Review Article

What Are the bona fide GSK3 Substrates?

Table 2

-GSK3 inhibition in vivo. Potential functional outcomes of pharmacological inhibition of GSK3.

Substrate group 1—Metabolic: Overall Effect is anti-diabetic

GSIncrease glycogen synthesis and glucose disposal (anti-diabetic)
UnknownTurn off hepatic glucose output (anti-diabetic)
CREBReduce glucagon action (anti-diabetic)
IRS1Stabilise IRS1 protein and enhance insulin action (anti-diabetic)
Inhibitor2Inhibit PP1 (not clear if beneficial)

Substrate group 2—Growth: Predicted effect would be oncogenic, except for effect on mdm2/p53 and PTEN

BCL3Stabilise BCL3 (increased oncogenic potential)
c-junInduce c-jun activity (increased oncogenic potential)
c-mycStabilize c-myc protein (increased oncogenic potential)
Mcl-1Stabilise Mcl-1 (antiapoptotic)
p130RbIncrease p130Rb degradation (cell cycle progression)
PTENDecrease PI3K signaling (decrease growth factor signaling)
IRS1Stabilise IRS1 and enhance PI3K signaling (increase growth)
HIF1aStabilize HIF1a (could induce cell growth)
eIF2BEnhance protein translation (aid cell growth)
VDACEnhance VDAC interaction with mitochondria (antiapoptotic)
CTPSEnhance CTP production (aid cell growth)
FAKIncrease FAK activity (enhance cell spreading and migration)
Mdm2Stabilise p53 (tumour suppression)

Substrate group 3—Alzheimer’s disease: Conducive to reducing AD pathology

TauReduce tangle formation (anti-AD?)
APPReduce abeta production (anti-AD?)
CRMP2Regulate axon outgrowth, reduce CRMP2 found in AD (anti-AD?)
MARK2Reduce tau phosphorylation (anti-AD?)
CalcipressinRegulate calcineurin action (anti-AD?)

Substrate group 4—Wnt and Hh signaling: Enhanced effect on Wnt and Hh signaling

b-cateninInduce b-catenin levels (induce wnt signaling)
AxinReduce axin levels (induce wnt signaling)
APCReduce APC b-catenin interaction (induce wnt signaling)
Ci155Reduce proteolysis of Ci155 (enhanced Hh signaling)

Substrate group 5—Other possible detrimental effects:

MAP1BReduce MAP1B interaction with microtubules (Wnt7a resistance)
MAP2CIncrease MAP2C interaction with microtubules (effect not clear)
CLASP2Alteration of actin-microtubule interaction (effect not clear)
Dynamin IReduced presynaptic ADBE (effect not clear)
Ngn2Impaired motor neuron designation (developmental?)
PC2Relocalise PC2 (enhance polycystic kidney disease)
MyocardinEnhance mycardin action (cardiac hypertrophy?)
NFATNuclear localization (compromise immune system?)
UnknownSuppress IL-1β, IL-6, TNF, IL-12 (compromise immune system?)
UnknownInduction of IL-10 (compromise immune system?)