QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

doi: 10.1242/10.1242/jcs.00384

This Article Summary Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doble, B. W. Articles by Woodgett, J. R. Search for Related Content PubMed PubMed Citation Articles by Doble, B. W. Articles by Woodgett, J. R. Social Bookmarking                         What's this?

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

Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada

^* Author for correspondence (e-mail: jwoodget{at}uhnres.utoronto.ca)

	Summary

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/ß-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.

Key words: Signal transduction, Phosphorylation, Wnt signalling, Insulin signalling, Protein structure-function

	Introduction

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase that was first isolated and purified as an enzyme capable of phosphorylating and inactivating the enzyme glycogen synthase (Embi et al., 1980; Woodgett and Cohen, 1984). We now know that, beyond its role in glycogen metabolism, GSK-3 acts as a downstream regulatory switch that determines the output of numerous signalling pathways initiated by diverse stimuli (reviewed in Frame and Cohen, 2001; Grimes and Jope, 2001; Woodgett, 2001). The pathways in which GSK-3 acts as a key regulator, when dysregulated, have been implicated in the development of human diseases such as diabetes, Alzheimer's disease, bipolar disorder and cancer.

Given its involvement in many pathophysiological processes and diseases, GSK-3 is a tempting therapeutic target. However, its involvement in multiple pathways also raises the issue of selectivity — how might we impact one process while leaving others untouched? We must also assess the full spectrum of GSK-3 functions to avoid later surprises. For example, although inhibition of GSK-3 may be desirable in one context (e.g. in preventing neuronal apoptosis), it could have serious implications for another — for example, it might accelerate hyperplasia by deregulating ß-catenin. That said, the recent development of small molecule inhibitors of GSK-3 has provided new tools for visualizing the cell from the perspective of GSK-3. Since it is highly active in most cell types, regulation of substrate phosphorylation occurs either by inactivation of GSK-3 or by changing substrate accessibility or recognition. Here, we present an overview of the various processes in which GSK-3 plays a key role and describe the current status of knowledge of GSK-3 regulation.

	GSK-3 variants

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
There are two mammalian GSK-3 isoforms encoded by distinct genes: GSK-3 and GSK-3ß (Woodgett, 1990) (Fig. 1). GSK-3 has a mass of 51 kDa, whereas GSK-3ß is a protein of 47 kDa. The difference in size is due to a glycine-rich extension at the N-terminus of GSK-3. Although highly homologous within their kinase domains (98% identity), the two gene products share only 36% identity in the last 76 C-terminal residues (Woodgett, 1990). Homologues of GSK-3 exist in all eukaryotes examined to date and display a high degree of homology; isoforms from species as distant as flies and humans display >90% sequence similarity within the kinase domain (reviewed in Ali et al., 2001).

View larger version (7K): [in this window] [in a new window]   Fig. 1. Schematic representation of mammalian GSK-3 and GSK-3ß. Sites of serine and tyrosine phosphorylation are indicated with blue arrowheads. The glycine-rich N-terminal domain unique to GSK-3 and the conserved kinase domain shared by both isoforms are highlighted.

GSK-3 and GSK-3ß, although structurally similar, are not functionally identical. This became obvious upon ablation of the GSK-3ß isoform in mice, which results in an embryonic lethal phenotype (Hoeflich et al., 2000). Embryos carrying homozygous deletions of exon 2 of GSK-3ß die around embryonic day 16 owing to massive liver degeneration caused by extensive hepatocyte apoptosis. The inability of GSK-3 to rescue the GSK-3ß-null mice indicates that the degenerative liver phenotype arises specifically from the loss of the beta isoform. This phenotype is remarkably similar to that of animals lacking RelA or I-B kinase 2 (Beg et al., 1995; Li et al., 1999), components of the NF-B signalling pathway (Ghosh and Karin, 2002; Rothwarf and Karin, 1999). Regulation of NF-B nuclear import is not disrupted in embryonic fibroblasts isolated from the GSK-3ß-null mice, which indicates that GSK-3 affects some other level of NF-B regulation. The specific target(s) of GSK-3ß in the regulation of NF-B signalling has not been identified. Other protein kinases can phosphorylate the p65 subunit of NF-B, increasing transactivation (Jang et al., 2001; Wang et al., 2000). GSK-3ß can phosphorylate the C-terminal domain (residues 354-551) of p65 in vitro (Schwabe and Brenner, 2002), but further studies are required to verify if p65 is a physiological GSK-3ß substrate and to assess the effect of this modification. The phenotype of mice lacking GSK-3 has not yet been reported.

A minor (15% of total) splice variant of GSK-3ß, GSK-3ß2, has recently been identified and contains a 13-residue insert within the kinase domain (Mukai et al., 2002). Analysis of the in vitro kinase activity of GSK-3ß2 revealed reduced activity towards the microtubule-associated protein tau, compared with `unspliced' GSK-3ß. An antibody selective for the novel splice-insertion polypeptide revealed that GSK-3ß2 is localized primarily to neuronal cell bodies, unlike unspliced GSK-3ß, which is also found in neuronal processes. It is unclear whether these substrate and subcellular localization differences can be generalized to other proteins or cells. Given the location of the insert within a highly conserved sequence, it probably forms a loop/hook, which might allow differential binding of the splice variant to scaffolding proteins that then expose the isoform to a distinct subset of target proteins (Mukai et al., 2002).

	GSK-3 phosphorylation: insights from crystal structures

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
1) T-loop phosphorylation
Three groups recently determined the crystal structure of GSK-3 (Bax et al., 2001; Dajani et al., 2001; ter Haar et al., 2001). The structure has provided insight into both its regulation and its preference for primed, pre-phosphorylated substrates. Protein kinases related to GSK-3, such as CDK2, p38 and ERK2, require phosphorylation of residues in their activation loops (T-loops) as a prerequisite for activity (Bellon et al., 1999; Brown et al., 1999; Canagarajah et al., 1997). A phosphothreonine is used by all three related kinases to align key ß-strand and -helical domains. The phosphorylation of a T-loop tyrosine is also required by p38 and ERK2 to open up the catalytic site for substrate access. The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3ß and GSK-3, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate-binding site, but there appear to be no constraints preventing the open conformation in the unphosphorylated state (Dajani et al., 2001). Thus, T-loop tyrosine phosphorylation of GSK-3 might facilitate substrate phosphorylation but is not strictly required for kinase activity (Dajani et al., 2001).

GSK-3 has an unusual preference for target proteins that are pre-phosphorylated at a `priming' residue located C-terminal to the site of GSK-3 phosphorylation (Fiol et al., 1987). The consensus sequence for GSK-3 substrates is Ser/Thr—X—X—X-Ser/Thr-P, where the first Ser or Thr is the target residue, X is any amino acid (but often Pro), and the last Ser-P/Thr-P is the site of priming phosphorylation. Although not strictly required, priming phosphorylation greatly increases the efficiency of substrate phosphorylation of most GSK-3 substrates by 100-1000-fold (Thomas et al., 1999). For example, glycogen synthase, the prototypical primed substrate, requires priming phosphorylation by casein kinase II (CK2) and then undergoes sequential multisite phosphorylation by GSK-3 (Fiol et al., 1988; Fiol et al., 1990).

The function expected for the `missing' phosphothreonine in the GSK-3's T-loop is believed to be replaced by the phosphorylated residue of a primed substrate, which binds to a positively charged pocket comprising R96, R180 and K205 (residue numbers for GSK-3ß). This not only optimizes the orientation of the kinase domains but also places the substrate at the correct position within the catalytic groove for phosphorylation to occur. There are some substrates that lack a priming site. These proteins often display negatively charged residues at or near the priming position that may mimic a phospho-residue.

2) Inhibitory serine phosphorylation
Stimulation of cells with insulin causes inactivation of GSK-3 through a phosphoinositide 3-kinase (PI 3-kinase)-dependent mechanism. PI-kinase-induced activation of PKB (also termed Akt) results in PKB phosphorylation of both GSK-3 isoforms (S9 of GSK-3ß; S21 of GSK-3) (Cross et al., 1995), which inhibits GSK-3 activity. This leads to the dephosphorylation of substrates including glycogen synthase and eukaryotic protein synthesis initiation factor-2B (eIF-2B), resulting in their functional activation and consequent increased glycogen and protein synthesis (reviewed in Cohen et al., 1997).

Numerous other stimuli also lead to inactivation of GSK-3 through S9/S21 phosphorylation, including growth factors such as EGF and PDGF that stimulate the GSK-3-inactivating kinase p90^RSK (also known as MAPKAP-K1) through MAP kinases (Brady et al., 1998; Saito et al., 1994), activators of p70 ribosomal S6 kinase (p70S6K) such as amino acids, (Armstrong et al., 2001; Krause et al., 2002; Terruzzi et al., 2002), activators of cAMP-activated protein kinase (PKA) (Fang et al., 2000; Li et al., 2000; Tanji et al., 2002) and PKC activators (Ballou et al., 2001; Fang et al., 2002).

The crystal structure of GSK-3 also helps to explain the inhibitory role of this serine phosphorylation (see Fig. 2A). Phosphorylation of S9/S21 creates a primed pseudosubstrate that binds intramolecularly to the positively charged pocket mentioned above. This folding precludes phosphorylation of substrates because the catalytic groove is occupied. Note that the mechanism of inhibition is competitive. A consequence of this is that primed substrates, in high enough concentrations, out-compete the pseudosubstrate and thus become phosphorylated (Frame et al., 2001). Thus, although less efficient, unprimed substrates may provide a more accurate measure of GSK-3 activity in kinase assays performed in vitro. Mutation of Arg96 to alanine disrupts the pocket of positive charge (Fig. 2B) (Frame et al., 2001). Interestingly, although a peptide of 11 residues that matches the phosphorylated N-terminus of GSK-3ß peptide-11 competitively inhibits both primed and unprimed substrates, a truncated version of this peptide (NTptide-8) inhibits phosphorylation only of primed substrates (Frame et al., 2001). Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinase domain could potentially be very effective for selective inhibition of primed substrates.

View larger version (39K): [in this window] [in a new window]   Fig. 2. (A) Regulation of GSK-3ß activity by serine phosphorylation. In the resting cell, GSK-3ß is constitutively active. Both unprimed substrates and substrates phosphorylated by a priming kinase (PK) are capable of being phosphorylated by the active GSK-3ß. The priming phospho-residue at position N + 4, binds a pocket of positive charge arising from the arginine (R) and lysine (K) residues indicated. This directs a serine or threonine at position N to the active catalytic site (C.S.). When an inactivating kinase (IK) such as PKB/Akt phosphorylates GSK-3ß on serine 9 (S9), the phosphorylated N-terminus becomes a primed pseudo-substrate that occupies the positive binding pocket and active site of the enzyme, acting as a competitive inhibitor for true substrates. This prevents phosphorylation of any substrates. (B) Effect of mutating arginine 96 to alanine (R96A) on GSK-3ß activity. Since arginine 96 is a crucial component of the positive pocket that binds primed substrates, its mutation to an uncharged alanine residue disrupts the pocket so that primed substrates can no longer bind. The enzyme retains activity. Also, the S9-phosphorylated pseudosubstrate is no longer capable of inactivating the enzyme. As a consequence, GSK-3ß, whether S9-phosphorylated or not, can phosphorylate unprimed substrates, but not primed substrates. Note that unprimed and primed substrates interact with GSK-3 through different interfaces.

	Physiological roles for tyrosine phosphorylation

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
The physiological significance of phosphorylation of Y216 of GSK-3ß in mammalian cells is unclear, since this phosphorylation is constitutive in resting cells (Hughes et al., 1993). The kinase(s) responsible has not been identified, although the tyrosine kinase (Zak1) that phosphorylates the Y216 equivalent is known in the slime mould (Kim et al., 1999). Mammalian GSK-3ß expressed in bacteria shows evidence of autophosphorylation on tyrosine, serine and threonine residues, which raises the possibility that tyrosine phosphorylation of GSK-3 in mammalian cells is an autocatalytic event (Wang et al., 1994). GSK-3 immunoprecipitated from mammalian cells does not show this behaviour, however (Hughes et al., 1993).

