New Insights into the Autoinhibition Mechanism of Glycogen Synthase Kinase-3β

Ilouz, Ronit; Pietrokovski, Shmuel; Eisenstein, Miriam; Eldar-Finkelman, Hagit

doi:10.1016/j.jmb.2008.08.079

Cited by 22 publications

(16 citation statements)

References 33 publications

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“…It has been previously shown that phosphorylation at serine 9 near the N‐terminus of GSK‐3β mimics the prephosphorylation of the enzyme's substrate. This pseudosubstrate binds to the catalytic core and inhibits activity [Ilouz et al, 2008]. After treatment with AG490, although GSK3α/β did show an increase in Jurkat cells, the level of the inactive form (phospho‐GSK3β) also increased over the same period (Fig.…”

Section: Discussionmentioning

confidence: 96%

Blockade of JAK2 activity suppressed accumulation of β‐catenin in leukemic cells

Liu¹,

Lai²,

Chuang³

et al. 2010

J of Cellular Biochemistry

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The Wnt/β-catenin pathway has been implicated in leukemogenesis. We found β-catenin abnormally accumulated in both human acute T cell leukemia Jurkat cells and human erythroleukemia HEL cells. β-Catenin can be significantly down-regulated by the Janus kinase 2 specific inhibitor AG490 in these two cells. AG490 also reduces the luciferase activity of a reporter plasmid driven by LEF/β-catenin promoter. Similar results were observed in HEL cells infected with lentivirus containing shRNA against JAK2 gene. After treatment with 50 µM AG490 or shRNA, the mRNA expression levels of β-catenin, APC, Axin, β-Trcp, GSK3α, and GSK3β were up-regulated within 12-16 h. However, only the protein levels of GSK3β and β-Trcp were found to have increased relative to untreated cells. Knockdown experiments revealed that the AG490-induced inhibition of β-catenin can be attenuated by shRNA targeting β-TrCP. Taken together; these results suggest that β-Trcp plays a key role in the cross-talk between JAK/STAT and Wnt/β-catenin signaling in leukemia cells.

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Section: Discussionmentioning

confidence: 96%

Blockade of JAK2 activity suppressed accumulation of β‐catenin in leukemic cells

Liu¹,

Lai²,

Chuang³

et al. 2010

J of Cellular Biochemistry

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“…GSK-3 activity is further regulated by regions outside the catalytic domain. Its N-terminal end contains a highly conserved RPRTTSF motif that acts as an auto-inhibitory pseudosubstrate when phosphorylated at serine (Frame and Cohen, 2001; Ilouz et al, 2008). Another site located within the C-terminal region of GSK-3β (Thr 390) was recently identified as an inhibitory site (Thornton et al, 2008).…”

Section: Evolutionary Structural and Regulatory Features Of Gsk-3-lmentioning

confidence: 99%

“…A combined approach of mutagenesis and computational protein–protein docking analyses identified a novel substrate-binding site within the catalytic core of GSK-3β formed by Phe 67, Gln 89, Phe93, and Asn 95 (Ilouz et al, 2006; Licht-Murava et al, 2011), and Asp 181 as an additional binding site for the N-terminal pseudosubstrate (Ilouz et al, 2008; Figure 3B). These residues are spatially located near the ATP-binding site and the phosphate binding pocket that interacts with the phospho-serine moiety of the substrate (Dajani et al, 2001; ter Haar et al, 2001; Figure 3B).…”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

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Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes and mechanisms of action and include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate–competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3. The available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.

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“…Insulin and growth factors inhibit GSK3b activity on prephosporylated (primed) substrates by phosphorylating its Nterminal serine 9, thus blocking the interaction of GSK3b with the phosphate group on primed substrates such as GS and eukaryotic initialization factor 2B (eIF2B). [7][8][9] Subsequently, the phosphorylation and inactivation of GS and eIF2B by GSK3b are completely prevented, contributing to the stimulation of glycogen and protein synthesis. GSK3b activity can also be inhibited in response to Wnt signaling.…”

Section: Mechanism Of Kinase Inactivation and Nonbinding Of Fratide Tmentioning

confidence: 99%

Mechanism of kinase inactivation and nonbinding of fratide to GSK3β due to K85M mutation: Molecular dynamics simulation and normal mode analysis

Jiang

et al. 2011

Biopolymers

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As a serine/threonine protein kinase, glycogen synthase kinase 3β (GSK3β) is an essential component of several cellular processes, including insulin, growth factor, and Wnt signaling. The conserved K85 is important to GSK3β activity and FRATide binding. To elucidate the mechanisms concerning kinase inactivation and nonbinding of FRATide to GSK3β, molecular dynamics (MD) simulation, molecular mechanics generalized Born/surface area (MM_GBSA) calculation, and normal mode analysis (NMA) were performed on both the wild-type (WT) and the K85M mutation of the GSK3β-FRATide complex. The results revealed that the periodic open-closed conformational change of the G loop, together with the compact conformation of the RD pocket, was disturbed in the K85M mutant, in contrast to those in the WT. This in turn caused inhibition of GSK3β. Specifically, the correct folding pattern of GSK3β was disrupted in the K85M mutant, resulting in the loss of two key hydrogen bonds between K214 of FRATide and E290 and K292 of GSK3β, respectively. Furthermore, MM_GBSA calculations indicated that the K85M mutation could lead to a less energy-favorable GSK3β-FRATide complex. In addition, NMA demonstrated that the "rocking" of the N- and C-terminal domains of GSK3β, which coordinates the mutual movement of both lobes, inducing the opening and closing of the active site of GSK3β, which may assist the entry of ATP into the ATP binding site and the release of the ADP product. Strikingly, this phenomenon was not clearly observed in the K85M mutation. This study provides a structural basis for the effect of the K85M mutation on the GSK3β-FRATide complex.

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New Insights into the Autoinhibition Mechanism of Glycogen Synthase Kinase-3β

Cited by 22 publications

References 33 publications

Blockade of JAK2 activity suppressed accumulation of β‐catenin in leukemic cells

Blockade of JAK2 activity suppressed accumulation of β‐catenin in leukemic cells

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Mechanism of kinase inactivation and nonbinding of fratide to GSK3β due to K85M mutation: Molecular dynamics simulation and normal mode analysis

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