mutLBSgeneDB

mutLBSgeneDB
mutated Ligand Binding Site gene DataBase

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	Gene Summary
	Ligand Binding Site Mutation Information
	Protein Structure Related Information
	Gene Expression and Gene-Gene Network
	Phenotype Information
	Pharmacological Information
	Conservation Information for LBS

Gene summary for CBL

Gene summary

Basic gene Info.	Gene symbol	CBL
	Gene name	Cbl proto-oncogene, E3 ubiquitin protein ligase
	Synonyms	C-CBL\|CBL2\|FRA11B\|NSLL\|RNF55
	Cytomap	UCSC genome browser: 11q23.3
	Type of gene	protein-coding
	RefGenes	NM_005188.3,
	Description	Cas-Br-M (murine) ecotropic retroviral transforming sequenceE3 ubiquitin-protein ligase CBLRING finger protein 55casitas B-lineage lymphoma proto-oncogenefragile site, folic acid type, rare, fra(11)(q23.3)oncogene CBL2proto-oncogene c-Cblsignal tra
	Modification date	20141222
dbXrefs	MIM : 165360
	HGNC : HGNC
	Ensembl : ENSG00000110395
	HPRD : 01320
	Vega : OTTHUMG00000166170
Protein	UniProt: P22681 go to UniProt's Cross Reference DB Table
Expression	CleanEX: HS_CBL
	BioGPS: 867
Pathway	NCI Pathway Interaction Database: CBL
	KEGG: CBL
	REACTOME: CBL
	Pathway Commons: CBL
Context	iHOP: CBL
	ligand binding site mutation search in PubMed: CBL
	UCL Cancer Institute: CBL
Assigned class in mutLBSgeneDB	C: This gene just belongs to mutLBSgenes.

Gene ontology having evidence of Inferred from Direct Assay (IDA) from Entrez

GO ID

GO Term

PubMed ID

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Ligand binding site mutations for CBL

Lollipop-style diagram of mutations at LBS in amino-acid sequence.
We represented ligand binding site mutations only. (You can see big image via clicking.)

: non-synonymous mutation on LBS, Circle size denotes number of samples.

Cancer type specific mutLBS sorted by frequency

LBS	AAchange of nsSNV	Cancer type	# samples
C401	M400T	COAD	2
C401	C401R	COAD	2
C381	C381Y	COAD	2
Y337	L338S	COAD	2
C381	C381R	COAD	1
C404	C404R	COAD	1
C416	P417L	COAD	1
C396	C396R	COAD	1
C419	C419R	COAD	1
K278,Y274	E276K	COAD	1
C396	P395S	COAD	1
C381	C381G	COAD	1
C384	C384Y	COAD	1
H398	H398R	COAD	1
C419	F418S	COAD	1
C396	P395L	COAD	1
C384	C384W	GBM	1
K278	R280W	LUAD	1
C401	C401F	LUAD	1
H398,C396	G397V	LUSC	1
C416	P417H	SKCM	1
C419	F418L	SKCM	1
Y274	D275H	STAD	1
K322	K322T	UCEC	1
K278,Y274	E276K	UCEC	1

cf) Cancer type abbreviation. BLCA: Bladder urothelial carcinoma, BRCA: Breast invasive carcinoma, CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma, COAD: Colon adenocarcinoma, GBM: Glioblastoma multiforme, LGG: Brain lower grade glioma, HNSC: Head and neck squamous cell carcinoma, KICH: Kidney chromophobe, KIRC: Kidney renal clear cell carcinoma, KIRP: Kidney renal papillary cell carcinoma, LAML: Acute myeloid leukemia, LUAD: Lung adenocarcinoma, LUSC: Lung squamous cell carcinoma, OV: Ovarian serous cystadenocarcinoma, PAAD: Pancreatic adenocarcinoma, PRAD: Prostate adenocarcinoma, SKCM: Skin cutaneous melanoma, STAD: Stomach adenocarcinoma, THCA: Thyroid carcinoma, UCEC: Uterine corpus endometrial carcinoma.

Clinical information for CBL from My Cancer Genome.