Although GSK-3 is tyrosine phosphorylated in resting cells, the level may not be stoichiometric. Apoptotic stimuli such as staurosporine treatment or neurotrophic factor withdrawal increase GSK-3 activity and tyrosine phosphorylation in certain neuronal cell lines (Bhat et al., 2000; Bijur and Jope, 2001). Moreover, LPA, through a pathway involving the G proteins G₁₂ and G₁₃, also increases GSK-3 activity in neuronal cells at least in part through enhanced tyrosine phosphorylation of Y216/Y279 (Sayas et al., 2002). Since treatment of primary neurons with LPA results in neurite retraction, treatment of a neuroblastoma cell line, Neuro2A, results in cell rounding (Sayas et al., 2002), and LPA also causes apoptosis of adult neurons (Steiner et al., 2000), this provides further circumstantial evidence for a role for tyrosine phosphorylation in apoptosis.

Recent work has revealed two possible candidates for kinases that might tyrosine phosphorylate GSK-3 under these circumstances. Transient increases in intracellular calcium increase GSK-3-mediated phosphorylation of the microtubule-associated protein tau, and the increased GSK-3 activity is attributed to elevated GSK-3 tyrosine phosphorylation (Hartigan and Johnson, 1999). The tyrosine kinase that may be responsible for the phosphorylation of GSK-3 is proline-rich tyrosine kinase 2 (PYK2), a calcium-sensitive enzyme. Active, but not kinase-dead, PYK2 increases tyrosine phosphorylation of GSK-3 both in PYK2-transfected cells and in vitro, and PYK2 and GSK-3ß co-immunoprecipitate in cells transfected with PYK2 (Hartigan et al., 2001). The Fyn tyrosine kinase is another potential player: insulin treatment of SH-SY5Y cells for 1 minute causes an increase in association of Fyn with GSK-3ß, a transient increase in GSK-3ß activity with a concomitant transient increase in GSK-3ß phosphorylation on Y216 and a transient increase in tau phosphorylation. The short duration of insulin treatment is crucial for the observed increase in GSK-3 activity (Lesort et al., 1999). Prolonged treatment with insulin, besides the well characterized inhibition of GSK-3 through serine phosphorylation (discussed above), has also been reported to inhibit GSK-3 through tyrosine dephosphorylation in Chinese hamster ovary cells (Murai et al., 1996). Further characterization of the proposed GSK-3-phosphorylating tyrosine kinases is required to substantiate a role for them in physiological processes.

The role of tyrosine phosphorylation of GSK-3 in Dictyostelium is better understood. Zak1 is essential for activation of GSK-3 during developmental patterning and is regulated downstream of certain cyclic AMP receptors involved in chemotaxis (Kim et al., 1999; Plyte et al., 1999). Unfortunately, identification of a mammalian orthologue of Zak1 has so far proven elusive. Kim et al. have recently described an opposing role for a protein tyrosine phosphatase, which dephosphorylates GSK-3 on tyrosine residues and results in a prestalk fate (Kim et al., 2002). Interestingly, phosphorylation of two tyrosine residues, both residing in the activation loop of GSK-3, appears to be modulated by cAMP in Dictyostelium (Kim et al., 2002). Both of these tyrosine residues, Y214 and Y220, are conserved in mammals (Y216 and Y219, respectively). Thus, Y219 — in addition to Y216 — might therefore play a role in GSK-3 regulation in mammals.

	The role of GSK-3 in the Wnt/ß-catenin pathway

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
The Wnts are a family of secreted, cysteine-rich, glycosylated, protein ligands that influence cell growth, differentiation, migration and fate (Miller, 2002; Polakis, 2000; Smalley and Dale, 1999). Members of the Wnt family have been identified in organisms ranging in complexity from the cnidarian Hydra to humans; at least 19 different Wnts exist in mammals (Miller, 2002). Severe developmental defects usually occur in mice that have defective Wnt signalling. One of the pathways regulated by Wnt molecules is termed the canonical Wnt pathway or the Wnt/ß-catenin pathway (reviewed in Huelsken and Behrens, 2002; Polakis, 2000; Seidensticker and Behrens, 2000; Sharpe et al., 2001) (Fig. 3). Here, we limit discussion of Wnt signalling to this signalling pathway. Wnt signal transduction ultimately results in the activation of genes regulated by the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of architectural transcription factors (reviewed in Barker et al., 2000; Brantjes et al., 2002; Novak and Dedhar, 1999). The effector molecule responsible for activating TCF/LEF-responsive genes is ß-catenin, which serves as a transactivator that binds to DNA-bound TCF/LEFs. As in insulin signalling, GSK-3 plays a key inhibitory role in the Wnt pathway. In unstimulated cells, GSK-3 phosphorylates the N-terminal domain of ß-catenin, thereby targeting it for ubiquitylation and proteasomal degradation. Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism. The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, ß-catenin is dephosphorylated (van Noort et al., 2002) and escapes the ubiquitylation-dependent destruction machinery. Unphosphorylated ß-catenin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator. Mutations in ß-catenin that prevent its phosphorylation by GSK-3 (gain-of-function mutations) have been found in cancers of the skin, colon, prostate, liver, endometrium and ovary (reviewed in Polakis, 2000). Many of the components of the Wnt pathway, and their functional roles, were first identified in studies of the Wnt pathway in Drosophila melanogaster, which is driven by the Wnt homologue, Wingless (Dierick and Bejsovec, 1999; Manoukian and Woodgett, 2002; Siegfried and Perrimon, 1994). In Drosophila, the GSK-3 homologue is termed Shaggy (Bourouis et al., 1990) or Zeste-white3 (Siegfried et al., 1990).

View larger version (48K): [in this window] [in a new window]   Fig. 3. Central role of GSK-3 in the Wnt/ß-catenin pathway. In unstimulated cells, CKI phosphorylates ß-catenin on S45, priming it for subsequent phosphorylation by GSK-3 (S41, S37, S33), which targets ß-catenin for ubiquitylation and proteasomal degradation. The ankyrin repeat protein, Diversin (Div), may help recruit CKI to the destruction complex. Wnt stimulation activates the receptor Frizzled, which then signals through Dishevelled (Dvl), using an unclear mechanism, to inactivate ß-catenin phosphorylation. Unphosphorylated ß-catenin accumulates and then translocates to the nucleus where it transactivates genes regulated by TCF/LEF transcription factors. The GSK-3-binding protein (GBP/FRAT) may be involved in transmission of a Wnt signal by regulating binding of GSK-3 to the scaffold protein, axin.

Phosphorylation of ß-catenin by GSK-3 occurs in a complex sometimes referred to as the destruction complex, which consists minimally of the proteins GSK-3, ß-catenin, axin/conductin and adenomatous polyposis coli (APC) (Hinoi et al., 2000). APC is a tumour suppressor protein commonly deleted in familial adenomatous polyposis and sporadic colorectal cancer (Polakis, 1997). Axin (and a related protein known as conductin or axil) harbors several protein-protein interaction domains and serves as a scaffolding protein that holds together the elements of the ß-catenin destruction complex. Both Axin and APC are phosphorylated by GSK-3. Phosphorylation of axin by GSK-3 increases its stability and binding to ß-catenin (Ikeda et al., 1998; Jho et al., 1999; Yamamoto et al., 1999). Phosphorylation of APC increases its binding to ß-catenin (Rubinfeld et al., 1996).

Five groups have recently determined that ß-catenin is also a primed substrate for GSK-3, with casein kinase I (CKI) acting as the priming kinase (Amit et al., 2002; Hagen et al., 2002; Hagen and Vidal-Puig, 2002; Liu et al., 2002; Sakanaka, 2002; Yanagawa et al., 2002). CKI phosphorylates S45, which lies four residues C-terminal to three GSK-3 targets at serines S33, S37 and S41. As a priming kinase, CKI functions as a negative regulator of Wnt signalling since it promotes GSK-3 function. Such a role contrasts with that proposed in several previous reports, which identified CKI as a positive transducer of Wnt signalling (Gao et al., 2002; Kishida et al., 2001; Lee et al., 2001; McKay et al., 2001). CKI binds to axin and Dishevelled and phosphorylates not only ß-catenin but also axin, Dishevelled and APC. Polakis has proposed a model in which CKI can act as both a positive and a negative regulator of Wnt signalling (Polakis, 2002). In this model, CKI plays a role in the destruction complex as the priming kinase for GSK-3 and is required for transmission of the Wnt signal by assisting in the activation of Dishevelled, perhaps by increasing its affinity for signalling intermediates (see below). A novel ankyrin-repeat-containing protein, Diversin, has been reported to recruit CKI to the destruction complex (Schwarz-Romond et al., 2002).

These data raise the possibility that GSK-3 plays only a latent role in regulation of ß-catenin. For example, if CKI activity is directly regulated by Wnt signalling, then phosphorylation of S45 would act as the trigger for subsequent phosphorylation by GSK-3. In this scenario, the activity of GSK-3 could be totally independent of Wnt regulation. However, phosphorylation of S45 appears to be constitutive, at least in some cell types. Although S45 phosphorylation has been reported to decrease upon Wnt stimulation, the phosphospecific antibodies used in those studies also detect S41, one of the GSK-3 targets (Amit et al., 2002). Antibodies selective for phosphoserine 45 do not reveal changes in stoichiometry in response to Wnt (Liu et al., 2002). Clearly, cells have evolved complex mechanisms to titrate ß-catenin levels, presumably to allow multiple layers of control.

Another interesting player in the regulation of the Wnt pathway, at least in vertebrates, is a GSK-3-binding protein termed GBP (also known as FRAT) (Farr et al., 2000; Ferkey and Kimelman, 2002; Fraser et al., 2002; Sumoy et al., 1999; Yost et al., 1998). Binding of GBP to GSK-3 precludes GSK-3 from binding to axin and thus interferes with ß-catenin phosphorylation. A small peptide derived from FRAT called FRAT-tide is sufficient to prevent axin-GSK-3 interaction and prevents phosphorylation of both axin and ß-catenin (Thomas et al., 1999). Comparison of mutations that affect binding of GSK-3 to axin and GBP, as well as analysis of the crystal structure of a GSK-3-FRAT-tide complex, indicates that the binding sites on GSK-3 for GBP/FRAT and axin overlap (Bax et al., 2001; Ferkey and Kimelman, 2002; Fraser et al., 2002). Treatment of Xenopus embryo extracts with CKI increases binding of GBP to Dishevelled (Lee et al., 2001).

GBP also plays a role in the nuclear export of GSK-3 (Franca-Koh et al., 2002). A mutant of GSK-3 that cannot bind to GBP accumulates in the nucleus. Moreover, a peptide that interferes with GBP binding to GSK-3 causes endogenous GSK-3 to accumulate in the nucleus. These findings suggest that GBP regulates access of GSK-3 to substrates partitioned between nuclear and cytoplasmic compartments. Since there are two known mammalian GBP homologues (Freemantle et al., 2002), each with dynamically regulated expression patterns during development, GBP could play an important role in modulating GSK-3 function, especially during development. Rather surprisingly, GBP homologues have not been identified in Drosophila or C. elegans, which indicates that the protein is not a core component of canonical Wnt signalling.

A critical aspect of GSK function in the Wnt pathway is that GSK-3 appears to be insulated from regulators of GSK-3 that lie outside of the Wnt pathway. For example, insulin signalling leads to inhibition of GSK-3 via serine S9/S21 phosphorylation but does not cause accumulation of ß-catenin. Conversely, Wnt signalling does not affect insulin signalling (Ding et al., 2000; Yuan et al., 1999). How this insulation occurs is unclear, but it probably stems from the effective sequestration of a fraction of GSK-3 with axin in the destruction complex. Note that tissues from mice lacking GSK-3ß do not show evidence of accumulated ß-catenin even though total GSK-3 levels are reduced by 50% and there is zero cellular GSK-3ß. Immunoprecipitation of axin from these tissues reveals that GSK-3ß is simply replaced by GSK-3 (in wild-type cells, both GSK-3 and GSK-3ß are found bound to axin) (E. Rubie and J.R.W., unpublished). Since cellular levels of GSK-3 exceed those of axin, the destruction machinery compensates for the loss of GSK-3ß by substituting GSK-3.

