| Structural highlights
Function
GSK3B_HUMAN 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. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. 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 and diabetes. 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-687' upon T-cell activation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/beta-catenin pathway and potential for aberrant cell proliferation. Development of GSK3alpha or GSK3beta paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3alpha. Here we report for the first time the crystal structure for GSK3alpha, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to approximately 37-fold selectivity for GSK3alpha over GSK3beta with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3alpha can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3beta and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3alpha structure and novel GSK3alpha inhibitors with improved selectivity, potency, and activity in disease-relevant systems.
Elucidation of the GSK3alpha Structure Informs the Design of Novel, Paralog-Selective Inhibitors.,Amaral B, Capacci A, Anderson T, Tezer C, Bajrami B, Lulla M, Lucas B, Chodaparambil JV, Marcotte D, Kumar PR, Murugan P, Spilker K, Cullivan M, Wang T, Peterson AC, Enyedy I, Ma B, Chen T, Yousaf Z, Calhoun M, Golonzhka O, Dillon GM, Koirala S ACS Chem Neurosci. 2023 Mar 15;14(6):1080-1094. doi: , 10.1021/acschemneuro.2c00476. Epub 2023 Feb 22. PMID:36812145[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M, Hunter T. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell. 1991 Feb 8;64(3):573-84. PMID:1846781
- ↑ Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294 ( Pt 3):625-9. PMID:8397507
- ↑ Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997 Mar 28;275(5308):1930-4. PMID:9072970
- ↑ Li Y, Bharti A, Chen D, Gong J, Kufe D. Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol Cell Biol. 1998 Dec;18(12):7216-24. PMID:9819408
- ↑ Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001 Jun;7(6):1321-7. PMID:11430833
- ↑ Cho JH, Johnson GV. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules. J Neurochem. 2004 Jan;88(2):349-58. PMID:14690523
- ↑ Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004 Oct;6(10):931-40. Epub 2004 Sep 26. PMID:15448698 doi:10.1038/ncb1173
- ↑ Hashimoto YK, Satoh T, Okamoto M, Takemori H. Importance of autophosphorylation at Ser186 in the A-loop of salt inducible kinase 1 for its sustained kinase activity. J Cell Biochem. 2008 Aug 1;104(5):1724-39. doi: 10.1002/jcb.21737. PMID:18348280 doi:10.1002/jcb.21737
- ↑ Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell. 2010 Oct 8;40(1):126-37. doi: 10.1016/j.molcel.2010.09.013. PMID:20932480 doi:10.1016/j.molcel.2010.09.013
- ↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
- ↑ Sun L, Lv F, Guo X, Gao G. Glycogen synthase kinase 3beta (GSK3beta) modulates antiviral activity of zinc-finger antiviral protein (ZAP). J Biol Chem. 2012 Jun 29;287(27):22882-8. doi: 10.1074/jbc.M111.306373. Epub 2012, Apr 18. PMID:22514281 doi:10.1074/jbc.M111.306373
- ↑ Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J. 2003 Feb 3;22(3):494-501. PMID:12554650 doi:10.1093/emboj/cdg068
- ↑ Amaral B, Capacci A, Anderson T, Tezer C, Bajrami B, Lulla M, Lucas B, Chodaparambil JV, Marcotte D, Kumar PR, Murugan P, Spilker K, Cullivan M, Wang T, Peterson AC, Enyedy I, Ma B, Chen T, Yousaf Z, Calhoun M, Golonzhka O, Dillon GM, Koirala S. Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors. ACS Chem Neurosci. 2023 Mar 15;14(6):1080-1094. PMID:36812145 doi:10.1021/acschemneuro.2c00476
|
