glycogen synthase kinase-3 ( gsk-3 ) is a cmgc serine / threonine protein kinase initially described as one of the kinases that phosphorylates and inhibits glycogen synthase .
it is now widely accepted though that gsk-3 plays an important role in various essential physiological processes , such as development , cell cycle , or apoptosis . apart from glycogen synthase
, a plethora of different substrates has been identified in all cellular compartments , that is , metabolic proteins , cytoskeletal proteins , and transduction   and transcription factors   ( see table 1 ) . in neuronal development , gsk-3 has been reported to control morphogenesis and axonal polarity , synaptogenesis , and survival [ 9 , 10 ] .
in addition , gsk-3 dysfunction has been associated with brain pathological conditions , such as alzheimer 's disease ( ad ) [ 11 , 12 ] or prion neurotoxicity .
thus , the deep knowledge of the role of both gsk-3 isoforms in brain metabolism will allow us to understand their contribution to neurodegenerative processes .
gsk-3 unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular bases of these disorders .
furthermore , gsk-3 appears to be a cellular nexus , integrating several signalling systems , including numerous second messengers and a wide selection of cellular stimulants .
gsk-3 has been highly conserved during evolution , and homolog genes have been identified in virtually every eukaryotic genome investigated , including species , such as dictyostelium discoideum , xenopus laevis , or drosophila melanogaster [ 1416 ] . in mammals ,
gsk-3 is encoded by two genes known as gsk-3 and gsk-3 [ 17 , 18 ] encoding gsk-3 ( 483 aa in humans ) and gsk-3 ( 433 aa ) proteins with apparent molecular masses of 51 and 47  kda , respectively .
both isoforms are almost identical ( 98% ) within their atp binding pocket but differ at their n- and c - terminal domains .
a neuron - specific splicing isoform ( 2 ) having an insertion of 13 aa within the substrate - binding domain has also been described .
mammalian gsk-3 and  are each widely expressed although some tissues show preferential levels of some of the two proteins .
crystallographic studies have revealed the three - dimensional structure of gsk-3 [ 21 , 22 ] .
its overall shape is shared by all kinases , with a small n - terminal lobe mostly consisting of -sheets and a large c - terminal lobe essentially formed of -helices .
the atp binding pocket is located between the two lobes and although , is well conserved among kinases , it is possible to obtain selective inhibitors by taking advantage of the small differences that exist between the different kinases .
current availability of crystal structures of complexes of gsk-3 with a variety of ligands , together with molecular modelling approaches , provides the necessary clues for enhancing selectivity towards gsk-3 .
some gsk-3 substrates do not require a very specific sequence , but rather a previous ( primed ) phosphorylation by a priming kinase on a ser or thr residue located four aminoacids , c - terminal to the ser or thr residue to be modified by gsk-3 ( see below for regulation through primed phosphorylation ) .
the crystal structure of human gsk-3 has provided a model for the binding of prephosphorylated substrates to the kinase . according to it ,
primed ser / thr is recognized by a positively charged binding pocket formed by residues arg96 ,
arg180 , and lys205 that facilitates the binding of the phosphate group of primed substrates .
gsk3 uses the phosphorylated serine or threonine at position + 4 of the substrate to align of the two domains for optimal catalytic activity [ 21 , 22 ] .
furthermore , crystal structures of gsk-3 complexes with interacting proteins frat / gbp and axin have allowed defining the molecular basis for those interactions , which play critical role in some signalling pathways ( see below for regulation through protein complex formation ) .
these studies confirm the partial overlap of the binding sites of axin and frat1/gbp predicted from genetic and biochemical studies [ 2 , 25 ] but reveal significant differences in the detailed interactions and identify key residues mediating the differential interaction with both proteins .
this ability of gsk-3 to bind two different proteins with high specificity via the same binding site is mediated by the conformational plasticity of the 285299 loop , while some residues in this versatile binding site are involved in interactions with both axin and frat ; others are involved uniquely with one or the other .
