8vme

Structural highlights

Function

GSK3B_MOUSE Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-679' upon T-cell activation. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation.^{[1] [2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 2000 Jul 6;406(6791):86-90. PMID:10894547 doi:http://dx.doi.org/10.1038/35017574
2. ↑ McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 2005 Apr 20;24(8):1571-83. Epub 2005 Mar 24. PMID:15791206 doi:http://dx.doi.org/10.1038/sj.emboj.7600633
3. ↑ Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006 Mar 17;21(6):749-60. PMID:16543145 doi:http://dx.doi.org/10.1016/j.molcel.2006.02.009
4. ↑ Garrido JJ, Simon D, Varea O, Wandosell F. GSK3 alpha and GSK3 beta are necessary for axon formation. FEBS Lett. 2007 Apr 17;581(8):1579-86. Epub 2007 Mar 19. PMID:17391670 doi:http://dx.doi.org/10.1016/j.febslet.2007.03.018
5. ↑ Tanabe K, Liu Z, Patel S, Doble BW, Li L, Cras-Meneur C, Martinez SC, Welling CM, White MF, Bernal-Mizrachi E, Woodgett JR, Permutt MA. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 2008 Feb;6(2):e37. doi: 10.1371/journal.pbio.0060037. PMID:18288891 doi:http://dx.doi.org/10.1371/journal.pbio.0060037
6. ↑ Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y. DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol. 2010 Apr;30(7):1757-68. doi: 10.1128/MCB.01047-09. Epub 2010 Feb, 1. PMID:20123978 doi:http://dx.doi.org/10.1128/MCB.01047-09
7. ↑ Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E. Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta. Cell. 2011 Feb 4;144(3):341-52. doi: 10.1016/j.cell.2010.12.033. PMID:21295697 doi:http://dx.doi.org/10.1016/j.cell.2010.12.033
8. ↑ Wakatsuki S, Saitoh F, Araki T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol. 2011 Nov 6;13(12):1415-23. doi: 10.1038/ncb2373. PMID:22057101 doi:http://dx.doi.org/10.1038/ncb2373