Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5TQK3H)

• DOT Name: F-box/WD repeat-containing protein 5 (FBXW5)
• Synonyms: F-box and WD-40 domain-containing protein 5
• Gene Name: FBXW5
• Related Disease:
  Non-small-cell lung cancer
  Gastric cancer
  Metastatic malignant neoplasm
  Neoplasm
  Non-alcoholic steatohepatitis
  Stomach cancer
• UniProt ID: FBXW5_HUMAN
• Pfam ID: PF12937 ; PF00400
• Sequence:
  MDEGGTPLLPDSLVYQIFLSLGPADVLAAGLVCRQWQAVSRDEFLWREQFYRYYQVARDV
  PRHPAAMSWYEEFQRLYDTVPCVEVQTLREHTDQVLHLSFSHSGYQFASCSKDCTVKIWS
  NDLTISLLHSADMRPYNWSYTQFSQFNKDDSLLLASGVFLGPHNSSSGEIAVISLDSFAL
  LSRVRNKPYDVFGCWLTETSLISGNLHRIGDITSCSVLWLNNAFQDVESENVNVVKRLFK
  IQNLNASTVRTVMVADCSRFDSPDLLLEAGDPATSPCRIFDLGSDNEEVVAGPAPAHAKE
  GLRHFLDRVLEGRAQPQLSERMLETKVAELLAQGHTKPPERSATGAKSKYLIFTTGCLTY
  SPHQIGIKQILPHQMTTAGPVLGEGRGSDAFFDALDHVIDIHGHIIGMGLSPDNRYLYVN
  SRAWPNGAVVADPMQPPPIAEEIDLLVFDLKTMREVRRALRAHRAYTPNDECFFIFLDVS
  RDFVASGAEDRHGYIWDRHYNICLARLRHEDVVNSVVFSPQEQELLLTASDDATIKAWRS
  PRTMRVLQAPRPRPRTFFSWLASQRR
• Function: Substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes. Substrate recognition component of the SCF(FBXW5) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication. The SCF(FBXW5) complex also mediates ubiquitination and degradation of actin-regulator EPS8 during G2 phase, leading to the transient degradation of EPS8 and subsequent cell shape changes required to allow mitotic progression. Substrate-specific adapter of the DCX(FBXW5) E3 ubiquitin-protein ligase complex which mediates the polyubiquitination and subsequent degradation of TSC2. May also act as a negative regulator of MAP3K7/TAK1 signaling in the interleukin-1B (IL1B) signaling pathway.
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Antigen processing (R-HSA-983168)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Limited	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[2]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]
Non-alcoholic steatohepatitis	DIST4788	Limited	Biomarker	[3]
Stomach cancer	DISKIJSX	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of F-box/WD repeat-containing protein 5 (FBXW5).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of F-box/WD repeat-containing protein 5 (FBXW5).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of F-box/WD repeat-containing protein 5 (FBXW5).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of F-box/WD repeat-containing protein 5 (FBXW5).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of F-box/WD repeat-containing protein 5 (FBXW5).	[8]

References

• [1] CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth.Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16868-73. doi: 10.1073/pnas.1306358110. Epub 2013 Sep 30.
• [2] FBXW5 Promotes Tumorigenesis and Metastasis in Gastric Cancer via Activation of the FAK-Src Signaling Pathway.Cancers (Basel). 2019 Jun 17;11(6):836. doi: 10.3390/cancers11060836.
• [3] F-box/WD Repeat-Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal-Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice.Hepatology. 2019 Dec;70(6):1942-1957. doi: 10.1002/hep.30537. Epub 2019 Mar 15.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [6] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [7] 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.
• [8] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.