as already mentioned above , one of the main characteristics of gsk-3 is that its activity is high in resting , unstimulated cells while regulated by extracellular signals that typically induce a rapid and reversible decrease in enzymatic activity .
glycogen synthase kinase-3 is a dual specificity kinase differentially regulated by tyrosine and serine / threonine phosphorylation . and
for many years , it was believed to be a constitutively active kinase ; however , it has become apparent that the activity of gsk-3 may be regulated by a variety of means .
in fact , control of gsk-3 activity occurs by complex mechanisms that are each dependent upon specific signalling pathways .
the first regulatory mechanism described of gsk-3 activity involved the phosphorylation of specific residues of gsk-3 by other kinases , and more recently through autophosphorylation [ 17 , 28 ] .  
the first one corresponds with a serine residue at positions 21 in gsk-3 and 9 in gsk-3. it has been clearly established that phosphorylation of serine 21 or 9 correlates with the inhibition of its kinase activity [ 2931 ] .
many protein kinases are capable of phosphorylating gsk-3 at this residue , such as akt , ilk , pka , and p90rsk [ 32 , 33 ] , and many physiological situations of inhibition of gsk-3 correlate with serine phosphorylation , such as insulin / igf1 , ngf , or estradiol treatments , not only in neurons .
one is the threonine 43 , present only in the isoform gsk-3 , which    may be phosphorylated by erk .
second , serine 389 and threonine 390 present in gsk-3 have been shown to be phosphorylated by p38 mapk . in both cases , the data suggested that this phosphorylation may increase the capacity of ser-9 to be phosphorylated rather than promote a direct inhibition ( see figure 1 ) .
in contrast , tyrosine phosphorylation present in positions 279 in gsk-3 or 216 in gsk-3 , appears to correlate with an increase of its kinase activity .
different candidates such as pyk-2 and fyn kinases have been reported to be able to phosphorylate gsk-3 in vitro on tyrosine .
in addition , mek1/2 has been showed to have this capacity only in fibroblasts [ 38 , 39 ] .
this data contrast with those reported in dictyostelium discoideum where there is compelling evidence indicating that zak 1 is responsible for generating tyrosine phosphorylation in gsk-3 [ 14 , 40 ] .
more recently , an alternative hypothesis has been proposed for the regulation of gsk-3 tyrosine phosphorylation .
this hypothesis suggests that in mammalian systems phosphotyrosine in gsk-3 corresponds to an intramolecular autophosphorylation event and may be regulated by hsp90 .
molecular dynamics and crystallographic studies clearly suggest that tyr216 renders the kinase active through interactions with arg220 and arg223 , stabilizing the activation loop and allowing full substrate accessibility [ 42 , 43 ]
. however , this hypothesis still lacks a cellular demonstration .   however , our data indicated that not all pharmacological inhibitors of gsk-3 decrease the level of phosphotyrosine
. therefore , lithium chloride inhibits gsk-3 activity , but this inhibition does not alter its ptyr content . moreover , in neuronal cells , tyrosine phosphorylation of residue 216 or 279 increased following exposure to lpa   and even upon exposure of neurons to -amyloid or prp [ 13 , 45 , 46 ] in a clear correlation with an increase in gsk-3 activity .
in addition , in many neuronal cells , the pharmacological inhibition of tyrosine phosphatases with ortho - vanadate increases the basal level of gsk-3-ptyr .
thus , considering all these data , in addition to this tantalizing autoregulatory system proposed , we hypothesized that some as - yet - unidentified tyrosine kinases and phosphatases may also regulate this kinase ( see figure 2 ) .
one regulatory mechanism that is still not fully understood involves the interaction of the gsk-3 with structural proteins ( scaffold proteins ) .
it is well known that gsk-3 contributes to a multiprotein complex formed by axin and adenomatous polyposis coli ( apc ) , among others ( for review see , i.e. , ) .