Casitas B-lineage Lymphoma (CBL) proto-oncogene is a gene that encodes the CBL protein, which is a RING finger E3 ubiquitin ligase. This ligase is an enzyme that functions in the tagging of substrates for degradation by the proteasome. Fusions, nonsense and silent mutations are observed in cancers such as acute myeloid leukemia, colorectal cancer, endometrial cancer, and skin cancer. Related Pathways: Receptor tyrosine kinase/growth factor signaling. Modified: December 4, 2015

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Protein structure related information for CBL

Relative protein structure stability change (ΔΔE) using Mupro 1.1
Mupro score denotes assessment of the effect of mutations on thermodynamic stability.
(ΔΔE<0: mutation decreases stability, ΔΔE>0: mutation increases stability)

: nsSNV at non-LBS

: nsSNV at LBS

nsSNVs sorted by the relative stability change of protein structure by each mutation
Blue: mutations of positive stability change. and red : the most recurrent mutation for this gene.

LBS	AAchange of nsSNV	Relative stability change
C396	P395S	-1.5812814
Y337	L338S	-1.4391104
K278	E276K	-1.2605691
Y274	E276K	-1.2605691
C419	C419R	-1.2210171
C401	M400T	-1.209203
C416	P417H	-1.1873471
C381	C381G	-1.1530926
K278	R280W	-1.073273
C396	P395L	-1.0085469
C384	C384W	-1.0007209
C384	C384Y	-0.97933082
C404	C404R	-0.96861751
Y274	D275H	-0.82147731
C419	F418S	-0.75819217
C381	C381R	-0.74487231
C381	C381Y	-0.72455429
C416	P417L	-0.61766411
C401	C401R	-0.57927356
C401	C401F	-0.57577783
H398	H398R	-0.4599376
K322	K322T	-0.40928021
C419	F418L	-0.23736811
H398	G397V	-0.13785901
C396	G397V	-0.13785901
C396	C396R	-0.003188997

(MuPro1.1: Jianlin Cheng et al., Prediction of Protein Stability Changes for Single-Site Mutations Using Support Vector Machines, PROTEINS: Structure, Function, and Bioinformatics. 2006, 62:1125-1132)

Structure image for CBL from PDB

PDB ID	PDB title	PDB structure
1B47	STRUCTURE OF THE N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE IN ZAP-70

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Differential gene expression and gene-gene network for CBL

Differential gene expression between mutated and non-mutated LBS samples in all 16 major cancer types

CBL_COAD_DE

Differential co-expressed gene network based on protein-protein interaction data (CePIN)

* Left PPI network was created from samples with mutations in the LBS of CBL and the right PPI network was created from samples without mutations in the LBS of CBL. Only genes with p-value < 0.05 are shown.
Red circle: input gene. Orange circle: LBSgene. Blue circle: other gene.

* In COAD

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Phenotype information for CBL

Gene level disease information (DisGeNet)

Disease ID	Disease name	# PubMed	Association type
umls:C0349639	Leukemia, Myelomonocytic, Juvenile	13	Biomarker, GeneticVariation
umls:C3150803	NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA	2	Biomarker, GeneticVariation
umls:C0008073	Developmental Disabilities	1	Biomarker
umls:C0010417	Cryptorchidism	1	Biomarker
umls:C0018273	Growth Disorders	1	Biomarker
umls:C0042384	Vasculitis	1	Biomarker
umls:C0028326	Noonan Syndrome	1	Biomarker, GeneticVariation

Mutation level pathogenic information (ClinVar annotation)

Allele ID	AA change	Clinical significance	Origin	Phenotype IDs
38778	C396R	Pathogenic	Germline	MedGen:CN166718
48876	C401R	Pathogenic	Germline	MedGen:CN166718
179154	R280W	Uncertain significance	Germline	MedGen:CN166718

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Pharmacological information for CBL

Gene expression profile of anticancer drug treated cell-lines (CCLE)
Heatmap showing the correlation between gene expression and drug response across all the cell-lines. We chose the top 20 among 138 drugs.We used Pearson's correlation coefficient.