	GSK-3 and the Hedgehog pathway

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Groups examining Hedgehog (Hh) signalling in Drosophila recently discovered yet another novel function for GSK-3 (Jia et al., 2002; Price and Kalderon, 2002). The Hh pathway is somewhat similar to the Wnt pathway: both Wnt and Hh are secreted signalling proteins involved in embryonic patterning that often work in concert (reviewed in Ingham and McMahon, 2001). Whereas the Wnt pathway uses ß-catenin to transduce its signals to the nucleus, the Hh pathway employs a protein called Cubitus interruptus (Ci) in flies or Gli in mammals (Ingham and McMahon, 2001). In the absence of a Hh signal, Ci is targeted for proteolysis. Unlike in Wnt signalling, proteolysis does not result in total degradation of Ci but instead processes it from a 155-residue form (Ci155) to a truncated 75-residue amino acid form (Ci75) that functions as a transcriptional repressor (Aza-Blanc et al., 1997). GSK-3, in combination with CKI and the priming kinase PKA, phosphorylates Ci155 to target it for proteolytic processing in the absence of a Hh signal (Jia et al., 2002; Price and Kalderon, 2002). Activation of Hh signalling results in translocation of full-length Ci155 to the nucleus, where it activates Hh target genes. As in the Wnt pathway, several of the molecules involved in Hh signal transduction have been implicated in cancer (reviewed in Taipale and Beachy, 2001). Notably, familial germline mutations in one allele of the Hh receptor, Patched, are associated with an almost complete penetrance of basal cell carcinoma (Johnson et al., 1996; Taipale, 2001). Although GSK-3 phosphorylation of the mammalian homologues of Ci has yet to be reported, all contain multiple GSK-3 consensus sites next to PKA sites (Ruis i Altaba, 1999; Jia et al., 2002). It seems likely, on the basis of the conservation of the Wnt pathway, that the Gli proteins will soon be confirmed as GSK-3 substrates.

	Other GSK-3 substrates

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Numerous putative GSK-3 substrates have roles in a wide spectrum of cellular processes, including glycogen metabolism, transcription, translation, cytoskeletal regulation, intracellular vesicular transport, cell cycle progression, circadian rhythm regulation and apoptosis. Phosphorylation of these substrates by GSK-3 is most often inhibitory, as in the cases of glycogen synthase, ß-catenin and Ci. Although a detailed description of the function of all of the substrates is beyond the scope of this review, a list of many of the best-characterized substrates as well as some newly identified substrates, with a brief description of their function and the role of GSK-3 phosphorylation, is shown in Table 1.

	Other GSK-3-binding proteins

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Besides GBP, axin and APC, several other new GSK-3-binding partners have recently been identified. The tumour-suppressor protein p53, for example, has recently been shown to bind and activate GSK-3 in the nucleus of neuroblastoma cells treated with camptothecin, a topoisomerase I inhibitor that causes DNA damage and subsequently elicits a p53 response (Watcharasit et al., 2002). The activation of GSK-3 occurs without changes in its phosphorylation and is restricted to nuclear GSK-3 and involves an unknown mechanism. In addition, a yeast two-hybrid screen identified the A-kinase-anchoring protein AKAP220 as a GSK-3-binding partner (Tanji et al., 2002). AKAPs are scaffolding proteins, and the interaction between AKAP220 and GSK-3 occurrs in a complex that also containsPKA and type 1 protein phosphatase. The interaction between AKAP220 and GSK-3 enhances PKA-mediated inhibition of GSK-3.

Presenilin 1 (PS1) is one of the two mammalian presenilins identified through association of mutations in these proteins with early-onset familial Alzheimer's disease. Besides having a role in proteolytic processing of proteins at the cell membrane such as amyloid precursor protein, presenilin also binds to ß-catenin and has been implicated in regulating its cellular levels. PS1 may also function as a scaffolding protein that binds PKA, GSK-3 and ß-catenin (Palacino et al., 2001). This novel quaternary complex functions in a similar manner to the axin complex, using PS1 to couple the priming phosphorylation by PKA (on S45 of ß-catenin) to subsequent phosphorylation by GSK-3.

	GSK-3 and human disease

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Many of the pathways that use GSK-3 as a regulator have links to human diseases. As described above, GSK-3 is a core component of two pathways involved in cell fate determination and morphology, the Wnt and Hedgehog pathways, which are both involved in several forms of human cancer. There are also numerous studies linking GSK-3 to Alzheimer's disease, on the basis of GSK-3-mediated hyperphosphorylation of tau, which is associated with neurofibrillary tangles, one of the hallmarks of Alzheimer's disease (reviewed in De Ferrari and Inestrosa, 2000; Maccioni et al., 2001; Mattson, 2001). The GSK-3 inhibitor lithium (Stambolic et al., 1996), used for decades as a therapy for bipolar disorder, also implicates GSK-3 activity in the underlying causes of this disease (Detera-Wadleigh, 2001; Gould and Manji, 2002; Manji et al., 1999). In support of a role for GSK-3 in mood regulation is the fact that another mood-stabilizing drug, valproate, also inhibits GSK-3, although probably through an indirect mechanism (Chen et al., 1999; De Sarno et al., 2002). Note that lithium and valproate also affect neuronal inositol metabolism, and their mood-stabilizing properties might be related to this effect (Williams, 2002; Hall et al., 2002; Li et al., 2002). Apart from a role in neurological pathologies, GSK-3 may also play a role in the development of non-insulin-dependent diabetes mellitus (NIDDM), a disease often associated with chronic inhibition of muscle glycogen synthase (reviewed in Kaidanovich and Eldar-Finkelman, 2002).

	Small molecule inhibitors of GSK-3

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
Given the association of abnormal GSK-3 activity and various human diseases, GSK-3 is emerging as a potential therapeutic target, particularly true where its over-expression may be linked to pathology — for example, in NIDDM and neurodegenerative diseases (Eldar-Finkelman, 2002) — but it may also be relevant for some of the more recently identified functions of GSK-3, such as its role in activating NF-kB, a well characterized target for anti-inflammatory agents (Hoeflich et al., 2000). The best-characterized inhibitor of GSK-3 is lithium (Klein and Melton, 1996; Stambolic et al., 1996). Although fairly specific for GSK-3, compared with other protein kinases, lithium also affects other enzymes, and a relatively high dose is required (Ki is mM) to inhibit GSK-3 activity in cell culture (Stambolic et al., 1996). The mode of inhibition is through competition for Mg²⁺ (Ryves and Harwood, 2001). Recently, the bivalent form of zinc, which mimics insulin action, has also been shown to inhibit GSK-3 when used at a concentration of 15 µM in a cell culture system (Ilouz et al., 2002). In vitro, another metal ion, beryllium, inhibits GSK-3 to half maximal activity at a concentration of 6 µM (Ryves et al., 2002).

Several new GSK-3 inhibitors have recently been developed, most of which are ATP competitive (Martinez et al., 2002a; Martinez et al., 2002b). A list of these drugs, their mode of action and some of their reported effects in cell culture and patients is shown in Table 2.

There may be a skeleton in the closet, however, for anti-GSK-3 therapeutics. In addition to the problem of its broad range of functions, inhibition of the enzyme could presumably lead to enhanced accumulation of ß-catenin, a known oncogene. To mitigate this complication, drugs that selectively target non-axin-associated GSK-3 would be desirable, especially for chronic diseases, such as diabetes. On the positive side, long-term lithium treatment is not associated with enhanced incidence of cancer, although the lithium-treated patient cohort is not typical of the general population.

	Perspectives

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 
An enzyme that has as many proposed substrates as GSK-3 requires numerous levels of regulation to confer signal-dependent specificity. Several different mechanisms regulating the phosphorylation of GSK-3 substrates have been described: (1) inactivation of GSK-3 through serine phosphorylation; (2) activation of GSK-3 through tyrosine phosphorylation; (3) inactivation of GSK-3 through tyrosine dephosphorylation; (4) covalent modification of substrates through priming phosphorylation; (5) inhibition or facilitation of GSK-3-mediated substrate phosphorylation through interaction of GSK-3 with binding or scaffolding proteins; (6) targeting of GSK-3 to different subcellular localizations; (7) differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity; and (8) integration of parallel signals conveyed by a single stimulus.

Although our understanding of GSK-3 regulation is increasing, there are still several outstanding issues: (1) putative GSK-3 substrates need to be verified and classified as to whether they require priming phosphorylation; (2) proteins that have been identified as GSK-3-interacting proteins require characterization to identify sites of interaction and mechanisms that regulating binding; (3) the mechanism of Wnt-mediated inactivation of GSK-3 remains to be established; (4) the basis for the specific requirement for GSK-3ß in regulating NFB function remains unclear (GSK-3 does not substitute); and (5) the specificity of newly emerging GSK-3 inhibitors must be validated.

GSK-3 has reliably and regularly provided surprises ever since its discovery, and several of these have proven to be new signalling paradigms. There is little reason to doubt that there are more revelations in store, but with enhanced tools, such as selective inhibitors, knockout mice and modified binding proteins, there is hope that the true cellular roles for this multi-talented kinase will be appreciated and its utility as a therapeutic target be realized. But there are certainly easier molecules to study...

	Acknowledgments

 
J.R.W. is a Canadian Institutes of Health Research (CIHR) Senior Scientist and International Scholar of the Howard Hughes Medical Institute and is supported by grants from the Canadian Institutes of Health Research, the Terry Fox Foundation and the National Cancer Institute of Canada. B.W.D. is supported by a CIHR post-doctoral fellowship.

	Footnotes

 
Also known as cell adhesion kinase beta; focal adhesion kinase 2; protein tyrosine kinase 2 beta, cell adhsion kinase beta, calcium-dependent kinase, realted adhesion focal tyrosine kinase.

Frequently rearranged in advanced T-cell lymphocytes

	References

Top Summary Introduction GSK-3 variants GSK-3 phosphorylation: insights... Physiological roles for tyrosine... The role of GSK-3... GSK-3 and the Hedgehog... Other GSK-3 substrates Other GSK-3-binding proteins GSK-3 and human disease Small molecule inhibitors of... Perspectives References

 

Ali, A., Hoeflich, K. P. and Woodgett, J. R. (2001). Glycogen synthase kinase-3: properties, functions, and regulation. Chem. Rev. 101,2527 -2540.[CrossRef][Medline]

Amit, S., Hatzubai, A., Birman, Y., Andersen, J. S., Ben-Shushan, E., Mann, M., Ben-Neriah, Y. and Alkalay, I. (2002). Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16,1066 -1076.[Abstract/Free Full Text]

Armstrong, J. L., Bonavaud, S. M., Toole, B. J. and Yeaman, S. J. (2001). Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J. Biol. Chem. 276,952 -956.[Abstract/Free Full Text]

Aza-Blanc, P., Ramirez-Weber, F. A., Laget, M. P., Schwartz, C. and Kornberg, T. B. (1997). Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89,1043 -1053.[CrossRef][Medline]

Ballou, L. M., Tian, P. Y., Lin, H. Y., Jiang, Y. P. and Lin, R. Z. (2001). Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptor. J. Biol. Chem. 276,40910 -40916.[Abstract/Free Full Text]

Barker, N., Morin, P. J. and Clevers, H. (2000). The Yin-Yang of TCF/beta-catenin signaling. Adv. Cancer Res. 77,1 -24.[Medline]

Bax, B., Carter, P. S., Lewis, C., Guy, A. R., Bridges, A., Tanner, R., Pettman, G., Mannix, C., Culbert, A. A., Brown, M. J. et al. (2001). The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. Structure (Camb) 9,1143 -1152.[Medline]

Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. and Crabtree, G. R. (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275,1930 -1934.[Abstract/Free Full Text]

Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. and Baltimore, D. (1995). Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376,167 -170.[CrossRef][Medline]

Bellon, S., Fitzgibbon, M. J., Fox, T., Hsiao, H. M. and Wilson, K. P. (1999). The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure Fold. Des. 7,1057 -1065.[Medline]

Benjamin, W. B., Pentyala, S. N., Woodgett, J. R., Hod, Y. and Marshak, D. (1994). ATP citrate-lyase and glycogen synthase kinase-3 beta in 3T3-L1 cells during differentiation into adipocytes. Biochem J. 300,477 -482.