indeed , in the absence of ligand , gsk-3 is able to phosphorylate -catenin for targeting it for proteasome degradation .
more recently , some data suggests that this complex may be specific for gsk-32 isoform , which opens the possibility of a deeper analysis of  specific functions of gsk-3 isoforms . 
another system of protein - kinase interaction was denoted as gsk-3-binding protein ( gbp or frat ) [ 25 , 50 ] .
three different frats have been cloned and characterized ; however , their mechanism of action is not well understood .
frat1 appears to act as an inhibitory system , whereas frat2 appears to preferentially increase gsk-3-mediated phosphorylation in some residues .
surprisingly , recent data demonstrated that frat is dispensable because the triple frat - knockout mouse lacks any major defect in brain development .
all these data indicated that the precise role of frat in gsk-3 regulation is still to be defined .    using the binding site on gsk-3 for frat / gbp ,
gskip can block phosphorylation of different substrates and functions as a negative regulator of gsk-3 beta .
as previously mentioned , the specificity of many kinases is governed by a consensus sequence of aminoacids sequence . however , as almost general rule , gsk-3 substrates do not require a very specific sequence , but a previous ( primed ) phosphorylation residue modified by a priming kinase located four aminoacids , c - terminal , to the ser or thr residue to be modified by gsk-3 .
the crystal structure of human gsk-3 provides a model for the binding of prephosphorylated substrates to the kinase ( pdb i d are 1i09   and 1h8f ) . according to it ,
primed ser / thr is recognized by a positively charged binding pocket formed by residues arg96 ,
arg180 , and lys205 that facilitates the binding of the phosphate group of primed substrates .
some  priming kinases  have been identified , such as cdk-5 [ 5557 ] , par-1 , casein kinase i , pk - c , or pk - a . however , it is not clear so far whether a second set of  nonprimed  substrates may define a different group of functions .
in addition , different glycogen synthase kinase-3 isoforms appear to exhibit distinct substrate preference in the brain . in developmental brain ,
the presence of gsk-3 was high at e18 and peaked on p8 , decreasing after that period .
in addition , this report showed that the developmental profile of gsk-3 and gsk-3 is different , having  downregulated after birth which suggested a differential role in neuronal development .
however , the putative differential role of each isoform has been explored in few reports , that is , .
it is important to indicate that a portion of gsk-3 , mostly  , has been reported to be associated in the growth cone .
this gsk-3 pool appears to respond rapidly , being modified by phosphorylation and/or relocated in the growth cone by external signals such as semaphorins   or ngf .  
gsk-3 activity is also dependent on its subcellular localization ; some data illustrated the presence of gsk-3 and  in many neuronal compartments and in primary neurons , either in axon , dendrite , or in nucleus [ 66 , 67 ] .
in addition , gsk-3 has been found in the cytoplasm , nucleus and the mitochondria .
considering the list of gsk-3 substrates reported , it is evident that most of its activity should occur in the cytoplasm and in the nucleus , while we have less information about gsk-3 potential targets in the mitochondria .
recent data suggested that proteins such as mcl-1   and hexokinase   may be regulated by gsk-3 activity .
it has been suggested that nuclear gsk-3 may be involved in phosphorylation of many transcription factors such as cyclin d1 , -catenin , hsf-1 , nfat , and camp - response element - binding protein , among others ( table 1 ) , for review see [ 28 , 70 , 71 ] .
also , it has been proposed that gsk-3 in the nucleus may have a role in alternative splicing .
in addition , proapoptotic stimuli induce nuclear accumulation of gsk-3 ; however , this hypothesis has been not established in other neuronal death paradigms ( d. simon , unpublished observations ) .  
further insight into gsk-3 regulation has been gained very recently by revealing an essential role of multivesicular endosomes in the wnt signalling pathway .
