Palinurin And Furanosesquiterpenoids

Very recently extracts and compounds obtained from the marine organism Ircinia sp., and, more particularly, the furanoterpenoids isolated from the mediterranean sponges Ircinia dendroides, Ircinia variabilis, and Ircinia oros have been claimed as inhibitors of GSK-3 52 . Fractionation and purification of active components from these extracts, guided by a GSK-3 inhibition assay, resulted in the isolation of furanosesquit-erpenoids as new GSK-3 inhibitors with potential use as therapeutic agents....

Mouse Models With Reduced Gsk3 Activity

Another strategy to investigate the implications of GSK-3 dysregulation is to suppress its expression. The first study done in a mouse model was by Hoeflich et al. 40 . In this study the GSK-3P gene has been disrupted by targeted deletion. These investigators showed that GSK-3P is absolutely essential for survival. The generated GSK-3P-knockout mice developed normally to mid-gestation but died around day 14 following massive tumor necrosis factor-a (TNF-a)-induced hepatocyte apoptosis, which...

Outcomes Of Lithiums Inhibition Of Gsk3

The identification of a specific inhibitor for any enzyme provides a valuable investigative tool. Such has been the case with the use of lithium as a selective inhibitor of GSK-3. However, lithium has other targets in addition to GSK-3. Although lithium has been reported to affect numerous cellular functions 13 , only for a limited number of actions can the effects of lithium be attributed to inhibition of GSK-3 based on existing data. Discussed below are some examples of the actions of lithium...

ARA014418 and Tau Splicing

Recently a novel role for GSK-3 was demonstrated in transcriptional processes related to alternative splicing of human Tau exon 10, providing Figure 13.1 X-ray crystal structure of GSK-3 co-crystallized with GSK-3 inhibitor AR-A014418 showing binding within the ATP pocket. See color plates. Figure 13.1 X-ray crystal structure of GSK-3 co-crystallized with GSK-3 inhibitor AR-A014418 showing binding within the ATP pocket. See color plates. evidence for pleiotrophic involvement of GSK-3 in Tau...

References

The renaissance of GSK-3. Nat. Rev. Mol. Cell. Biol., 2, 769-776. 2. Nikoulina S.E., Ciaraldi T.P., Mudailar S., Mohideen P., Carter L., Henry R.R. (2000). Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes, 49, 263-271. 3. Lovestone S., Reynolds C.H., Latimer D., Davis D.R., Anderton B.H., Gallo J.M., Hanger D., Mulot S., Marquardt B. (1994). Alzheimer's disease-like phos-phorylation of the...

Radioactivity Based Assays

The high sensitivity achieved with radioactivity detection were at the basis of the first kinase activity assays some 40 years ago, and radiometric assays are still widely used because of that and the fact that they are not limited by the substrate being assayed. The principle of the method is very simple, and the assay is straightforward. The assay measures direct transfer of the radiolabeled phosphate moiety to the substrate, and it is not affected by other binding events. The classical...

Gsk3 And Insulin Resistance

GSK-3, one of the final regulatory proteins in glycogen production, is an attractive target for non-insulin-dependent diabetes mellitus (NIDDM). In NIDDM biopsy tissue GSK-3 activity is inversely correlated to glycogen synthase activity implicating GSK-3 as contributing to insulin resistance 27,28 . Insulin and insulin receptors are expressed in the brain, including the medial temporal regions that support the formation of memory 29 . Some NIDDM patients are also afflicted with verbal and...

ARA014418 in Psychiatry

The therapeutic potential of GSK-3 inhibitors as an antidepressant approach has been demonstrated by the ability of AR-A014418 to affect behavioral changes in animal models. In rats, administration of AR-A014418 reduced immobility time in forced swim tests 62 . In addition the specificity of this effect is supported by studies where AR-A014418 inhibited spontaneous as well as amphetamine-induced activity. These behavioral changes are consistent with the effects of current antidepressant...

Autoinhibition By Gsk3 Aterminus

AKT phosphorylates Ser9 leads to inactivation of GSK-3p 28,29 . In GSK-3a, Ser21 is the homologous site but is separated from the kinase domain by Figure 4.3 Comparison of the substrate-binding grooves of GSK-3P and Cdk2. The structures of phosphorylated GSK-3P pdb 1gng and Cdk2 in complex with a peptide pdb 1qmz were used to show the differences between the substrate-binding grooves of GSK-3P and other map kinases. GSK-3P was superimposed onto Cdk2 to model the peptide in the GSK-3P...

Wnt and Intestinal Stem Cells

The intestinal epithelium is a self-renewing tissue that represents a unique system for studying interconnected cell behaviors such as proliferation, differentiation, and migration. The epithelium of intestine is organized into two morphologically and functionally distinct compartments proliferative crypt, which is maintained by multipotent stem progenitor cells, and differentiated villus, the cells of which are derived from several surrounding crypts. Slowly dividing ISCs are postulated to...

Functional Cellbased Assays For Gsk3 Inhibition

After primary screening in any of the in vitro kinase activity assays described above, a cell-based assay is used to test the small molecules' activity with actual cells, testing at the same time for cell permeability and potential effects on cell viability. Cell-based assays can confirm the activity of agents tested in target-based screening assays and can assess the agent's pharmacologic effects 26 . Furthermore, recent advances in proteomics and protein array technologies, combined with the...

Structures With Wnt Signaling Pathway Peptides

The Wnt signaling pathway plays a key role in many developmental processes and has different effects in different organisms. In Drosophila, Wnt signaling affects segment polarity 49 . It affects axis induction in Xenopus and plays a role in carcinogenesis in humans reviewed in 50 . The major components of the Wnt signaling pathway are APC adenomatous polyposis coli , Axin, P-catenin, GSK-3P, Wnt, Frizzled, and Disheveled 51 . The Wnt signaling molecule binds to the extracellular domain of the...

The Discovery Of Gsk3

It is a great honour to have been asked to write the introduction to this book, which celebrates 25 years of research on glycogen synthase kinase 3 GSK-3 , and to recall the events that led to the identification and characterisation of this fascinating protein kinase, which is involved in regulating so many cellular processes. In late 1971 I had joined the Department of Biochemistry at the University of Dundee as a junior member of the Faculty after spending two years as a postdoctoral fellow...

Info

GSK3P with 6-Bromoindirubin-3'-oxime threonine. The Tyr216 phosphorylation site is conserved in many kinases and is located in the activation loop. Both these phosphorylation sites are also present in GSK-3a where Ser21 is the inactivating phosphorylation site and Tyr279 is the activation loop phosphorylation site. The crystal structure of Tyr216 phosphorylated GSK-3P confirms the role of pTyr216 as a gatekeeper of the substrate-binding groove PDB 1GNG and 1O9U 10,11 . Compared with the apo...