Bhat, R. V., Shanley, J., Correll, M. P., Fieles, W. E., Keith, R. A., Scott, C. W. and Lee, C. M. (2000). Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc. Natl. Acad. Sci. USA 97,11074 -11079.[Abstract/Free Full Text]

Bijur, G. N. and Jope, R. S. (2001). Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J. Biol. Chem. 276,37436 -37442.[Abstract/Free Full Text]

Bourouis, M., Moore, P., Ruel, L., Grau, Y., Heitzler, P. and Simpson, P. (1990). An early embryonic product of the gene shaggy encodes a serine/threonine protein kinase related to the CDC28/cdc2+ subfamily. EMBO J. 9,2877 -2884.[Medline]

Boyle, W. J., Smeal, T., Defize, L. H., Angel, P., Woodgett, J. R., Karin, M. and Hunter, T. (1991). Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64,573 -584.[CrossRef][Medline]

Brady, M. J., Bourbonais, F. J. and Saltiel, A. R. (1998). The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells. J. Biol. Chem. 273,14063 -14066.[Abstract/Free Full Text]

Brantjes, H., Barker, N., van Es, J. and Clevers, H. (2002). TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. Biol. Chem. 383,255 -261.[CrossRef][Medline]

Breton, J. J. and Chabot-Fletcher, M. C. (1997). The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB. J. Pharmacol. Exp. Ther. 282,459 -466.[Abstract/Free Full Text]

Brown, N. R., Noble, M. E., Endicott, J. A. and Johnson, L. N. (1999). The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat. Cell Biol. 1,438 -443.[CrossRef][Medline]

Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H. and Goldsmith, E. J. (1997). Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90,859 -869.[CrossRef][Medline]

Carmichael, J., Sugars, K. L., Bao, Y. and Rubinsztein, D. C. (2002). GSK-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J. Biol. Chem. 277,33791 -33798.[Abstract/Free Full Text]

Chen, G., Huang, L. D., Jiang, Y. M. and Manji, H. K. (1999). The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J. Neurochem. 72,1327 -1230.[CrossRef][Medline]

Chu, B., Soncin, F., Price, B. D., Stevenson, M. A. and Calderwood, S. K. (1996). Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J. Biol. Chem. 271,30847 -30857.[Abstract/Free Full Text]

Coghlan, M. P., Culbert, A. A., Cross, D. A., Corcoran, S. L., Yates, J. W., Pearce, N. J., Rausch, O. L., Murphy, G. J., Carter, P. S., Roxbee Cox, L. et al. (2000). Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 7, 793-803.[CrossRef][Medline]

Cohen, P., Alessi, D. R. and Cross, D. A. (1997). PDK1, one of the missing links in insulin signal transduction? FEBS Lett. 410, 3-10.[CrossRef][Medline]

Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. and Hemmings, B. A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378,785 -789.[CrossRef][Medline]

Cross, D. A., Culbert, A. A., Chalmers, K. A., Facci, L., Skaper, S. D. and Reith, A. D. (2001). Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J. Neurochem. 77, 94-102.[Medline]

Dajani, R., Fraser, E., Roe, S. M., Young, N., Good, V., Dale, T. C. and Pearl, L. H. (2001). Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105,721 -732.[CrossRef][Medline]

Damiens, E., Baratte, B., Marie, D., Eisenbrand, G. and Meijer, L. (2001). Anti-mitotic properties of indirubin-3'-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene 20,3786 -37897.[CrossRef][Medline]

De Ferrari, G. V. and Inestrosa, N. C. (2000). Wnt signaling function in Alzheimer's disease. Brain Res Rev 33,1 -12.[CrossRef][Medline]

De Sarno, P., Li, X. and Jope, R. S. (2002). Regulation of Akt and glycogen synthase kinase-3beta phosphorylation by sodium valproate and lithium. Neuropharmacology 43,1158 -1164.[CrossRef][Medline]

Dent, P., Campbell, D. G., Hubbard, M. J. and Cohen, P. (1989). Multisite phosphorylation of the glycogen-binding subunit of protein phosphatase-1G by cyclic AMP-dependent protein kinase and glycogen synthase kinase-3. FEBS Lett. 248, 67-72.[CrossRef][Medline]

Dent, P., Lavoinne, A., Nakielny, S., Caudwell, F. B., Watt, P. and Cohen, P. (1990). The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature 348,302 -308.[CrossRef][Medline]

Detera-Wadleigh, S. D. (2001). Lithium-related genetics of bipolar disorder. Ann. Med. 33,272 -285.[Medline]

Diehl, J. A., Cheng, M., Roussel, M. F. and Sherr, C. J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12,3499 -3511.[Abstract/Free Full Text]

Dierick, H. and Bejsovec, A. (1999). Cellular mechanisms of wingless/Wnt signal transduction. Curr. Top. Dev. Biol. 43,153 -190.[Medline]

Ding, V. W., Chen, R. H. and McCormick, F. (2000). Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J. Biol. Chem. 275,32475 -32481.[Abstract/Free Full Text]

Eldar-Finkelman, H. (2002). Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol. Med. 8,126 -132.[CrossRef][Medline]

Eldar-Finkelman, H. and Krebs, E. G. (1997). Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc. Natl. Acad. Sci. USA 94,9660 -9664.[Abstract/Free Full Text]

Embi, N., Rylatt, D. B. and Cohen, P. (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107,519 -527.[Medline]

Fang, X., Yu, S., Tanyi, J. L., Lu, Y., Woodgett, J. R. and Mills, G. B. (2002). Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. Mol. Cell. Biol. 22,2099 -2110.[Abstract/Free Full Text]

Fang, X., Yu, S. X., Lu, Y., Bast, R. C., Jr, Woodgett, J. R. and Mills, G. B. (2000). Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl. Acad. Sci. USA 97,11960 -11965.[Abstract/Free Full Text]

Farr, G. H., 3rd, Ferkey, D. M., Yost, C., Pierce, S. B., Weaver, C. and Kimelman, D. (2000). Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification. J. Cell Biol. 148,691 -702.[Abstract/Free Full Text]

Ferkey, D. M. and Kimelman, D. (2002). Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin. J. Biol. Chem. 277,16147 -16152.[Abstract/Free Full Text]

Fiol, C. J., Mahrenholz, A. M., Wang, Y., Roeske, R. W. and Roach, P. J. (1987). Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J. Biol. Chem. 262,14042 -14048.[Abstract/Free Full Text]

Fiol, C. J., Haseman, J. H., Wang, Y. H., Roach, P. J., Roeske, R. W., Kowalczuk, M. and DePaoli-Roach, A. A. (1988). Phosphoserine as a recognition determinant for glycogen synthase kinase-3: phosphorylation of a synthetic peptide based on the G-component of protein phosphatase-1. Arch. Biochem. Biophys. 267,797 -802.[CrossRef][Medline]

Fiol, C. J., Wang, A., Roeske, R. W. and Roach, P. J. (1990). Ordered multisite protein phosphorylation. Analysis of glycogen synthase kinase 3 action using model peptide substrates. J. Biol. Chem. 265,6061 -6065.[Abstract/Free Full Text]

Fiol, C. J., Williams, J. S., Chou, C. H., Wang, Q. M., Roach, P. J. and Andrisani, O. M. (1994). A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. J. Biol. Chem. 269,32187 -32193.[Abstract/Free Full Text]

Forlenza, O. V., Spink, J. M., Dayanandan, R., Anderton, B. H., Olesen, O. F. and Lovestone, S. (2000). Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons. J. Neural. Transm. 107,1201 -1212.[CrossRef]

Frame, S. and Cohen, P. (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359,1 -16.[CrossRef][Medline]

Frame, S., Cohen, P. and Biondi, R. M. (2001). A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7,1321 -1327.[CrossRef][Medline]

Franca-Koh, J., Yeo, M., Fraser, E., Young, N. and Dale, T. C. (2002). The regulation of glycogen synthase Kinse-3 nuclear export by Frat/GBP. J. Biol. Chem. 277,43844 -43848.[Abstract/Free Full Text]

Fraser, E., Young, N., Dajani, R., Franca-Koh, J., Ryves, J., Williams, R. S., Yeo, M., Webster, M. T., Richardson, C., Smalley, M. J. et al. (2002). Identification of the Axin and Frat binding region of glycogen synthase kinase-3. J. Biol. Chem. 277,2176 -2185.[Abstract/Free Full Text]

Freemantle, S. J., Portland, H. B., Ewings, K., Dmitrovsky, F., DiPetrillo, K., Spinella, M. J. and Dmitrovsky, E. (2002). Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2. Gene 291, 17-27.[CrossRef][Medline]

Gao, Z. H., Seeling, J. M., Hill, V., Yochum, A. and Virshup, D. M. (2002). Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proc. Natl. Acad. Sci. USA 99,1182 -1187.[Abstract/Free Full Text]

Ghosh, S. and Karin, M. (2002). Missing pieces in the NF-kappaB puzzle. Cell 109,S81 -96.

Gould, T. D. and Manji, H. K. (2002). The Wnt signaling pathway in bipolar disorder. Neuroscientist 8, 497-511.[Abstract/Free Full Text]

Grimes, C. A. and Jope, R. S. (2001). The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog. Neurobiol. 65,391 -426.[CrossRef][Medline]

Hagen, T. and Vidal-Puig, A. (2002). Characterisation of the phosphorylation of beta-catenin at the GSK-3 priming site Ser45. Biochem. Biophys. Res. Commun. 294,324 -328.[CrossRef][Medline]

Hagen, T., di Daniel, E., Culbert, A. A. and Reith, A. D. (2002). Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells. J. Biol. Chem. 277,23330 -23335.[Abstract/Free Full Text]

Hall, A. C., Brennan, A., Goold, R. G., Cleverley, K., Lucas, F. R., Gordon-Weeks, P. R. and Salinas, P. C. (2002). Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons. Mol. Cell. Neurosci. 20,257 -270.[CrossRef][Medline]

Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P. and Anderton, B. H. (1992). Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett. 147,58 -62.[CrossRef][Medline]

Hartigan, J. A. and Johnson, G. V. (1999). Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J. Biol. Chem. 274,21395 -21401.[Abstract/Free Full Text]

Hartigan, J. A., Xiong, W. C. and Johnson, G. V. (2001). Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem. Biophys. Res. Commun. 284,485 -489.[CrossRef][Medline]

Hers, I., Tavare, J. M. and Denton, R. M. (1999). The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. FEBS Lett. 460,433 -436.[CrossRef][Medline]

Hinoi, T., Yamamoto, H., Kishida, M., Takada, S., Kishida, S. and Kikuchi, A. (2000). Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependent phosphorylation of beta-catenin and down-regulates beta-catenin. J. Biol. Chem. 275,34399 -34406.[Abstract/Free Full Text]

Hoeflich, K. P., Luo, J., Rubie, E. A., Tsao, M. S., Jin, O. and Woodgett, J. R. (2000). Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406,86 -90.[CrossRef][Medline]

Huelsken, J. and Behrens, J. (2002). The Wnt signalling pathway. J. Cell Sci. 115,3977 -3978.[Free Full Text]

Hughes, K., Ramakrishna, S., Benjamin, W. B. and Woodgett, J. R. (1992). Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. Biochem. J. 288,309 -314.

Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F. and Woodgett, J. R. (1993). Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12,803 -808.[Medline]

Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S. and Kikuchi, A. (1998). Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 17,1371 -1384.[CrossRef][Medline]

Ilouz, R., Kaidanovich, O., Gurwitz, D. and Eldar-Finkelman, H. (2002). Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: insight into the insulin-mimetic action of zinc. Biochem. Biophys. Res. Commun. 295,102 -106.[CrossRef][Medline]

Ingham, P. W. and McMahon, A. P. (2001). Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15,3059 -3087.[Free Full Text]

Jang, M. K., Goo, Y. H., Sohn, Y. C., Kim, Y. S., Lee, S. K., Kang, H., Cheong, J. and Lee, J. W. (2001). Ca2+/calmodulin-dependent protein kinase IV stimulates nuclear factor-kappa B transactivation via phosphorylation of the p65 subunit. J. Biol. Chem. 276,20005 -20010.[Abstract/Free Full Text]

Jho, E., Lomvardas, S. and Costantini, F. (1999). A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression. Biochem. Biophys. Res. Commun 266, 28-35.[CrossRef][Medline]

Jia, J., Amanai, K., Wang, G., Tang, J., Wang, B. and Jiang, J. (2002). Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416,548 -452.[CrossRef][Medline]

Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, A. G., Myers, R. M., Cox, D. R., Epstein, E. H., Jr et al. (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272,1668 -1671.[Abstract]

Kaidanovich, O. and Eldar-Finkelman, H. (2002). The role of glycogen synthase kinase-3 in insulin resistance and Type 2 diabetes. Expert Opin. Ther. Targets 6, 555-561.[CrossRef][Medline]

Khaled, M., Larribere, L., Bille, K., Aberdam, E., Ortonne, J. P., Ballotti, R. and Bertolotto, C. (2002). Glycogen synthase kinase 3b is activated by cAMP and plays an active role in the regulation of melanogenesis. J. Biol. Chem. 277,33690 -33697.[Abstract/Free Full Text]

Kim, L., Harwood, A. and Kimmel, A. R. (2002). Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates cell fate choice. Dev. Cell 3, 523-532.[CrossRef][Medline]

Kim, L., Liu, J. and Kimmel, A. R. (1999). The novel tyrosine kinase ZAK1 activates GSK3 to direct cell fate specification. Cell 99,399 -408.[CrossRef][Medline]

Kirschenbaum, F., Hsu, S. C., Cordell, B. and McCarthy, J. V. (2001). Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276,30701 -30707.[Abstract/Free Full Text]

Kishida, M., Hino, S., Michiue, T., Yamamoto, H., Kishida, S., Fukui, A., Asashima, M. and Kikuchi, A. (2001). Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase Iepsilon. J. Biol. Chem. 276,33147 -33155.[Abstract/Free Full Text]

Klein, P. S. and Melton, D. A. (1996). A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA 93,8455 -8459.[Abstract/Free Full Text]

Knockaert, M., Wieking, K., Schmitt, S., Leost, M., Grant, K. M., Mottram, J. C., Kunick, C. and Meijer, L. (2002). Intracellular targets of Paullones. Identification following affinity purification on immobilized inhibitor. J. Biol. Chem. 277,25493 -25501.[Abstract/Free Full Text]

Krause, U., Bertrand, L., Maisin, L., Rosa, M. and Hue, L. (2002). Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur. J. Biochem. 269,3742 -3750.[Medline]

Leclerc, S., Garnier, M., Hoessel, R., Marko, D., Bibb, J. A., Snyder, G. L., Greengard, P., Biernat, J., Wu, Y. Z., Mandelkow, E. M. et al. (2001). Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J. Biol. Chem. 276,251 -260.[Abstract/Free Full Text]

Lee, E., Salic, A. and Kirschner, M. W. (2001). Physiological regulation of [beta]-catenin stability by Tcf3 and CK1epsilon. J. Cell Biol. 154,983 -993.[Abstract/Free Full Text]

Leost, M., Schultz, C., Link, A., Wu, Y. Z., Biernat, J., Mandelkow, E. M., Bibb, J. A., Snyder, G. L., Greengard, P., Zaharevitz, D. W. et al. (2000). Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur. J. Biochem. 267,5983 -5994.[Medline]

Lesort, M., Jope, R. S. and Johnson, G. V. (1999). Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J. Neurochem. 72,576 -584.[CrossRef][Medline]

Li, M., Wang, X., Meintzer, M. K., Laessig, T., Birnbaum, M. J. and Heidenreich, K. A. (2000). Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol. Cell. Biol. 20,9356 -9363.[Abstract/Free Full Text]

Li, Q., van Antwerp, D., Mercurio, F., Lee, K. F. and Verma, I. M. (1999). Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284,321 -325.[Abstract/Free Full Text]

Li, X., Bijur, G. N. and Jope, R. S. (2002). Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord. 4,137 -144.[CrossRef][Medline]

Li, Y., Bharti, A., Chen, D., Gong, J. and Kufe, D. (1998). Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol. Cell. Biol. 18,7216 -7224.[Abstract/Free Full Text]

Liu, C., Li, Y., Semenov, M., Han, C., Baeg, G. H., Tan, Y., Zhang, Z., Lin, X. and He, X. (2002). Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108,837 -847.[CrossRef][Medline]

Lochhead, P. A., Coghlan, M., Rice, S. Q. and Sutherland, C. (2001). Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes 50,937 -946.[Abstract/Free Full Text]

Maccioni, R. B., Munoz, J. P. and Barbeito, L. (2001). The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch. Med. Res. 32,367 -381.[CrossRef][Medline]

Manji, H. K., Moore, G. J. and Chen, G. (1999). Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol. Psychiatry 46,929 -940.[CrossRef][Medline]

Manoukian, A. S. and Woodgett, J. R. (2002). Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv. Cancer Res. 84,203 -229.[Medline]

Martinek, S., Inonog, S., Manoukian, A. S. and Young, M. W. (2001). A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105,769 -779.[CrossRef][Medline]

Martinez, A., Alonso, M., Castro, A., Perez, C. and Moreno, F. J. (2002a). First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. J. Med. Chem. 45,1292 -1299.[CrossRef][Medline]

Martinez, A., Castro, A., Dorronsoro, I. and Alonso, M. (2002b). Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med. Res. Rev. 22,373 -384.[CrossRef][Medline]

Mattson, M. P. (2001). Neuronal death and GSK-3beta: a tau fetish? Trends Neurosci. 24,255 -256.

McKay, R. M., Peters, J. M. and Graff, J. M. (2001). The casein kinase I family in Wnt signaling. Dev. Biol. 235,388 -396.[CrossRef][Medline]

Meijer, L., Thunnissen, A. M., White, A. W., Garnier, M., Nikolic, M., Tsai, L. H., Walter, J., Cleverley, K. E., Salinas, P. C., Wu, Y. Z. et al. (2000). Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem. Biol. 7,51 -63.[CrossRef][Medline]

Mettey, Y., Gompel, M., Thomas, V., Garnier, M., Leost, M., Ceballos-Picot, I., Noble, M., Endicott, J., Vierfond, J. M. and Meijer, L. (2003). Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J. Med. Chem. 46,222 -236.[CrossRef][Medline]

Miller, J. R. (2002). The Wnts. Genome Biol. 3, REVIEWS3001.

Morfini, G., Szebenyi, G., Elluru, R., Ratner, N. and Brady, S. T. (2002). Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21,281 -293.[CrossRef][Medline]

Mukai, F., Ishiguro, K., Sano, Y. and Fujita, S. C. (2002). Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J. Neurochem. 81,1073 -1083.[CrossRef][Medline]

Murai, H., Okazaki, M. and Kikuchi, A. (1996). Tyrosine dephosphorylation of glycogen synthase kinase-3 is involved in its extracellular signal-dependent inactivation. FEBS Lett. 392,153 -160.[CrossRef][Medline]

Novak, A. and Dedhar, S. (1999). Signaling through beta-catenin and Lef/Tcf. Cell Mol. Life Sci. 56,523 -537.[CrossRef][Medline]

Palacino, J. J., Murphy, M. P., Murayama, O., Iwasaki, K., Fujiwara, M., Takashima, A., Golde, T. E. and Wolozin, B. (2001). Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion. J. Biol. Chem. 276,38563 -38569.[Abstract/Free Full Text]

Park, I. K., Roach, P., Bondor, J., Fox, S. P. and DePaoli-Roach, A. A. (1994). Molecular mechanism of the synergistic phosphorylation of phosphatase inhibitor-2. Cloning, expression, and site-directed mutagenesis of inhibitor-2. J. Biol. Chem. 269,944 -954.[Abstract/Free Full Text]

Plyte, S. E., O'Donovan, E., Woodgett, J. R. and Harwood, A. J. (1999). Glycogen synthase kinase-3 (GSK-3) is regulated during Dictyostelium development via the serpentine receptor cAR3. Development 126,325 -333.[Abstract]

Polakis, P. (1997). The adenomatous polyposis coli (APC) tumor suppressor. Biochim. Biophys. Acta 1332,F127 -F147.[Medline]

Polakis, P. (2000). Wnt signaling and cancer. Genes Dev. 14,1837 -1851.[Free Full Text]

Polakis, P. (2002). Casein Kinase 1: A Wnt'er of disconnect. Curr. Biol. 12, R499.[CrossRef][Medline]

Price, M. A. and Kalderon, D. (2002). Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108,823 -835.[CrossRef][Medline]

Pulverer, B. J., Fisher, C., Vousden, K., Littlewood, T., Evan, G. and Woodgett, J. R. (1994). Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. Oncogene 9,59 -70.[Medline]

Rothwarf, D. M. and Karin, M. (1999). The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. Sci STKE 1999, RE1.

Rubinfeld, B., Albert, I., Porfiri, E., Fiol, C., Munemitsu, S. and Polakis, P. (1996). Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 272,1023 -1026.[Abstract]

Ruiz i Altaba, A. (1999) Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 15,418 -425.[CrossRef][Medline]

Ryves, W. J. and Harwood, A. J. (2001). Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem. Biophys. Res. Commun. 280,720 -725.[CrossRef][Medline]

Ryves, W. J., Dajani, R., Pearl, L. and Harwood, A. J. (2002). Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites. Biochem. Biophys. Res. Commun. 290,967 -972.[CrossRef][Medline]

Saito, Y., Vandenheede, J. R. and Cohen, P. (1994). The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells. Biochem. J. 303, 27-31.

Sakanaka, C. (2002). Phosphorylation and regulation of beta-catenin by casein kinase I epsilon. J. Biochem. (Tokyo) 132,697 -703.[Abstract/Free Full Text]

Sayas, C. L., Avila, J. and Wandosell, F. (2002). Glycogen synthase kinase-3 is activated in neuronal cells by galpha 12 and galpha 13 by rho-independent and rho-dependent mechanisms. J. Neurosci. 22,6863 -6875.[Abstract/Free Full Text]

Schwabe, R. F. and Brenner, D. A. (2002). Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 283,G204 -G211.[Abstract/Free Full Text]

Schwarz-Romond, T., Asbrand, C., Bakkers, J., Kuhl, M., Schaeffer, H. J., Huelsken, J., Behrens, J., Hammerschmidt, M. and Birchmeier, W. (2002). The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev. 16,2073 -2084.[Abstract/Free Full Text]

Sears, R., Nuckolls, F., Haura, E., Taya, Y., Tamai, K. and Nevins, J. R. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14,2501 -2514.[Abstract/Free Full Text]

Seidensticker, M. J. and Behrens, J. (2000). Biochemical interactions in the wnt pathway. Biochim. Biophys. Acta 1495,168 -182.[Medline]

Sharpe, C., Lawrence, N. and Martinez Arias, A. (2001). Wnt signalling: a theme with nuclear variations. Bioessays 23,311 -318.[CrossRef][Medline]

Siegfried, E. and Perrimon, N. (1994). Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling. Bioessays 16,395 -404.[CrossRef][Medline]

Siegfried, E., Perkins, L. A., Capaci, T. M. and Perrimon, N. (1990). Putative protein kinase product of the Drosophila segment-polarity gene zeste-white3. Nature 345,825 -829.[CrossRef][Medline]

Singh, L. P., Denslow, N. D. and Wahba, A. J. (1996). Modulation of rabbit reticulocyte guanine nucleotide exchange factor activity by casein kinases 1 and 2 and glycogen synthase kinase 3. Biochemistry 35,3206 -3212.[CrossRef][Medline]