a combination of protease protection assays , detergent permeabilization , and cryoimmunoelectron microscopy demonstrated that wnt activation of the frizzled and lrp6 receptors triggers sequestration of gsk-3 into these membrane - bounded organelles , leading to decreased gsk-3 levels in the cytosol .
this process seems to require -catenin , forming a feed - forward loop by facilitating gsk-3 sequestration .
this regulation involves the removal by calpain of a fragment from the n - terminal region of gsk-3 , including the regulatory serines 9/21 .
the same study showed that both isoforms  and  are cleaved by calpain , although with different susceptibility .
it is noteworthy to consider that a similar mechanism has been described for -catenin in hippocampal neurons , where after nmda - receptor - dependent activation , calpain induced the cleavage of -catenin at the n terminus , generating stable and truncated forms which maintain its transcriptional capacity . likewise
, gsk-3 truncation is mediated by extracellular calcium and can be inhibited by memantine , an nmda antagonist used for the treatment of alzheimer 's disease .
interestingly , gsk-3 has also been recently shown to be cleaved at the n - terminus ( and subsequently activated ) by matrix metalloproteinase-2 ( mmp-2 ) in cardiomyoblasts .
the regulation of gsk-3 , as previously mentioned , is an essential regulatory key controlling many physiological processes in neurons .
many external signals may trigger pathways that finally may activate or inhibit gsk-3 activity , either transiently or in more sustained way . these  physiological pathways 
could be subdivided in two major clusters , those that essentially have to inhibit gsk-3 activity , and second , those that may , at least transiently , trigger gsk-3 activity . among these pathways ,
the signalling triggered by insulin or igf-1 [ 19 , 79 , 80 ] and ngf / bdnf / nt3 [ 81 , 82 ] has similar features .
these tyrosine kinase receptors initiated cytoplasm signals in which the inhibition of gsk-3 activity is a common feature .
it is generally accepted that the kinase implicated in this inhibition is pkb / akt [ 2931 ] , even though kinases such as pka or ilk have also been implicated [ 32 , 33 ] . in all cases , phosphorylation on serine 21 and 9 (  and  , resp . )
the second well - documented pathway is wnt / wingless signalling [ 83 , 84 ] .
this signalling has been widely studied , and it has been shown to be essential in early embryonic patterning , cell fate , cellular polarity , and cell movement in both vertebrates and invertebrates [ 47 , 85 ] . in many if not all cell systems , the canonical wnt pathway is formed by a set of phylogenetically conserved proteins including the wnt receptor frizzled ( fz ) , and a coreceptor lrp5/6 ; dishevelled ( dsh ) , and a scaffolding protein that activates a complex formed by axin / apc / gsk3-/-catenin [ 47 , 8588 ] .   in this pathway , in the absence of ligand , gsk-3 phosphorylates -catenin , among other proteins , this phosphorylation constituting part of a degradation signal for -catenin . however , in the presence of wnt , the receptor complex triggers a signal in which dsh inhibits the activity of gsk-3 by a mechanism not completely understood , so far .
this system appears to be specific for gsk-3 as no counterpart has been described for gsk-3 to date ; however , some gsk-3 activity appears to be necessary for wnt signalling [ 89 , 90 ] .
more recently , a bioinformatics - based screen for proteins whose stability may be controlled by gsk-3   has led to the identification of a number of multiple wnt signalling target proteins , suggesting that this pathway controls a broad range of cellular activities apart form -catenin - mediated transcriptional activation .
furthermore , gsk-3-mediated wnt signalling seems to regulate the turnover of many cellular proteins [ 74 , 91 ] , indicating that gsk-3 phosphorylation - dependent protein degradation may be a widespread cellular mechanism to regulate a variety of cellular processes in response to extracellular signals . functional segregation of the insulin / growth factor and wnt roles requires either that there be no exchange between the subsets of the cellular gsk-3 pool committed to each role , or that the recruitment of gsk-3 to the axin - apc complex can reverse or override inhibitory ser9 phosphorylation present in a recruited gsk-3 molecule .
