Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2EZDGR)

• DOT Name: F-box/WD repeat-containing protein 1A (BTRC)
• Synonyms: E3RSIkappaB; Epididymis tissue protein Li 2a; F-box and WD repeats protein beta-TrCP; pIkappaBalpha-E3 receptor subunit
• Gene Name: BTRC
• Related Disease:
  Breast carcinoma
  Diabetic kidney disease
  Adult glioblastoma
  Advanced cancer
  Astrocytoma
  B-cell lymphoma
  Colonic neoplasm
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Huntington disease
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Pneumonia
  Pneumonitis
  Precancerous condition
  Prostate neoplasm
  Psoriasis
  Sleep disorder
  Split hand-foot malformation 3
  Stomach cancer
  Thyroid gland papillary carcinoma
  Triple negative breast cancer
  Breast cancer
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Nasopharyngeal carcinoma
  Plasma cell myeloma
  Primitive neuroectodermal tumor
  Split hand-foot malformation
  Carcinoma of liver and intrahepatic biliary tract
  Cutaneous melanoma
  Familial adenomatous polyposis
  Liver cancer
  Melanoma
  Neuroblastoma
• UniProt ID: FBW1A_HUMAN
• PDB ID: 1P22; 2P64; 6M90; 6M91; 6M92; 6M93; 6M94; 6TTU
• Pfam ID: PF12125 ; PF12937 ; PF00400
• Sequence:
  MDPAEAVLQEKALKFMCSMPRSLWLGCSSLADSMPSLRCLYNPGTGALTAFQNSSEREDC
  NNGEPPRKIIPEKNSLRQTYNSCARLCLNQETVCLASTAMKTENCVAKTKLANGTSSMIV
  PKQRKLSASYEKEKELCVKYFEQWSESDQVEFVEHLISQMCHYQHGHINSYLKPMLQRDF
  ITALPARGLDHIAENILSYLDAKSLCAAELVCKEWYRVTSDGMLWKKLIERMVRTDSLWR
  GLAERRGWGQYLFKNKPPDGNAPPNSFYRALYPKIIQDIETIESNWRCGRHSLQRIHCRS
  ETSKGVYCLQYDDQKIVSGLRDNTIKIWDKNTLECKRILTGHTGSVLCLQYDERVIITGS
  SDSTVRVWDVNTGEMLNTLIHHCEAVLHLRFNNGMMVTCSKDRSIAVWDMASPTDITLRR
  VLVGHRAAVNVVDFDDKYIVSASGDRTIKVWNTSTCEFVRTLNGHKRGIACLQYRDRLVV
  SGSSDNTIRLWDIECGACLRVLEGHEELVRCIRFDNKRIVSGAYDGKIKVWDLVAALDPR
  APAGTLCLRTLVEHSGRVFRLQFDEFQIVSSSHDDTILIWDFLNDPAAQAEPPRSPSRTY
  TYISR
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds to phosphorylated target proteins. SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling. SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1, ATF4, CDC25A, DLG1, FBXO5, PER1, SMAD3, SMAD4, SNAI1 and probably NFKB2. SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22'. The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation. SCF(BTRC) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis. SCF(BTRC) mediates the ubiquitination and subsequent degradation of nuclear NFE2L1. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and PER2. May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3. Mediates ubiquitination of REST, thereby leading to its proteasomal degradation. SCF(BTRC) mediates the ubiquitination and subsequent proteasomal degradation of KLF4; thereby negatively regulating cell pluripotency maintenance and embryogenesis. SCF(BTRC) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF.
• Tissue Specificity: Expressed in epididymis (at protein level).
