Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5EZ7PD)

• DOT Name: F-box/LRR-repeat protein 2 (FBXL2)
• Synonyms: F-box and leucine-rich repeat protein 2; F-box protein FBL2/FBL3
• Gene Name: FBXL2
• Related Disease:
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Childhood acute lymphoblastic leukemia
  Gastric cancer
  Hepatitis C virus infection
  Neoplasm
  Stomach cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: FBXL2_HUMAN
• PDB ID: 6O60
• Pfam ID: PF12937 ; PF13516
• Sequence:
  MVFSNNDEGLINKKLPKELLLRIFSFLDIVTLCRCAQISKAWNILALDGSNWQRIDLFNF
  QTDVEGRVVENISKRCGGFLRKLSLRGCIGVGDSSLKTFAQNCRNIEHLNLNGCTKITDS
  TCYSLSRFCSKLKHLDLTSCVSITNSSLKGISEGCRNLEYLNLSWCDQITKDGIEALVRG
  CRGLKALLLRGCTQLEDEALKHIQNYCHELVSLNLQSCSRITDEGVVQICRGCHRLQALC
  LSGCSNLTDASLTALGLNCPRLQILEAARCSHLTDAGFTLLARNCHELEKMDLEECILIT
  DSTLIQLSIHCPKLQALSLSHCELITDDGILHLSNSTCGHERLRVLELDNCLLITDVALE
  HLENCRGLERLELYDCQQVTRAGIKRMRAQLPHVKVHAYFAPVTPPTAVAGSGQRLCRCC
  VIL
• Function: Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin. This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin. Through CCND2 and CCND3 degradation induces cell-cycle arrest in G(0). SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy. PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant. The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6). The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3.
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, pancreas and placenta.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[6]
Liver cancer	DISDE4BI	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[12]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/LRR-repeat protein 2 (FBXL2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of F-box/LRR-repeat protein 2 (FBXL2).	[14]

References

• [1] F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation.Blood. 2012 Mar 29;119(13):3132-41. doi: 10.1182/blood-2011-06-358911. Epub 2012 Feb 8.
• [2] Neuronal expression of F-box and leucine-rich-repeat protein 2 decreases over Braak stages in the brains of Alzheimer's disease patients.Neurodegener Dis. 2013;11(1):1-12. doi: 10.1159/000336016. Epub 2012 Mar 27.
• [3] F-box protein FBXL2 inhibits gastric cancer proliferation by ubiquitin-mediated degradation of forkhead box M1.FEBS Lett. 2016 Feb;590(4):445-52. doi: 10.1002/1873-3468.12071. Epub 2016 Feb 8.
• [4] NS5A Promotes Constitutive Degradation of IP3R3 to Counteract Apoptosis Induced by Hepatitis C Virus.Cell Rep. 2018 Oct 23;25(4):833-840.e3. doi: 10.1016/j.celrep.2018.09.088.
• [5] PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth.Nature. 2017 Jun 22;546(7659):554-558. doi: 10.1038/nature22965. Epub 2017 Jun 14.
• [6] miRNA-346 promotes proliferation, migration and invasion in liver cancer.Oncol Lett. 2017 Sep;14(3):3255-3260. doi: 10.3892/ol.2017.6561. Epub 2017 Jul 8.
• [7] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.