phosphatases capable of removing extant ser9 phosphorylation are certainly known to be associated with the axin - apc complex [ 92 , 93 ] .
alternatively , the very substantial enhancement in activity towards -catenin afforded by the axin  scaffolding  may simply allow a primed -catenin substrate to outcompete a pser9-gsk-3 n - terminal peptide for access to the substrate - binding site .  
estrogens regulate many physiological processes and fulfil a wide range of functions during development and differentiation in mammals of both sexes .
the actions of estrogens are mediated by estrogen receptors and have been classified as either  genomic actions  or  nongenomic , rapid actions . 
the genomic actions are based on the capacity of the estrogen receptors ( ers ) to modulate transcriptional activity either directly or through coactivators or corepressors , that is , [ 94 , 95 ] .
more recently , it has been shown that in addition to its direct transcriptional activity , estrogen receptors activate a set of cytoplasm signals in a similar manner to some growth factors .
hence , it has been reported that estradiol acts synergistically with igf-1 in the brain or in neurons , activating the pi3k / akt pathway [ 34 , 96 , 97 ] .
this inhibitory phosphorylation is time- and concentration dependent , and an antagonist of estradiol prevents this event .
the kinase responsible is sensitive to the inhibition of the pi3k pathway , and for this reason , it seems that the best candidate would be akt [ 98 , 99 ] .
a more detailed analysis of these new signals will give us clear evidence whether this pathway is completely convergent with those using pi3k / akt / gsk3 , as previously mentioned . in neurons
, lpa has been shown to induce neurite retraction and the rounding up of neuroblastoma cell lines . in some primary neurons
, it also promotes growth cone collapse and neurite retraction [ 37 , 101 ] .
this bioactive lipid acts as a growth factor through specific seven transmembrane domain receptors , denoted as lpa 14 [ 102 , 103 ] .
we described that gsk3 activity was increased after lpa treatment in diverse neuronal cells of different species in correlation with the neurite retraction process [ 104 , 105 ] .
this activation correlated with an increase in gsk3-ptyr and may be downstream g12 or g13 [ 101 , 105 , 106 ] .
the previous inhibition of gsk3 activity prevents , at least in part , the growth cone collapse response .
similarly , it has been reported that three different gsk-3 antagonists ( licl , sb-216763 , and sb-415286 ) can inhibit the growth cone collapse response induced by sema 3a .    however , the exact mechanism of how this activation of gsk3 occurs is not known , so far .
many reports indicate that in dictyostelium discoideum gsk-3 activity may increase in response to camp binding to a heptahelical g - protein - coupled receptor . in this system , a tyrosine kinase and a tyrosine phosphatase have been described as regulators of gsk-3 activity [ 14 , 40 ] , but similar kinase and phosphatase have not been found in mammals .   
furthermore , it has been reported that reelin and netrin increased gsk-3 activity , similar to what lpa did .
this netrin or reelin - dependent gsk-3 activation seems not to be a particular characteristic of the cell line or neuron used but rather a more general physiological process [ 107109 ] . indeed , even in situations where the final balance is an inhibition of gsk-3 kinase activity , such as following the addition of igf1/insulin or after estradiol addition , a transient activation of gsk-3 could be observed [ 34 , 38 ] .
all these data suggest that the upregulation and downregulation of this kinase is more complex than might initially have been considered .
deregulation of gsk-3 has been linked to a wide range of human pathological conditions including type ii diabetes , muscle wasting , cancer and neurological disorders such as bipolar disorder , schizophrenia , depression , stroke , sleep disorders , and alzheimer 's disease ( ad ) , among others , for a review see .  
lithium and valproic acid are mood stabilizers widely used in the chronic treatment of bipolar disorders .