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Hedgehog sig.ling pathway (hsa04340)
  Hippo sig.ling pathway (hsa04390)
  Circadian rhythm (hsa04710)
  Shigellosis (hsa05131)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Prolactin receptor signaling (R-HSA-1170546)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Downstream TCR signaling (R-HSA-202424)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Circadian Clock (R-HSA-400253)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  Neddylation (R-HSA-8951664)
  Interleukin-1 signaling (R-HSA-9020702)
  GSK3B and BTRC (R-HSA-9762114)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[1]
Diabetic kidney disease	DISJMWEY	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[9]
Gastric neoplasm	DISOKN4Y	Strong	Genetic Variation	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Huntington disease	DISQPLA4	Strong	Biomarker	[12]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Pneumonia	DIS8EF3M	Strong	Biomarker	[16]
Pneumonitis	DIS88E0K	Strong	Biomarker	[16]
Precancerous condition	DISV06FL	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[18]
Psoriasis	DIS59VMN	Strong	Biomarker	[19]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[20]
Split hand-foot malformation 3	DISIIYAQ	Strong	Altered Expression	[21]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[9]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[1]
Lung cancer	DISCM4YA	moderate	Altered Expression	[4]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	moderate	Genetic Variation	[24]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[25]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[26]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Altered Expression	[24]
Split hand-foot malformation	DIS8PKGD	moderate	Genetic Variation	[27]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[28]
Cutaneous melanoma	DIS3MMH9	Limited	Genetic Variation	[29]
Familial adenomatous polyposis	DISW53RE	Limited	Altered Expression	[30]
Liver cancer	DISDE4BI	Limited	Biomarker	[28]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[29]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of F-box/WD repeat-containing protein 1A (BTRC).	[32]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of F-box/WD repeat-containing protein 1A (BTRC).	[32]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[33]
Marinol	DM70IK5	Approved	Marinol increases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[34]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[36]
Calphostin C	DM9X2D0	Terminated	Calphostin C increases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of F-box/WD repeat-containing protein 1A (BTRC).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[40]
Mepacrine	DMU8L7C	Investigative	Mepacrine decreases the expression of F-box/WD repeat-containing protein 1A (BTRC).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of F-box/WD repeat-containing protein 1A (BTRC).	[38]

References

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• [2] Activation of GSK3/-TrCP axis via PHLPP1 exacerbates Nrf2 degradation leading to impairment in cell survival pathway during diabetic nephropathy.Free Radic Biol Med. 2018 May 20;120:414-424. doi: 10.1016/j.freeradbiomed.2018.04.550. Epub 2018 Apr 12.
• [3] Mislocalization of the E3 ligase, -transducin repeat-containing protein 1 (-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt.J Biol Chem. 2011 Jun 3;286(22):19777-88. doi: 10.1074/jbc.M111.237081. Epub 2011 Mar 28.
• [4] USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and -TrCP and promotes cancer malignancy.Nat Commun. 2018 Sep 28;9(1):3996. doi: 10.1038/s41467-018-06178-1.
• [5] -TrCP1 promotes cell proliferation via TNF-dependent NF-B activation in diffuse large B cell lymphoma.Cancer Biol Ther. 2020;21(3):241-247. doi: 10.1080/15384047.2019.1683332. Epub 2019 Nov 15.
• [6] Overexpression of human beta TrCP1 deleted of its F box induces tumorigenesis in transgenic mice.Oncogene. 2005 Mar 24;24(13):2271-6. doi: 10.1038/sj.onc.1208418.
• [7] Copy number variation of E3 ubiquitin ligase genes in peripheral blood leukocyte and colorectal cancer.Sci Rep. 2016 Jul 15;6:29869. doi: 10.1038/srep29869.
• [8] TSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-B signaling.Nat Commun. 2018 Apr 12;9(1):1423. doi: 10.1038/s41467-018-03716-9.
• [9] Somatic mutations of the beta-TrCP gene in gastric cancer.APMIS. 2007 Feb;115(2):127-33. doi: 10.1111/j.1600-0463.2007.apm_562.x.
• [10] -transducin repeat-containing E3 ubiquitin protein ligase inhibits migration, invasion and proliferation of glioma cells.Oncol Lett. 2017 Sep;14(3):3131-3135. doi: 10.3892/ol.2017.6533. Epub 2017 Jul 7.
• [11] CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and TrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells.Cell Signal. 2015 Sep;27(9):1694-702. doi: 10.1016/j.cellsig.2015.05.006. Epub 2015 May 22.
• [12] Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington's disease.EMBO J. 2010 Jul 21;29(14):2433-45. doi: 10.1038/emboj.2010.117. Epub 2010 Jun 8.
• [13] Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis.Oncogene. 2008 Jul 24;27(32):4488-96. doi: 10.1038/onc.2008.83. Epub 2008 Mar 31.
