to a conflict of interest, please provide that information here.][If this letter is being submitted at revision and if there have been any changes in authors added to/deleted from the paper or if the order of author citation has changed since the original submission, please include a statement acknowledging those changes, before each author (including authors deleted fro...

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GSK-3: tricks of the trade for a multi-tasking kinase

Cited by 1,898 publications

References 161 publications

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

The Apical Polarity Determinant Crumbs 2 Is a Novel Regulator of ESC-Derived Neural Progenitors

6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

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