lithium ions directly inhibit gsk-3 , most likely by competing with magnesium , while valproic acid is able to inhibit gsk-3 activity in relevant therapeutic concentrations in human neuroblastoma cells   although in vivo direct inhibition of gsk-3 by valproic acid remains a matter of debate .
the precise mechanism of action by which lithium exerts its therapeutic effects is not known , but it is conceivable that the acute effects on gsk-3 result in changes in gene regulation and cellular changes which could affect the neuronal plasticity over time . actually , lithium is also an inhibitor of several phosphomonoesterases   and phosphoglucomutases , but the fact that gsk-3 has been shown to be significantly inhibited at therapeutic lithium concentrations [ 118120 ] suggests that at least a significant proportion of lithium 's therapeutic actions in bipolar disorder results from the inhibition of gsk-3 , underlying its importance as a therapeutic target for this disorder [ 121 , 122 ] .   lymphocytes of patients with schizophrenia show impaired gsk-3 protein levels and activity , whereas gsk-3 has been reported to be reduced in the frontal cortex of postmortem schizophrenic brains .
since the wnt family of genes plays a central role in normal brain development , it is possible that gsk-3 impairment may lead to abnormal neuronal development .
more recently , a direct association has been shown between gsk-3 and the n - terminal region of disrupted - in - schizophrenia-1 ( disc1 ) , a strong genetic risk factor associated with schizophrenia . moreover
, mounting evidence suggests that gsk-3 is a crucial node that mediates various cellular processes that are controlled by multiple signalling molecules such as disc-1 , par3 , par6 , and wnt proteins that regulate neurodevelopment .  
interestingly , increased levels of gsk-3 have also been reported in postmortem analysis of brains from ad patients compared to age - matched control samples , whereas a spatial and temporal pattern of increased active gsk-3 expression correlates with the progression of nft and neurodegeneration .
apart from being the major kinase to phosphorylate tau both in vitro and in vivo , gsk-3 has been recently proposed as the link between the two major histopathological hallmarks of ad , the extracellular amyloid plaques and the intracellular nft [ 129 , 130 ] .  
exposure of primary neuronal cultures to a induces activation of gsk-3 , tau phosphorylation , and cell death [ 133 , 134 ] , whereas blockade of gsk-3 expression by antisense oligonucleotides or its activity by lithium inhibits a-induced toxicity [ 135 , 136 ] .
gsk-3 inhibition per se decreases a production in cells and in an animal model of amyloidosis [ 61 , 120 ] , most likely through a mechanism involving inhibition of -secretase .
furthermore , amyloid precursor protein ( app ) itself is a substrate for gsk-3 in vitro and in vivo .
finally , modulation of the gsk-3 signalling pathway by chronic lithium treatment of transgenic animals might also have neuroprotective effects by regulating app maturation and processing . in tauopathies such as frontotemporal dementia with parkinsonism ( ftdp ) linked to chromosome 17 ,
the presence of some mutations in tau protein correlates with the onset of the disease [ 139 , 140 ] .
treatment of transgenic mice overexpressing mutant human tau ( p301l , 4ron ) , with the gsk-3 inhibitor lithium , has been shown to significantly decrease the levels of tau phosphorylation and significantly reduce the levels of aggregated , insoluble tau .
administration in this model of a second gsk-3 inhibitor , ar - a014418 , also correlated with reduced insoluble tau levels , supporting the notion that lithium exerts its effect through gsk-3 inhibition .
more recently , chronic lithium administration has also been shown to reduce tau phosphorylation in the 3xtg - ad mice , but did not significantly alter the amyloid load .
an increase in gsk-3 activity has also been shown to coincide with cell death following middle cerebral artery occlusion in mice which results in cortical infarcts , and a reduction in infarct volume with the gsk-3 inhibitor lithium was demonstrated , indicating that gsk-3 inhibition may be beneficial in stroke .
in fact , pharmacological inhibition of gsk-3 reduced infarct volume and improved behaviour in a focal cerebral ischemia model .