• [14] Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.J Natl Cancer Inst. 2004 Aug 4;96(15):1161-70. doi: 10.1093/jnci/djh219.
• [15] The -TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor.Nat Commun. 2017 Jan 16;8:14002. doi: 10.1038/ncomms14002.
• [16] Involvement of p38-TrCP-Tristetraprolin-TNF axis in radiation pneumonitis.Oncotarget. 2017 Jul 18;8(29):47767-47779. doi: 10.18632/oncotarget.17770.
• [17] Expediting dynamics approach to understand the influence of 14-3-3 causing metastatic cancer through the interaction of YAP1 and -TRCP.Mol Biosyst. 2017 Sep 26;13(10):1981-1992. doi: 10.1039/c7mb00271h.
• [18] Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase.J Biol Chem. 2006 Jul 14;281(28):19320-6. doi: 10.1074/jbc.M513203200. Epub 2006 May 1.
• [19] Increased TrCP are associated with imiquimod-induced psoriasis-like skin inflammation in mice via NF-B signaling pathway.Gene. 2016 Oct 30;592(1):164-171. doi: 10.1016/j.gene.2016.07.066. Epub 2016 Jul 28.
• [20] Interactive structural analysis of TrCP1 and PER2 phosphoswitch binding through dynamics simulation assay.Arch Biochem Biophys. 2018 Aug 1;651:34-42. doi: 10.1016/j.abb.2018.05.020. Epub 2018 May 30.
• [21] Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region.Am J Med Genet A. 2006 Jul 1;140(13):1384-95. doi: 10.1002/ajmg.a.31247.
• [22] SCF(-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2.J Exp Med. 2012 Jul 2;209(7):1289-307. doi: 10.1084/jem.20112446. Epub 2012 Jun 18.
• [23] -TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells.Exp Mol Med. 2015 Feb 27;47(2):e143. doi: 10.1038/emm.2014.127.
• [24] Absence of detectable alterations in the putative tumor suppressor gene BTRC in cerebellar medulloblastomas and cutaneous basal cell carcinomas.Acta Neuropathol. 2003 Oct;106(4):287-90. doi: 10.1007/s00401-003-0745-7. Epub 2003 Jul 24.
• [25] EBV-miR-BART10-3p facilitates epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma by targeting BTRC.Oncotarget. 2015 Dec 8;6(39):41766-82. doi: 10.18632/oncotarget.6155.
• [26] MicroRNA-324-5p suppresses the migration and invasion of MM cells by inhibiting the SCF(-TrCP) E3 ligase.Oncol Lett. 2018 Oct;16(4):5331-5338. doi: 10.3892/ol.2018.9245. Epub 2018 Aug 1.
• [27] Clinical, genetic, and molecular aspects of split-hand/foot malformation: an update.Am J Med Genet A. 2013 Nov;161A(11):2860-72. doi: 10.1002/ajmg.a.36239. Epub 2013 Sep 24.
• [28] Reciprocal regulation between TrCP and Smurf1 suppresses proliferative capacity of liver cancer cells.J Cell Physiol. 2017 Dec;232(12):3347-3359. doi: 10.1002/jcp.25780. Epub 2017 Mar 6.
• [29] Genetic Variants in WNT2B and BTRC Predict Melanoma Survival.J Invest Dermatol. 2017 Aug;137(8):1749-1756. doi: 10.1016/j.jid.2017.04.023. Epub 2017 May 10.
• [30] FIP200 inhibits -catenin-mediated transcription by promoting APC-independent -catenin ubiquitination.Oncogene. 2013 May 9;32(19):2421-32. doi: 10.1038/onc.2012.262. Epub 2012 Jul 2.
• [31] Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(-TRCP) in neuroblastoma cells.Cancer. 2011 Nov 15;117(22):5189-202. doi: 10.1002/cncr.26145. Epub 2011 Apr 26.
• [32] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [33] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [34] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [35] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [36] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [37] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [38] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [39] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Quinacrine induces the apoptosis of human leukemia U937 cells through FOXP3/miR-183/-TrCP/SP1 axis-mediated BAX upregulation. Toxicol Appl Pharmacol. 2017 Nov 1;334:35-46. doi: 10.1016/j.taap.2017.08.019. Epub 2017 Sep 1.