Smalley, M. J. and Dale, T. C. (1999). Wnt signalling in mammalian development and cancer. Cancer Metastasis Rev. 18,215 -230.[CrossRef][Medline]

Smith, D. G., Buffet, M., Fenwick, A. E., Haigh, D., Ife, R. J., Saunders, M., Slingsby, B. P., Stacey, R. and Ward, R. W. (2001). 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg. Med. Chem. Lett. 11,635 -639.[CrossRef][Medline]

Stambolic, V., Ruel, L. and Woodgett, J. R. (1996). Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6,1664 -1668.[CrossRef][Medline]

Steiner, M. R., Holtsberg, F. W., Keller, J. N., Mattson, M. P. and Steiner, S. M. (2000). Lysophosphatidic acid induction of neuronal apoptosis and necrosis. Ann. N Y Acad. Sci. 905,132 -141.[Medline]

Sumoy, L., Kiefer, J. and Kimelman, D. (1999). Conservation of intracellular Wnt signaling components in dorsal-ventral axis formation in zebrafish. Dev. Genes Evol. 209, 48-58.[CrossRef][Medline]

Taipale, J. and Beachy, P. A. (2001). The Hedgehog and Wnt signalling pathways in cancer. Nature 411,349 -354.[CrossRef][Medline]

Takeda, K., Takemoto, C., Kobayashi, I., Watanabe, A., Nobukuni, Y., Fisher, D. E. and Tachibana, M. (2000). Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Hum. Mol. Genet. 9, 125-132.[Abstract/Free Full Text]

Tanji, C., Yamamoto, H., Yorioka, N., Kohno, N., Kikuchi, K. and Kikuchi, A. (2002). A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta) and mediates protein kinase A-dependent inhibition of GSK-3beta. J. Biol. Chem. 277,36955 -36961.[Abstract/Free Full Text]

ter Haar, E., Coll, J. T., Austen, D. A., Hsiao, H. M., Swenson, L. and Jain, J. (2001). Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat. Struct. Biol. 8, 593-596.[CrossRef][Medline]

Terruzzi, I., Allibardi, S., Bendinelli, P., Maroni, P., Piccoletti, R., Vesco, F., Samaja, M. and Luzi, L. (2002). Amino acid- and lipid-induced insulin resistance in rat heart: molecular mechanisms. Mol. Cell. Endocrinol. 190,135 -145.[CrossRef][Medline]

Thomas, G. M., Frame, S., Goedert, M., Nathke, I., Polakis, P. and Cohen, P. (1999). A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. FEBS Lett. 458,247 -251.[CrossRef][Medline]

van Noort, M., Meeldijk, J., van der Zee, R., Destree, O. and Clevers, H. (2002). Wnt signaling controls the phosphorylation status of beta-catenin. J. Biol. Chem. 277,17901 -17905.[Abstract/Free Full Text]

Wang, Q. M., Fiol, C. J., DePaoli-Roach, A. A. and Roach, P. J. (1994). Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J. Biol. Chem. 269,14566 -14574.[Abstract/Free Full Text]

Wang, D., Westerheide, S. D., Hanson, J. L. and Baldwin, A. S., Jr (2000). Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J. Biol. Chem. 275,32592 -32597.[Abstract/Free Full Text]

Watcharasit, P., Bijur, G. N., Zmijewski, J. W., Song, L., Zmijewska, A., Chen, X., Johnson, G. V. and Jope, R. S. (2002). Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. Proc. Natl. Acad. Sci. USA 99,7951 -7955.[Abstract/Free Full Text]

Welsh, G. I. and Proud, C. G. (1993). Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem. J. 294,625 -629.

Williams, R. S., Cheng, L., Mudge, A. W. and Harwood, A. J. (2002). A common mechanism of action for three mood-stabilizing drugs. Nature 417,292 -295.[CrossRef][Medline]

Woodgett, J. R. (1990). Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9,2431 -2438.[Medline]

Woodgett, J. R. (2001). Judging a protein by more than its name: GSK-3. Sci STKE 2001,RE12 .

Woodgett, J. R. and Cohen, P. (1984). Multisite phosphorylation of glycogen synthase. Molecular basis for the substrate specificity of glycogen synthase kinase-3 and casein kinase-II (glycogen synthase kinase-5). Biochim. Biophys. Acta 788,339 -347.[CrossRef][Medline]

Yamamoto, H., Kishida, S., Kishida, M., Ikeda, S., Takada, S. and Kikuchi, A. (1999). Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J. Biol. Chem. 274,10681 -10684.[Abstract/Free Full Text]

Yanagawa, S., Matsuda, Y., Lee, J. S., Matsubayashi, H., Sese, S., Kadowaki, T. and Ishimoto, A. (2002). Casein kinase I phosphorylates the Armadillo protein and induces its degradation in Drosophila. EMBO J. 21,1733 -1742.[CrossRef][Medline]

Yost, C., Farr, G. H., 3rd, Pierce, S. B., Ferkey, D. M., Chen, M. M. and Kimelman, D. (1998). GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93,1031 -1041.[CrossRef][Medline]

Yost, C., Torres, M., Miller, J. R., Huang, E., Kimelman, D. and Moon, R. T. (1996). The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10,1443 -1454.[Abstract/Free Full Text]

Yuan, H., Mao, J., Li, L. and Wu, D. (1999). Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor-1 activation. J. Biol. Chem. 274,30419 -30423.[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

Related articles in JCS:

Multi-tasking with GSK3

JCS 2003 116: 702. [Full Text]  

This article has been cited by other articles:

				J. Jin, G.-L. Wang, X. Shi, G. J. Darlington, and N. A. Timchenko The Age-Associated Decline of Glycogen Synthase Kinase 3{beta} Plays a Critical Role in the Inhibition of Liver Regeneration Mol. Cell. Biol., July 15, 2009; 29(14): 3867 - 3880. [Abstract] [Full Text] [PDF]

				C. Morel, S. M. Carlson, F. M. White, and R. J. Davis Mcl-1 Integrates the Opposing Actions of Signaling Pathways That Mediate Survival and Apoptosis Mol. Cell. Biol., July 15, 2009; 29(14): 3845 - 3852. [Abstract] [Full Text] [PDF]

				T. M. E. Scales, S. Lin, M. Kraus, R. G. Goold, and P. R. Gordon-Weeks Nonprimed and DYRK1A-primed GSK3{beta}-phosphorylation sites on MAP1B regulate microtubule dynamics in growing axons J. Cell Sci., July 15, 2009; 122(14): 2424 - 2435. [Abstract] [Full Text] [PDF]

				I. T. Struewing, S. N. Durham, C. D. Barnett, and C. D. Mao Enhanced Endothelial Cell Senescence by Lithium-induced Matrix Metalloproteinase-1 Expression J. Biol. Chem., June 26, 2009; 284(26): 17595 - 17606. [Abstract] [Full Text] [PDF]

				M. Liedtke and M. L. Cleary Therapeutic targeting of MLL Blood, June 11, 2009; 113(24): 6061 - 6068. [Abstract] [Full Text] [PDF]

				G. Y. Oudit and J. M. Penninger Cardiac regulation by phosphoinositide 3-kinases and PTEN Cardiovasc Res, May 1, 2009; 82(2): 250 - 260. [Abstract] [Full Text] [PDF]

				Y.-W. Qiang, B. Hu, Y. Chen, Y. Zhong, B. Shi, B. Barlogie, and J. D. Shaughnessy Jr Bortezomib induces osteoblast differentiation via Wnt-independent activation of {beta}-catenin/TCF signaling Blood, April 30, 2009; 113(18): 4319 - 4330. [Abstract] [Full Text] [PDF]

				T. Force and J. R. Woodgett Unique and Overlapping Functions of GSK-3 Isoforms in Cell Differentiation and Proliferation and Cardiovascular Development J. Biol. Chem., April 10, 2009; 284(15): 9643 - 9647. [Abstract] [Full Text] [PDF]

				A. Plotnikov, B. Varghese, T. H. Tran, C. Liu, H. Rui, and S. Y. Fuchs Impaired Turnover of Prolactin Receptor Contributes to Transformation of Human Breast Cells Cancer Res., April 1, 2009; 69(7): 3165 - 3172. [Abstract] [Full Text] [PDF]

				M. T. Bengoechea-Alonso and J. Ericsson A Phosphorylation Cascade Controls the Degradation of Active SREBP1 J. Biol. Chem., February 27, 2009; 284(9): 5885 - 5895. [Abstract] [Full Text] [PDF]

				R. W. Tsika, C. Schramm, G. Simmer, D. P. Fitzsimons, R. L. Moss, and J. Ji Overexpression of TEAD-1 in Transgenic Mouse Striated Muscles Produces a Slower Skeletal Muscle Contractile Phenotype J. Biol. Chem., December 26, 2008; 283(52): 36154 - 36167. [Abstract] [Full Text] [PDF]

				C.-S. Hwang and A. Varshavsky Regulation of peptide import through phosphorylation of Ubr1, the ubiquitin ligase of the N-end rule pathway PNAS, December 9, 2008; 105(49): 19188 - 19193. [Abstract] [Full Text] [PDF]

				A. L. Franciscovich, A. D. V. Mortimer, A. A. Freeman, J. Gu, and S. Sanyal Overexpression Screen in Drosophila Identifies Neuronal Roles of GSK-3{beta}/shaggy as a Regulator of AP-1-Dependent Developmental Plasticity Genetics, December 1, 2008; 180(4): 2057 - 2071. [Abstract] [Full Text] [PDF]

				J. L. Larabee, K. DeGiusti, J. L. Regens, and J. D. Ballard Bacillus anthracis Edema Toxin Activates Nuclear Glycogen Synthase Kinase 3{beta} Infect. Immun., November 1, 2008; 76(11): 4895 - 4904. [Abstract] [Full Text] [PDF]

				T. Jin and L. Liu Minireview: The Wnt Signaling Pathway Effector TCF7L2 and Type 2 Diabetes Mellitus Mol. Endocrinol., November 1, 2008; 22(11): 2383 - 2392. [Abstract] [Full Text] [PDF]

				O. Sokolova, P. M. Bozko, and M. Naumann Helicobacter pylori Suppresses Glycogen Synthase Kinase 3{beta} to Promote {beta}-Catenin Activity J. Biol. Chem., October 24, 2008; 283(43): 29367 - 29374. [Abstract] [Full Text] [PDF]

				J.-M. Beaulieu and M. G. Caron Looking at Lithium: Molecular Moods and Complex Behaviour Mol. Interv., October 1, 2008; 8(5): 230 - 241. [Abstract] [Full Text] [PDF]

				D. M. Gupta, N. J. Panetta, M. T. Longaker, and H. P. Lorenz Tissue Engineering Applications for Cleft Palate Reconstruction Speech Science and Orofacial Disorders, October 1, 2008; 18(2): 73 - 86. [Abstract] [Full Text] [PDF]

				E. Beurel and R. S. Jope Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3 J. Biol. Chem., August 8, 2008; 283(32): 21934 - 21944. [Abstract] [Full Text] [PDF]

				J. Mankouri, A. Milward, K. R. Pryde, L. Warter, A. Martin, and M. Harris A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B J. Gen. Virol., August 1, 2008; 89(8): 1911 - 1920. [Abstract] [Full Text] [PDF]

				Y.-W. Qiang, J. D. Shaughnessy Jr, and S. Yaccoby Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth Blood, July 15, 2008; 112(2): 374 - 382. [Abstract] [Full Text] [PDF]

				T. Jin Mechanisms underlying proglucagon gene expression J. Endocrinol., July 1, 2008; 198(1): 17 - 28. [Abstract] [Full Text] [PDF]

				M. P. Flynn, E. T. Maizels, A. B. Karlsson, T. McAvoy, J.-H. Ahn, A. C. Nairn, and M. Hunzicker-Dunn Luteinizing Hormone Receptor Activation in Ovarian Granulosa Cells Promotes Protein Kinase A-Dependent Dephosphorylation of Microtubule-Associated Protein 2D Mol. Endocrinol., July 1, 2008; 22(7): 1695 - 1710. [Abstract] [Full Text] [PDF]

