Trends in Molecular Medicine
ReviewGlycogen synthase kinase 3: an emerging therapeutic target
Section snippets
GSK-3 regulation
The GSK-3 enzyme and its unique properties have been described in recent comprehensive reviews 1, 2, 3. Mammalian GSK-3 exists as two isoforms, α and β, sharing 98% homology in their catalytic domain. Both isoforms are ubiquitously expressed in cells and tissues, and have similar (although not identical) biochemical properties. Unlike most protein kinases, GSK-3 is constitutively active in cells, and its activity can be inhibited by a variety of extracellular stimuli, including insulin,
Role of GSK-3 in insulin resistance and diabetes
Insulin resistance is an early change associated with the onset of non-insulin-dependent diabetes mellitus (NIDDM) or type 2 diabetes. The major defect in insulin resistance is the inability of peripheral tissues, such as muscle, liver and fat, to respond normally to physiological concentrations of insulin. Since one of the major characteristics of diabetic muscle is the severe inhibition of glycogen synthase and the loss of glycogen synthesis [20], it is reasonable to assume that a defect in
GSK-3 and tau
GSK-3 interacts with several neuronal proteins that are directly linked with Alzheimer's disease (AD). The microtubule-associated protein tau, a neuron-specific structural protein abundant in the brain, is a major component of neurofibrillary tangles, which are an intraneuronal aggregate of paired helical filaments (PHFs) and one of the most notable neuropathological hallmarks of AD, as reviewed in Ref. [34]. The tau protein in neurofibrillary tangles (also termed PHF-tau) is
GSK-3 and bipolar disorder
A notable recent development is the implication of a role for GSK-3 in psychiatric disorders. Lithium ions, used as a primary mood stabilizer in the chronic treatment of patients with bipolar disorder, were shown to be a selective inhibitor of GSK-3, as reviewed in Ref. [53]. A series of studies demonstrated that lithium ions mimic the loss of GSK-3 activity in intact cells. Lithium was shown to cause activation of glycogen synthesis [54], stabilization and accumulation of β-catenin [55],
GSK-3 inhibitors: a potential therapeutic approach
The paradigm that GSK-3 acts as a suppressor in signaling pathways points to a potential role for GSK-3 inhibitors in therapeutic interventions. Such inhibitors might be useful in pathological conditions associated with abnormally increased levels of GSK-3 activity such as type 2 diabetes and AD. In addition, specific inhibitors of GSK-3 mimic the therapeutic action of the mood stabilizers lithium and valproic acid and might therefore be plausible drugs in treating patients with bipolar
References (61)
- et al.
The multifaceted roles of glycogen synthase kinase 3β in cellular signaling
Prog. Neurobiol.
(2001) Mitogen-activated protein kinase activation is not sufficient for stimulation of glucose transport or glycogen synthase in 3T3-L1 adipocytes
J. Biol. Chem.
(1993)Glycogen synthase kinase-3: functions in oncogenesis and development
Biochim. Biophys. Acta.
(1992)- et al.
Okadaic acid a serine/threonine phosphatase inhibitor, induces tyrosine dephosphorylation/inactivation of protein kinase FA/GSK-3 α in A431 cells
J. Biol. Chem
(1994) - et al.
Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase-3 β-dependent pathway
J. Biol. Chem.
(1999) Glycogen synthase kinase 3β is tyrosine phosphorylated by PYK2
Biochem. Biophys. Res. Commun.
(2001)The novel tyrosine kinase ZAK1 activates GSK3 to direct cell fate specification
Cell
(1999)Crystal structure of glycogen synthase kinase 3 β: structural basis for phosphate-primed substrate specificity and autoinhibition
Cell
(2001)A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation
Mol. Cell
(2001)Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling
J. Biol. Chem.
(1994)
The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)
J. Biol. Chem.
Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function
J. Biol. Chem.
Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase
Neurosci. Lett.
Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau
FEBS Lett.
Phosphorylation of tau by glycogen synthase kinase 3β in intact mammalian cells influences the stability of microtubules
Neurosci. Lett.
Glycogen synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice
J. Biol. Chem.
Amyloid β peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3 β in rat hippocampal neurons
Neurosci. Lett.
Direct association of presenilin-1 with β-catenin
FEBS Lett.
Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3
J. Biol. Chem.
Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway
J. Biol. Chem.
Glycogen synthase kinase-3 β facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium
J. Biol. Chem.
Glycogen synthase kinase-3 β activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal
J. Biol. Chem.
The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth
J. Biol. Chem.
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription
Chem. Biol.
The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3 β
Neurosci. Lett.
Judging a protein more than its name: GSK-3
Sci. STKE
GSK-3 takes centre stage more than 20 years after its discovery
Biochem. J.
The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle
Nature
The role of glucose 6-phosphate in the control of glycogen synthase
FASEB J.
Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus
Science
Cited by (401)
Recent advances of PROTACs technology in neurodegenerative diseases
2023, Arabian Journal of ChemistryLithium treatment mitigates the diabetogenic effects of chronic cortico-therapy
2023, Biomedicine and PharmacotherapyGSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit
2023, Biochimica et Biophysica Acta - Molecular Basis of Disease