Drug information targeting mutLBSgene (Approved drugs only)

Drug status

DrugBank ID

Name

Type

Drug structure

Gene-centered ligand-gene interaction network

Ligands binding to mutated ligand binding site of CBL go to BioLip

Ligand ID	Ligand short name	Ligand long name	PDB ID	PDB name	mutLBS
ZN		ZINC(2+)	1fbv	A	C381 C384 C401 C404
ZN		ZINC(2+)	2k4d	A	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	A	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	B	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	C	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	D	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	E	C381 C384 C401 C404
ZN		ZINC(2+)	2y1m	F	C381 C384 C401 C404
ZN		ZINC(2+)	2y1n	A	C381 C384 C401 C404
ZN		ZINC(2+)	2y1n	C	C381 C384 C401 C404
ZN		ZINC(2+)	4a49	A	C381 C384 C401 C404
ZN		ZINC(2+)	4a4b	A	C381 C384 C401 C404
ZN		ZINC(2+)	4a4c	A	C381 C384 C401 C404
ZN		ZINC(2+)	1fbv	A	C396 H398 C416 C419
ZN		ZINC(2+)	2k4d	A	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	A	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	B	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	C	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	D	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	E	C396 H398 C416 C419
ZN		ZINC(2+)	2y1m	F	C396 H398 C416 C419
ZN		ZINC(2+)	2y1n	A	C396 H398 C416 C419
ZN		ZINC(2+)	2y1n	C	C396 H398 C416 C419
ZN		ZINC(2+)	4a49	A	C396 H398 C416 C419
ZN		ZINC(2+)	4a4b	A	C396 H398 C416 C419
ZN		ZINC(2+)	4a4c	A	C396 H398 C416 C419
III		Peptide ligand (ARG,ALA,VAL,GLU,ASN,GLN,TYR,SER,PHE)	1yvh	A	Y274
III		Peptide ligand (ASN,ASP,TYR,ILE,ASP,ASN,PRO)	3bun	B	Y274
III		Peptide ligand (SER,PHE,ASN,PRO,TYR,GLU,PRO,GLU,LEU)	3buw	B	Y274
III		Peptide ligand (SER,PHE,ASN,PRO,TYR,GLU,PRO,GLU,LEU)	3buw	D	Y274
III		Peptide ligand (ASN,GLU,SER,VAL,ASP,TYR,ARG,ALA)	3bux	B	Y274
III		Peptide ligand (ASN,GLU,SER,VAL,ASP,TYR,ARG,ALA)	3bux	D	Y274
III		Peptide ligand (ARG,TYR,ASP,ALA)	3plf	B	Y274
III		Peptide ligand (ARG,TYR,ASP,ALA)	3plf	D	Y274
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	2y1n	C	Y274 K278 K322 Y337
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	2y1n	A	Y274 K278 Y337
III		Peptide ligand (SER,PHE,LEU,GLN,ARG,TYR,SER,SER,ASP,PRO,THR)	3buo	B	Y274 K322
III		Peptide ligand (SER,PHE,LEU,GLN,ARG,TYR,SER,SER,ASP,PRO,THR)	3buo	D	Y274 K322
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	1fbv	A	Y274 K322 Y337
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	2cbl	A	Y274 K322 Y337
III		Peptide ligand (SER,PHE,LEU,GLN,ARG,TYR,SER,SER,ASP,PRO,THR)	3ob2	B	Y274 K322 Y337
III		Peptide ligand (ACE,TYR,THR,PRO,GLU,PRO,NH2)	4gpl	B	Y274 K322 Y337
III		Peptide ligand (THR,ASN,GLU,TYR,THR,GLU,GLY,PRO,THR)	3bum	B	Y274 Y337
III		Peptide ligand (ARG,ASN,THR,ASN,GLU,TYR,THR,GLU,GLY,PRO)	3ob1	B	Y274 Y337
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	4a4b	A	Y274 Y337
III		Peptide ligand (SER,ASP,GLY,TYR,THR,PRO,GLU,PRO,ALA)	4a4c	A	Y274 Y337

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Conservation information for LBS of CBL

Multiple alignments for P22681 in multiple species

LBS

AA sequence

# species

Species