Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3RKZI9)

• DOT Name: E3 ubiquitin-protein ligase CBL-C (CBLC)
• Synonyms: EC 2.3.2.27; RING finger protein 57; RING-type E3 ubiquitin transferase CBL-C; SH3-binding protein CBL-3; SH3-binding protein CBL-C; Signal transduction protein CBL-C
• Gene Name: CBLC
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Lung adenocarcinoma
  Non-small-cell lung cancer
• UniProt ID: CBLC_HUMAN
• PDB ID: 3OP0; 3VRN; 3VRO; 3VRP; 3VRQ; 3VRR
• EC Number: 2.3.2.27
• Pfam ID: PF02262 ; PF02761 ; PF02762 ; PF13920
• Sequence:
  MALAVAPWGRQWEEARALGRAVRMLQRLEEQCVDPRLSVSPPSLRDLLPRTAQLLREVAH
  SRRAAGGGGPGGPGGSGDFLLIYLANLEAKSRQVAALLPPRGRRSANDELFRAGSRLRRQ
  LAKLAIIFSHMHAELHALFPGGKYCGHMYQLTKAPAHTFWRESCGARCVLPWAEFESLLG
  TCHPVEPGCTALALRTTIDLTCSGHVSIFEFDVFTRLFQPWPTLLKNWQLLAVNHPGYMA
  FLTYDEVQERLQACRDKPGSYIFRPSCTRLGQWAIGYVSSDGSILQTIPANKPLSQVLLE
  GQKDGFYLYPDGKTHNPDLTELGQAEPQQRIHVSEEQLQLYWAMDSTFELCKICAESNKD
  VKIEPCGHLLCSCCLAAWQHSDSQTCPFCRCEIKGWEAVSIYQFHGQATAEDSGNSSDQE
  GRELELGQVPLSAPPLPPRPDLPPRKPRNAQPKVRLLKGNSPPAALGPQDPAPA
• Function: Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419'. In collaboration with CD2AP may act as regulatory checkpoint for Ret signaling by modulating the rate of RET degradation after ligand activation; CD2AP converts it from an inhibitor to a promoter of RET degradation; the function limits the potency of GDNF on neuronal survival.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase CBL-C (CBLC).	[10]

2 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 E3 ubiquitin-protein ligase CBL-C (CBLC).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase CBL-C (CBLC).	[9]

References

• [1] Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma.Cancer Res. 2018 Sep 1;78(17):4984-4996. doi: 10.1158/0008-5472.CAN-17-3858. Epub 2018 Jun 26.
• [2] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [3] Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.Oncotarget. 2015 May 10;6(13):10746-58. doi: 10.18632/oncotarget.3628.
• [4] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [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] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.