				K. Ganesan, T. Ivanova, Y. Wu, V. Rajasegaran, J. Wu, M. H. Lee, K. Yu, S. Y. Rha, H. C. Chung, B. Ylstra, et al. Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel {beta}-Catenin/TCF Target Gene Cancer Res., June 1, 2008; 68(11): 4277 - 4286. [Abstract] [Full Text] [PDF]

				R. O. Nunes, M. Schmidt, G. Dueck, H. Baarsma, A. J. Halayko, H. A. M. Kerstjens, H. Meurs, and R. Gosens GSK-3/{beta}-catenin signaling axis in airway smooth muscle: role in mitogenic signaling Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1110 - L1118. [Abstract] [Full Text] [PDF]

				N. Izumi, K. Fumoto, S. Izumi, and A. Kikuchi GSK-3{beta} Regulates Proper Mitotic Spindle Formation in Cooperation with a Component of the {gamma}-Tubulin Ring Complex, GCP5 J. Biol. Chem., May 9, 2008; 283(19): 12981 - 12991. [Abstract] [Full Text] [PDF]

				T. M. Thornton, G. Pedraza-Alva, B. Deng, C. D. Wood, A. Aronshtam, J. L. Clements, G. Sabio, R. J. Davis, D. E. Matthews, B. Doble, et al. Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3{beta} Inactivation Science, May 2, 2008; 320(5876): 667 - 670. [Abstract] [Full Text] [PDF]

				F. Yi, J. Sun, G. E. Lim, I. G. Fantus, P. L. Brubaker, and T. Jin Cross Talk between the Insulin and Wnt Signaling Pathways: Evidence from Intestinal Endocrine L Cells Endocrinology, May 1, 2008; 149(5): 2341 - 2351. [Abstract] [Full Text] [PDF]

				C. Ma, K. A. Bower, G. Chen, X. Shi, Z.-J. Ke, and J. Luo Interaction between ERK and GSK3{beta} Mediates Basic Fibroblast Growth Factor-induced Apoptosis in SK-N-MC Neuroblastoma Cells J. Biol. Chem., April 4, 2008; 283(14): 9248 - 9256. [Abstract] [Full Text] [PDF]

				X. Liu, J. D. Allen, J. T. Arnold, and M. R. Blackman Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells Carcinogenesis, April 1, 2008; 29(4): 816 - 823. [Abstract] [Full Text] [PDF]

				M. Hayakawa, M. Matsushima, H. Hagiwara, T. Oshima, T. Fujino, K. Ando, K. Kikugawa, H. Tanaka, K. Miyazawa, and M. Kitagawa Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCF(FWD1/beta-TrCP)-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1. Genes Cells, April 1, 2008; 13(4): 329 - 342. [Abstract] [Full Text] [PDF]

				R. Gong, A. Rifai, Y. Ge, S. Chen, and L. D. Dworkin Hepatocyte Growth Factor Suppresses Proinflammatory NF{kappa}B Activation through GSK3{beta} Inactivation in Renal Tubular Epithelial Cells J. Biol. Chem., March 21, 2008; 283(12): 7401 - 7410. [Abstract] [Full Text] [PDF]

				Y. Leng, M.-H. Liang, M. Ren, Z. Marinova, P. Leeds, and D.-M. Chuang Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition J. Neurosci., March 5, 2008; 28(10): 2576 - 2588. [Abstract] [Full Text] [PDF]

				A. Plotnikov, Y. Li, T. H. Tran, W. Tang, J. P. Palazzo, H. Rui, and S. Y. Fuchs Oncogene-Mediated Inhibition of Glycogen Synthase Kinase 3{beta} Impairs Degradation of Prolactin Receptor Cancer Res., March 1, 2008; 68(5): 1354 - 1361. [Abstract] [Full Text] [PDF]

				V. Hongisto, J. C. Vainio, R. Thompson, M. J. Courtney, and E. T. Coffey The Wnt Pool of Glycogen Synthase Kinase 3{beta} Is Critical for Trophic-Deprivation-Induced Neuronal Death Mol. Cell. Biol., March 1, 2008; 28(5): 1515 - 1527. [Abstract] [Full Text] [PDF]

				U. Ullmann, C. Gilles, M. De Rycke, H. Van de Velde, K. Sermon, and I. Liebaers GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the up-regulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions Mol. Hum. Reprod., March 1, 2008; 14(3): 169 - 179. [Abstract] [Full Text] [PDF]

				H. Witte, D. Neukirchen, and F. Bradke Microtubule stabilization specifies initial neuronal polarization J. Cell Biol., February 6, 2008; 180(3): 619 - 632. [Abstract] [Full Text] [PDF]

				P. Hayward, T. Kalmar, and A. Martinez Arias Wnt/Notch signalling and information processing during development Development, February 1, 2008; 135(3): 411 - 424. [Abstract] [Full Text] [PDF]

				L. Wan, H. Niu, B. Futcher, C. Zhang, K. M. Shokat, S. J. Boulton, and N. M. Hollingsworth Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast Genes & Dev., February 1, 2008; 22(3): 386 - 397. [Abstract] [Full Text] [PDF]

				K. Unfried, U. Sydlik, K. Bierhals, A. Weissenberg, and J. Abel Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L358 - L367. [Abstract] [Full Text] [PDF]

				T.-S. Cheng, Y.-L. Hsiao, C.-C. Lin, C.-T. R. Yu, C.-M. Hsu, M.-S. Chang, C.-I Lee, C.-Y. F. Huang, S.-L. Howng, and Y.-R. Hong Glycogen Synthase Kinase 3 Interacts with and Phosphorylates the Spindle-associated Protein Astrin J. Biol. Chem., January 25, 2008; 283(4): 2454 - 2464. [Abstract] [Full Text] [PDF]

				M. O. Nowicki, N. Dmitrieva, A. M. Stein, J. L. Cutter, J. Godlewski, Y. Saeki, M. Nita, M. E. Berens, L. M. Sander, H. B. Newton, et al. Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3 Neuro-oncol, January 1, 2008; 10(5): 690 - 699. [Abstract] [Full Text] [PDF]

				R. Liao and T. Force Not All Hypertrophy Is Created Equal Circ. Res., November 26, 2007; 101(11): 1069 - 1072. [Full Text] [PDF]

				S. Hirotani, P. Zhai, H. Tomita, J. Galeotti, J. P. Marquez, S. Gao, C. Hong, A. Yatani, J. Avila, and J. Sadoshima Inhibition of Glycogen Synthase Kinase 3{beta} During Heart Failure Is Protective Circ. Res., November 26, 2007; 101(11): 1164 - 1174. [Abstract] [Full Text] [PDF]

				X. Zhang, M.-T. Ling, Q. Wang, C.-K. Lau, S. C. L. Leung, T. K. Lee, A. L. M. Cheung, Y.-C. Wong, and X. Wang Identification of a Novel Inhibitor of Differentiation-1 (ID-1) Binding Partner, Caveolin-1, and Its Role in Epithelial-Mesenchymal Transition and Resistance to Apoptosis in Prostate Cancer Cells J. Biol. Chem., November 16, 2007; 282(46): 33284 - 33294. [Abstract] [Full Text] [PDF]

				P. Zhai, S. Gao, E. Holle, X. Yu, A. Yatani, T. Wagner, and J. Sadoshima Glycogen Synthase Kinase-3{alpha} Reduces Cardiac Growth and Pressure Overload-induced Cardiac Hypertrophy by Inhibition of Extracellular Signal-regulated Kinases J. Biol. Chem., November 9, 2007; 282(45): 33181 - 33191. [Abstract] [Full Text] [PDF]

				H. Yamamoto, S. K. Yoo, M. Nishita, A. Kikuchi, and Y. Minami Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2. Genes Cells, November 1, 2007; 12(11): 1215 - 1223. [Abstract] [Full Text] [PDF]

				R. Gosens, G. Dueck, E. Rector, R. O. Nunes, W. T. Gerthoffer, H. Unruh, J. Zaagsma, H. Meurs, and A. J. Halayko Cooperative regulation of GSK-3 by muscarinic and PDGF receptors is associated with airway myocyte proliferation Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1348 - L1358. [Abstract] [Full Text] [PDF]

				H. Umehara, T. Kimura, S. Ohtsuka, T. Nakamura, K. Kitajima, M. Ikawa, M. Okabe, H. Niwa, and T. Nakano Efficient Derivation of Embryonic Stem Cells by Inhibition of Glycogen Synthase Kinase-3 Stem Cells, November 1, 2007; 25(11): 2705 - 2711. [Abstract] [Full Text] [PDF]

				R. Mishra, M. K. Barthwal, G. Sondarva, B. Rana, L. Wong, M. Chatterjee, J. R. Woodgett, and A. Rana Glycogen Synthase Kinase-3beta Induces Neuronal Cell Death via Direct Phosphorylation of Mixed Lineage Kinase 3 J. Biol. Chem., October 19, 2007; 282(42): 30393 - 30405. [Abstract] [Full Text] [PDF]

				A. N. Abell, D. A. Granger, and G. L. Johnson MEKK4 Stimulation of p38 and JNK Activity Is Negatively Regulated by GSK3beta J. Biol. Chem., October 19, 2007; 282(42): 30476 - 30484. [Abstract] [Full Text] [PDF]

				F. De Santa, S. Albini, E. Mezzaroma, L. Baron, A. Felsani, and M. Caruso pRb-Dependent Cyclin D3 Protein Stabilization Is Required for Myogenic Differentiation Mol. Cell. Biol., October 15, 2007; 27(20): 7248 - 7265. [Abstract] [Full Text] [PDF]

				K. L. Failor, Y. Desyatnikov, L. A. Finger, and G. L. Firestone Glucocorticoid-Induced Degradation of Glycogen Synthase Kinase-3 Protein Is Triggered by Serum- and Glucocorticoid-Induced Protein Kinase and Akt Signaling and Controls {beta}-Catenin Dynamics and Tight Junction Formation in Mammary Epithelial Tumor Cells Mol. Endocrinol., October 1, 2007; 21(10): 2403 - 2415. [Abstract] [Full Text] [PDF]

				T. P. Ciaraldi, S. E. Nikoulina, R. A. Bandukwala, L. Carter, and R. R. Henry Role of Glycogen Synthase Kinase-3{alpha} in Insulin Action in Cultured Human Skeletal Muscle Cells Endocrinology, September 1, 2007; 148(9): 4393 - 4399. [Abstract] [Full Text] [PDF]

				C. Feng, A. Yu, Y. Liu, J. Zhang, Z. Zong, W. Su, Z. Zhang, D. Yu, Q.-Y. Sun, and B. Yu Involvement of Protein Kinase B/AKT in Early Development of Mouse Fertilized Eggs Biol Reprod, September 1, 2007; 77(3): 560 - 568. [Abstract] [Full Text] [PDF]

				L. Li, K. Kozlowski, B. Wegner, T. Rashid, T. Yeung, C. Holmes, and B. J. Ballermann Phosphorylation of TIMAP by Glycogen Synthase Kinase-3beta Activates Its Associated Protein Phosphatase 1 J. Biol. Chem., August 31, 2007; 282(35): 25960 - 25969. [Abstract] [Full Text] [PDF]

				C. Ma, J. Wang, Y. Gao, T.-W. Gao, G. Chen, K. A. Bower, M. Odetallah, M. Ding, Z. Ke, and J. Luo The Role of Glycogen Synthase Kinase 3{beta} in the Transformation of Epidermal Cells Cancer Res., August 15, 2007; 67(16): 7756 - 7764. [Abstract] [Full Text] [PDF]

				K. Schlessinger, E. J. McManus, and A. Hall Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity J. Cell Biol., July 24, 2007; 178(3): 355 - 361. [Abstract] [Full Text] [PDF]

				A. V. Ougolkov, N. D. Bone, M. E. Fernandez-Zapico, N. E. Kay, and D. D. Billadeau Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor {kappa}B target genes and induction of apoptosis in chronic lymphocytic leukemia B cells Blood, July 15, 2007; 110(2): 735 - 742. [Abstract] [Full Text] [PDF]

