3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

Smith, David George Emslie; Buffet, Marianne; Fenwick, Ashley E.; Haigh, David; Ife, Robert J.; Saunders, Martin; Slingsby, Brian P.; Stacey, Rachel; Ward, Robert W.

doi:10.1016/s0960-894x(00)00721-6

Cited by 157 publications

(112 citation statements)

References 36 publications

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“…6, A (lanes 11-12) and B (lanes 8 -11)), similar to the results reported for the GlaxoSmithKline GSK-3 inhibitors SB-216763 and SB-415286, maleimides structurally similar to Ro31-8220 (25). However, Ro31-8220, SB-216763, and SB-415286 also inhibit p90 rsk2 (56,65), which phosphorylates GSK-3␤ Ser9 in vitro (66,67), suggesting that p90 rsk2 or a related kinase may phosphorylate GSK-3 in vivo, as well. Indeed, BIS-III, which potently inhibits p90 rsk2 but only weakly inhibits GSK-3 (56), blocks both basal and lithium-induced serine 9 phosphorylation (see Fig.…”

Section: Ser9supporting

confidence: 81%

Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium

Zhang

Phiel

Spece

et al. 2003

Journal of Biological Chemistry

407

329

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Glycogen synthase kinase-3 (GSK-3) is a critical, negative regulator of diverse signaling pathways. Lithium is a direct inhibitor of GSK-3 and has been widely used to test the putative role of GSK-3 in multiple settings. However, lithium also inhibits other targets, including inositol monophosphatase and structurally related phosphomonoesterases, and thus additional approaches are needed to attribute a given biological effect of lithium to a specific target. For example, lithium is known to increase the inhibitory N-terminal phosphorylation of GSK-3, but the target of lithium responsible for this indirect regulation has not been identified. We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action. We show here, using the GSK-3 interaction domain peptide, as well as small molecule inhibitors of GSK-3, that lithium induces GSK-3 N-terminal phosphorylation through direct inhibition of GSK-3 itself. Reduction of GSK-3 protein levels, either by RNA interference or by disruption of the mouse GSK-3␤ gene, causes increased N-terminal phosphorylation of GSK-3, confirming that GSK-3 regulates its own phosphorylation status. Finally, evidence is presented that N-terminal phosphorylation of GSK-3 can be regulated by the GSK-3-dependent protein phosphatase-1⅐inhibitor-2 complex.

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Section: Ser9supporting

confidence: 81%

Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium

Zhang

Phiel

Spece

et al. 2003

Journal of Biological Chemistry

407

329

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“…The Tgfβ receptor 1 antagonist SB431542 (10 μM; Sigma-Aldrich) or a pan-specific TGFβ-blocking antibody (200 μg/ml; R&D Systems) dissolved in the medium was used to inhibit Tgfβ signaling (10,22,23). Recombinant mouse Dkk1 (400 ng/ml; R&D Systems) or quercetin (10 μM; Sigma-Aldrich) was used to inhibit canonical Wnt signaling (21,41), and heparin beads soaked in the Gsk3b inhibitor SB216763 (10 μM; Sigma-Aldrich) or Wnt3a (1,000 ng/ml; R&D Systems) were used to activate canonical Wnt signaling (42).…”

Section: Methodsmentioning

confidence: 99%

A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium

Chen¹,

Cao²,

Qian³

et al. 2010

J. Clin. Invest.

125

109

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The developmental abnormalities associated with disruption of signaling by retinoic acid (RA), the biologically active form of vitamin A, have been known for decades from studies in animal models and humans. These include defects in the respiratory system, such as lung hypoplasia and agenesis. However, the molecular events controlled by RA that lead to formation of the lung primordium from the primitive foregut remain unclear. Here, we present evidence that endogenous RA acts as a major regulatory signal integrating Wnt and Tgfβ pathways in the control of Fgf10 expression during induction of the mouse primordial lung. We demonstrated that activation of Wnt signaling required for lung formation was dependent on local repression of its antagonist, Dickkopf homolog 1 (Dkk1), by endogenous RA. Moreover, we showed that simultaneously activating Wnt and repressing Tgfβ allowed induction of both lung buds in RA-deficient foreguts. The data in this study suggest that disruption of Wnt/Tgfβ/Fgf10 interactions represents the molecular basis for the classically reported failure to form lung buds in vitamin A deficiency.

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“…14 -20). GSK-3 inhibitors include indirubins (10), paullones (13), maleimides (21,22), and lithium (23).…”

mentioning

confidence: 99%

Intracellular Targets of Paullones

Knockaert¹,

Wieking²,

Schmitt³

et al. 2002

Journal of Biological Chemistry

135

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Numerous inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 (GSK-3) are being developed in view of their potential applications against cancers and neurodegenerative disorders. Among these, paullones constitute a family of potent and apparently selective cyclin-dependent kinase and GSK-3 inhibitors. However, their actual intracellular targets remain to be identified. To address this issue we have immobilized a paullone, gwennpaullone, on an agarose matrix. Extracts from various cell types and tissues were screened for proteins interacting with this matrix. This approach validated GSK-3␣ and GSK-3␤ as major intracellular paullone targets and also mitochondrial, but not cytoplasmic, malate dehydrogenase (MDH). Mitochondrial MDH was indeed inhibited by micromolar concentrations of paullones. Mitochondrial MDH was the major paullone-binding protein in the parasitic protozoon Leishmania mexicana, and paullones inhibited growth of the parasite. This simple batchwise affinity chromatography approach constitutes a straightforward method for the identification of intracellular targets of this particular class of novel anti-mitotic compounds. It has revealed an unexpected target, mitochondrial MDH, the inhibition of which may participate in the pharmacological effects of paullones.

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3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3)

Cited by 157 publications

References 36 publications

Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium

Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium

A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium

Intracellular Targets of Paullones

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