Glycogen synthase kinase-3 beta

Function

Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and an inactivating agent of glycogen synthase. Two isoforms, alpha (GSK3A) and beta, show a high degree of amino acid homology.

GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.

Disease relevance

Homozygous disruption of the Gsk3b locus in mice results in embryonic lethality during mid-gestation. This lethality phenotype could be rescued by inhibition of tumor necrosis factor.

Two SNPs at this gene, rs334558 (-50T/C) and rs3755557 (-1727A/T), are associated with efficacy of lithium treatment in bipolar disorder.

Signaling pathways

Pharmacological inhibition of ERK1/2 restores GSK-3 beta activity and protein synthesis levels in a model of tuberous sclerosis.

Interactions

GSK3B has been shown to interact with:

• KIAA1211L
• ATP2A2
• AKAP11,
• AXIN1,
• AXIN2,
• AR,
• CTNNB1,
• DNM1L,
• MACF1
• MUC1,
• SMAD3
• NOTCH1,
• NOTCH2,
• P53,
• PRKAR2A,
• SGK3, and
• TSC2.

References

References

1. (November 1994). "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation". The Biochemical Journal.
2. (September 1999). "Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter". Genomics.
3. (June 2010). "The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies". European Neuropsychopharmacology.
4. (December 1992). "Glycogen synthase kinase-3: functions in oncogenesis and development". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.
5. "Entrez Gene: GSK3B glycogen synthase kinase 3 beta".
6. (2013). "Haplotype analysis of GSK-3β gene polymorphisms in bipolar disorder lithium responders and nonresponders". Clinical Neuropharmacology.
7. (June 2017). "Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis". Scientific Reports.
8. EMBL-EBI. "EMBL European Bioinformatics Institute".
9. (June 2023). "SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases". Nature Communications.
10. (June 1998). "Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level". Genes to Cells.
11. (September 2000). "Hot spots in beta-catenin for interactions with LEF-1, conductin and APC". Nature Structural Biology.
12. (August 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 & Development.
13. (July 2004). "Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells". The Journal of Biological Chemistry.
14. (April 2001). "The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer". International Journal of Oncology.
15. (June 1999). "DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability". Molecular and Cellular Biology.
16. (August 1998). "Human dynamin-like protein interacts with the glycogen synthase kinase 3beta". Biochemical and Biophysical Research Communications.
17. (February 2011). "Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β". Cell.
18. (December 1998). "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Molecular and Cellular Biology.
19. (March 2001). "The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin". The Journal of Biological Chemistry.
20. (January 2008). "Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling". Genes & Development.
21. (June 2002). "Glycogen synthase kinase-3beta modulates notch signaling and stability". Current Biology.
22. (August 2003). "Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways". The Journal of Biological Chemistry.
23. (June 2002). "Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage". Proceedings of the National Academy of Sciences of the United States of America.
24. (October 2002). "A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta". The Journal of Biological Chemistry.
25. (May 2002). "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction". Biochemical and Biophysical Research Communications.
26. (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". The Journal of Biological Chemistry.
27. (September 2006). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell.
28. (July 2000). "Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation". Nature.