Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0F6DWV)

• DOT Name: Glycogen synthase kinase-3 alpha (GSK3A)
• Synonyms: GSK-3 alpha; EC 2.7.11.26; Serine/threonine-protein kinase GSK3A; EC 2.7.11.1
• Gene Name: GSK3A
• UniProt ID: GSK3A_HUMAN
• PDB ID: 7SXF; 7SXG
• EC Number: 2.7.11.1; 2.7.11.26
• Pfam ID: PF00069
• Sequence:
  MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGV
  GASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYT
  DIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFY
  SSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGV
  CHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSS
  IDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIK
  AHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLP
  PLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLT
  NSS
• Function: 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), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation. Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Dopaminergic sy.pse (hsa04728)
  Non-alcoholic fatty liver disease (hsa04932)
  Shigellosis (hsa05131)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Suppression of apoptosis (R-HSA-9635465)
  Maturation of nucleoprotein (R-HSA-9683610)
  Maturation of nucleoprotein (R-HSA-9694631)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)

Molecular Interaction Atlas (MIA) of This DOT

13 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[2]
Methamphetamine	DMPM4SK	Approved	Methamphetamine affects the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[5]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[1]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[3]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[2]
Adaphostin	DM16QSG	Phase 1	Adaphostin decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[9]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[12]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the phosphorylation of Glycogen synthase kinase-3 alpha (GSK3A).	[13]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycogen synthase kinase-3 alpha (GSK3A).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of Glycogen synthase kinase-3 alpha (GSK3A).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glycogen synthase kinase-3 alpha (GSK3A).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Glycogen synthase kinase-3 alpha (GSK3A).	[4]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Glycogen synthase kinase-3 alpha (GSK3A).	[11]

References

• [1] GSK3, snail, and adhesion molecule regulation by cyclosporine A in renal tubular cells. Toxicol Sci. 2012 Jun;127(2):425-37. doi: 10.1093/toxsci/kfs108. Epub 2012 Mar 12.
• [2] Increased galectin-3 facilitates leukemia cell survival from apoptotic stimuli. Biochem Biophys Res Commun. 2011 Aug 26;412(2):334-40. doi: 10.1016/j.bbrc.2011.07.099. Epub 2011 Jul 29.
• [3] Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells. J Agric Food Chem. 2006 Sep 20;54(19):7075-82. doi: 10.1021/jf0612530.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] Methamphetamine exposure upregulates the amyloid precursor protein and hyperphosphorylated tau expression: The roles of insulin signaling in SH-SY5Y cell line. J Toxicol Sci. 2019;44(7):493-503. doi: 10.2131/jts.44.493.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. Int J Cancer. 2004 Mar 20;109(2):167-73. doi: 10.1002/ijc.11720.
• [8] Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. Oncogene. 2004 Feb 19;23(7):1364-76. doi: 10.1038/sj.onc.1207248.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [11] Paraquat induces extrinsic pathway of apoptosis in A549 cells by induction of DR5 and repression of anti-apoptotic proteins, DDX3 and GSK3 expression. Toxicol In Vitro. 2017 Aug;42:123-129. doi: 10.1016/j.tiv.2017.04.016. Epub 2017 Apr 14.
• [12] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [13] The effects of short-term treatment of microcystin-LR on the insulin pathway in both the HL7702 cell line and livers of mice. Environ Toxicol. 2020 Jul;35(7):727-737. doi: 10.1002/tox.22907. Epub 2020 Feb 19.