				S. Taurin, K. Hogarth, N. Sandbo, D. M. Yau, and N. O. Dulin G{beta}{gamma}-mediated Prostacyclin Production and cAMP-dependent Protein Kinase Activation by Endothelin-1 Promotes Vascular Smooth Muscle Cell Hypertrophy through Inhibition of Glycogen Synthase Kinase-3 J. Biol. Chem., July 6, 2007; 282(27): 19518 - 19525. [Abstract] [Full Text] [PDF]

				P. Chen, Z. Gu, W. Liu, and Z. Yan Glycogen Synthase Kinase 3 Regulates N-Methyl-D-aspartate Receptor Channel Trafficking and Function in Cortical Neurons Mol. Pharmacol., July 1, 2007; 72(1): 40 - 51. [Abstract] [Full Text] [PDF]

				S. Bose, M A. Farah, H.-C. Jung, J.-H. Lee, and Y. Kim Molecular mechanism of bis(maltolato)oxovanadium(IV)-induced insulin signaling in 3T3-L1 and IM9 cells: impact of dexamethasone J. Mol. Endocrinol., June 1, 2007; 38(6): 627 - 649. [Abstract] [Full Text] [PDF]

				Q. Ding, X. He, J.-M. Hsu, W. Xia, C.-T. Chen, L.-Y. Li, D.-F. Lee, J.-C. Liu, Q. Zhong, X. Wang, et al. Degradation of Mcl-1 by {beta}-TrCP Mediates Glycogen Synthase Kinase 3-Induced Tumor Suppression and Chemosensitization Mol. Cell. Biol., June 1, 2007; 27(11): 4006 - 4017. [Abstract] [Full Text] [PDF]

				R. Baron and G. Rawadi Targeting the Wnt/{beta}-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton Endocrinology, June 1, 2007; 148(6): 2635 - 2643. [Abstract] [Full Text] [PDF]

				R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells J. Biol. Chem., April 20, 2007; 282(16): 12030 - 12037. [Abstract] [Full Text] [PDF]

				J. W. Tullai, J. Chen, M. E. Schaffer, E. Kamenetsky, S. Kasif, and G. M. Cooper Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent Cells J. Biol. Chem., March 30, 2007; 282(13): 9482 - 9491. [Abstract] [Full Text] [PDF]

				F. Neria, C. Caramelo, H. Peinado, F. R. Gonzalez-Pacheco, J. JP. Deudero, A. J. de Solis, R. Fernandez-Sanchez, S. Penate, A. Cano, and M{a} A. Castilla Mechanisms of endothelial cell protection by blockade of the JAK2 pathway Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1123 - C1131. [Abstract] [Full Text] [PDF]

				V. A.M. van de Schans, S. W.M. van den Borne, A. E. Strzelecka, B. J.A. Janssen, J. L.J. van der Velden, R. C.J. Langen, A. Wynshaw-Boris, J. F.M. Smits, and W. M. Blankesteijn Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy Hypertension, March 1, 2007; 49(3): 473 - 480. [Abstract] [Full Text] [PDF]

				M. Wrzaczek, W. Rozhon, and C. Jonak A Proteasome-regulated Glycogen Synthase Kinase-3 Modulates Disease Response in Plants J. Biol. Chem., February 23, 2007; 282(8): 5249 - 5255. [Abstract] [Full Text] [PDF]

				E. Rodionova, M. Conzelmann, E. Maraskovsky, M. Hess, M. Kirsch, T. Giese, A. D. Ho, M. Zoller, P. Dreger, and T. Luft GSK-3 mediates differentiation and activation of proinflammatory dendritic cells Blood, February 15, 2007; 109(4): 1584 - 1592. [Abstract] [Full Text] [PDF]

				M.-H. Liang and D.-M. Chuang Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival J. Biol. Chem., February 9, 2007; 282(6): 3904 - 3917. [Abstract] [Full Text] [PDF]

				E. I. Danek, J. Tcherkezian, I. Triki, M. Meriane, and N. Lamarche-Vane Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site J. Biol. Chem., February 9, 2007; 282(6): 3624 - 3631. [Abstract] [Full Text] [PDF]

				I. Oinuma, H. Katoh, and M. Negishi R-Ras Controls Axon Specification Upstream of Glycogen Synthase Kinase-3beta through Integrin-linked Kinase J. Biol. Chem., January 5, 2007; 282(1): 303 - 318. [Abstract] [Full Text] [PDF]

				D. Morrow, C. Sweeney, Y. A. Birney, S. Guha, N. Collins, P. M. Cummins, R. Murphy, D. Walls, E. M. Redmond, and P. A. Cahill Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo Am J Physiol Cell Physiol, January 1, 2007; 292(1): C488 - C496. [Abstract] [Full Text] [PDF]

				S. Naska, K. J. Park, G. E. Hannigan, S. Dedhar, F. D. Miller, and D. R. Kaplan An Essential Role for the Integrin-Linked Kinase-Glycogen Synthase Kinase-3{beta} Pathway during Dendrite Initiation and Growth J. Neurosci., December 20, 2006; 26(51): 13344 - 13356. [Abstract] [Full Text] [PDF]

				I. Shiojima and K. Walsh Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway Genes & Dev., December 15, 2006; 20(24): 3347 - 3365. [Abstract] [Full Text] [PDF]

				V. Rider, K. Isuzugawa, M. Twarog, S. Jones, B. Cameron, K. Imakawa, and J. Fang Progesterone initiates Wnt-{beta}-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells J. Endocrinol., December 1, 2006; 191(3): 537 - 548. [Abstract] [Full Text] [PDF]

				S. Seng, H. K. Avraham, S. Jiang, S. Venkatesh, and S. Avraham KLHL1/MRP2 Mediates Neurite Outgrowth in a Glycogen Synthase Kinase 3{beta}-Dependent Manner Mol. Cell. Biol., November 15, 2006; 26(22): 8371 - 8384. [Abstract] [Full Text] [PDF]

				T. P. Ciaraldi, D. K. Oh, L. Christiansen, S. E. Nikoulina, A. P. S. Kong, S. Baxi, S. Mudaliar, and R. R. Henry Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E891 - E898. [Abstract] [Full Text] [PDF]

				R. Ilouz, N. Kowalsman, M. Eisenstein, and H. Eldar-Finkelman Identification of Novel Glycogen Synthase Kinase-3beta Substrate-interacting Residues Suggests a Common Mechanism for Substrate Recognition J. Biol. Chem., October 13, 2006; 281(41): 30621 - 30630. [Abstract] [Full Text] [PDF]

				M.-H. Liang and D.-M. Chuang Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation J. Biol. Chem., October 13, 2006; 281(41): 30479 - 30484. [Abstract] [Full Text] [PDF]

				A. Gartner, X. Huang, and A. Hall Neuronal polarity is regulated by glycogen synthase kinase-3 (GSK-3{beta}) independently of Akt/PKB serine phosphorylation J. Cell Sci., October 1, 2006; 119(19): 3927 - 3934. [Abstract] [Full Text] [PDF]

				A. V. Ougolkov, M. E. Fernandez-Zapico, V. N. Bilim, T. C. Smyrk, S. T. Chari, and D. D. Billadeau Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3{beta} in Human Pancreatic Cancer: Association with Kinase Activity and Tumor Dedifferentiation Clin. Cancer Res., September 1, 2006; 12(17): 5074 - 5081. [Abstract] [Full Text] [PDF]

				J. Prickaerts, D. Moechars, K. Cryns, I. Lenaerts, H. van Craenendonck, I. Goris, G. Daneels, J. A. Bouwknecht, and T. Steckler Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J. Neurosci., August 30, 2006; 26(35): 9022 - 9029. [Abstract] [Full Text] [PDF]

				A. Hergovich, J. Lisztwan, C. R. Thoma, C. Wirbelauer, R. E. Barry, and W. Krek Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3 Mol. Cell. Biol., August 1, 2006; 26(15): 5784 - 5796. [Abstract] [Full Text] [PDF]

				S. J. Crozier, X. Zhang, J. Wang, J. Cheung, S. R. Kimball, and L. S. Jefferson Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion J Appl Physiol, August 1, 2006; 101(2): 576 - 582. [Abstract] [Full Text] [PDF]

				M.-A. Arevalo and A. Rodriguez-Tebar Activation of Casein Kinase II and Inhibition of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Phosphatase by Nerve Growth Factor/p75NTR Inhibit Glycogen Synthase Kinase-3beta and Stimulate Axonal Growth Mol. Biol. Cell, August 1, 2006; 17(8): 3369 - 3377. [Abstract] [Full Text] [PDF]

				P. Biswas, S. Canosa, D. Schoenfeld, J. Schoenfeld, P. Li, L. C. Cheas, J. Zhang, A. Cordova, B. Sumpio, and J. A. Madri PECAM-1 Affects GSK-3{beta}-Mediated {beta}-Catenin Phosphorylation and Degradation Am. J. Pathol., July 1, 2006; 169(1): 314 - 324. [Abstract] [Full Text] [PDF]

				A. Vines, S. Cahoon, I. Goldberg, U. Saxena, and S. Pillarisetti Novel Anti-inflammatory Role for Glycogen Synthase Kinase-3beta in the Inhibition of Tumor Necrosis Factor-{alpha}- and Interleukin-1beta-induced Inflammatory Gene Expression J. Biol. Chem., June 23, 2006; 281(25): 16985 - 16990. [Abstract] [Full Text] [PDF]

				A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M. O. Carruba, et al. Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3beta J. Biol. Chem., May 5, 2006; 281(18): 12950 - 12958. [Abstract] [Full Text] [PDF]

				S. Chien Mechanical and Chemical Regulation of Endothelial Cell Polarity Circ. Res., April 14, 2006; 98(7): 863 - 865. [Full Text] [PDF]

				X. Cai, M. Li, J. Vrana, and M. D. Schaller Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement. Mol. Cell. Biol., April 1, 2006; 26(7): 2857 - 2868. [Abstract] [Full Text] [PDF]

				W. Yan and H.-H. Tai Glycogen Synthase Kinase-3 Phosphorylation, T-Cell Factor Signaling Activation, and Cell Morphology Change following Stimulation of Thromboxane Receptor {alpha} J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 267 - 274. [Abstract] [Full Text] [PDF]

				C. L. Sayas, A. Ariaens, B. Ponsioen, and W. H. Moolenaar GSK-3 Is Activated by the Tyrosine Kinase Pyk2 during LPA1-mediated Neurite Retraction Mol. Biol. Cell, April 1, 2006; 17(4): 1834 - 1844. [Abstract] [Full Text] [PDF]

				M.-J. Boucher, L. Selander, L. Carlsson, and H. Edlund Phosphorylation Marks IPF1/PDX1 Protein for Degradation by Glycogen Synthase Kinase 3-dependent Mechanisms J. Biol. Chem., March 10, 2006; 281(10): 6395 - 6403. [Abstract] [Full Text] [PDF]

				X. Wu, F. Quondamatteo, T. Lefever, A. Czuchra, H. Meyer, A. Chrostek, R. Paus, L. Langbein, and C. Brakebusch Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes & Dev., March 1, 2006; 20(5): 571 - 585. [Abstract] [Full Text] [PDF]

				I. Goren, E. Muller, J. Pfeilschifter, and S. Frank Severely Impaired Insulin Signaling in Chronic Wounds of Diabetic ob/ob Mice: A Potential Role of Tumor Necrosis Factor-{alpha} Am. J. Pathol., March 1, 2006; 168(3): 765 - 777. [Abstract] [Full Text] [PDF]

				L. Yin, J. Wang, P. S. Klein, and M. A. Lazar Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science, February 17, 2006; 311(5763): 1002 - 1005. [Abstract] [Full Text] [PDF]

This Article Summary Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doble, B. W. Articles by Woodgett, J. R. Search for Related Content PubMed PubMed Citation Articles by Doble, B. W. Articles by Woodgett, J. R. Social Bookmarking                         What's this?