besides deregulation of its activity in neurodegenerative processes , mounting evidence further suggests a potential role for gsk-3 as a therapeutic target in a range or other pathologies , including pancreatic cancer , parenchymal renal diseases , and hiv-1-associated dementia , among others .   the recent discovery that glycogen synthase kinase-3 ( gsk-3 ) promotes inflammation through nuclear factor kappa b ( nfb ) has revealed new functions on regulating inflammatory processes .
furthermore , gsk-3 inhibition provides protection from inflammatory conditions in different animal model , suggesting that gsk-3 inhibitors may have multiple effects influencing these conditions . finally , recent developments suggest an active role of gsk-3 in various human cancers , although its role in tumourigenesis and cancer progression remains controversial . it may function as a  tumour suppressor  for certain types of tumours , whereas it seems to promote growth and development for some others .
deregulation of gsk-3 has been shown to promote gastrointestinal , pancreatic , and liver cancers and glioblastomas .
furthermore , gsk-3 inhibition attenuates cell survival and proliferation , induces cell senescence and apoptosis , and sensitizes tumour cells to chemotherapeutic agents   and ionizing radiation . nevertheless , an attractive target for a variety of human diseases , its therapeutic potential on tumourigenesis , and cancer chemotherapy still needs to be carefully evaluated .
the close involvement of gsk-3 activity in different human pathologies has sparked intense efforts in developing inhibitors as therapeutic agents .
thus , the discovery of small molecule gsk-3 inhibitors in the last few years has not only attracted significant attention to the protein as a therapeutic target but also has provided a means to further understand the physiological functions of gsk-3 and to gain further insight into the molecular basis of those disorders .  
in fact , at least one small molecule gsk-3 inhibitor program has made it to the clinic .
tideglusib ( np-12 ) is a synthetic small molecule form the tdzd chemical class   which is currently in phase ii development for two cns indications : alzheimer 's disease and progressive supranuclear palsy ( psp ) , a tauopathy .
three decades after its discovery as a protein kinase involved in glycogen metabolism , gsk-3 was revealed as a key enzyme in regulating many critical cellular processes , providing a link between many different substrates and various signalling pathways as well as gene expression .
modulation of its activity has also turned out to be much more complex than originally thought , as evident from what has been reviewed here .
furthermore , its role in a variety of highly relevant human pathological conditions has drawn significant attention to this enzyme as a potential therapeutic target , and the recent development of specific inhibitors has granted us new tools to dissect out its molecular and physiological functions while providing novel therapeutic agents . taken all together
, the next few years will certainly bring us further insights into the cellular functions of this fascinating enzyme .
 glycogen synthase kinase-3 ( gsk-3 ) unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular basis of these disorders . 
 gsk-3 is ubiquitously expressed and , unusually , constitutively active in resting , unstimulated cells . in mammals , gsk-3 and  
 are each expressed widely at both the rna and protein levels although some tissues show preferential levels of some of the two proteins . 
 neither gene appears to be acutely regulated at the transcriptional level , whereas the proteins are controlled posttranslationally , largely through protein - protein interactions or by posttranslational regulation . 
 control of gsk-3 activity thus occurs by complex mechanisms that are each dependent upon specific signalling pathways . 
 furthermore , gsk-3 appears to be a cellular nexus , integrating several signalling systems , including several second messengers and a wide selection of cellular stimulants . 
 this paper will focus on the different ways to control gsk-3 activity ( phosphorylation , protein complex formation , truncation , subcellular localization , etc . ) , the main signalling pathways involved in its control , and its pathological deregulation . 
1. Introduction
2. GSK-3 Structure
3. How Is GSK-3 Activity Controlled?
4. Pathways Controlling GSK-3 Activity in Neurons
5. Pathological Activation of GSK-3
6. GSK-3 as a Therapeutic Target
7. Conclusion