TISIDB

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm Note=Upon EGF stimulation, associates with endocytic vesicles.
Domain	PF02262 CBL proto-oncogene N-terminal domain 1 PF02761 CBL proto-oncogene N-terminus PF02762 CBL proto-oncogene N-terminus
Function	E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3.

> Gene Ontology [ TOP ]
Biological Process	GO:0000209 protein polyubiquitination GO:0001933 negative regulation of protein phosphorylation GO:0006469 negative regulation of protein kinase activity GO:0006606 protein import into nucleus GO:0006607 NLS-bearing protein import into nucleus GO:0006913 nucleocytoplasmic transport GO:0007173 epidermal growth factor receptor signaling pathway GO:0007175 negative regulation of epidermal growth factor-activated receptor activity GO:0007176 regulation of epidermal growth factor-activated receptor activity GO:0010469 regulation of receptor activity GO:0017038 protein import GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0033673 negative regulation of kinase activity GO:0034504 protein localization to nucleus GO:0038127 ERBB signaling pathway GO:0042058 regulation of epidermal growth factor receptor signaling pathway GO:0042059 negative regulation of epidermal growth factor receptor signaling pathway GO:0042326 negative regulation of phosphorylation GO:0044744 protein targeting to nucleus GO:0050730 regulation of peptidyl-tyrosine phosphorylation GO:0050732 negative regulation of peptidyl-tyrosine phosphorylation GO:0051169 nuclear transport GO:0051170 nuclear import GO:0051348 negative regulation of transferase activity GO:0061097 regulation of protein tyrosine kinase activity GO:0061099 negative regulation of protein tyrosine kinase activity GO:1901184 regulation of ERBB signaling pathway GO:1901185 negative regulation of ERBB signaling pathway GO:1902593 single-organism nuclear import GO:2000272 negative regulation of receptor activity
Molecular Function	GO:0001784 phosphotyrosine binding GO:0004842 ubiquitin-protein transferase activity GO:0016874 ligase activity GO:0017124 SH3 domain binding GO:0019787 ubiquitin-like protein transferase activity GO:0030971 receptor tyrosine kinase binding GO:0045309 protein phosphorylated amino acid binding GO:0051219 phosphoprotein binding GO:0061630 ubiquitin protein ligase activity GO:0061659 ubiquitin-like protein ligase activity GO:1990782 protein tyrosine kinase binding
Cellular Component	GO:0045121 membrane raft GO:0098589 membrane region GO:0098857 membrane microdomain

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04012 ErbB signaling pathway hsa04120 Ubiquitin mediated proteolysis hsa04144 Endocytosis hsa04660 T cell receptor signaling pathway hsa04910 Insulin signaling pathway
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-983695: Antigen activates B Cell Receptor (BCR) leading to generation of second messengers R-HSA-983168: Antigen processing R-HSA-983169: Class I MHC mediated antigen processing & presentation R-HSA-168256: Immune System R-HSA-983705: Signaling by the B Cell Receptor (BCR)

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between CBLB and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between CBLB and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
28184224	Hepatocellular Carcinoma	Inhibit immunity	Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation.
21248250	Lung Carcinoma	Inhibit immunity (T cell function)	The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo.
17364027	Thymic Lymphoma	Inhibit immunity	In vivo studies further demonstrated that Cblb(-/-) mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express B7 ligands and that introduction of the Cblb(-/-) mutation into tumor-prone ataxia telangiectasia mutated-deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb(-/-) mice contained massively infiltrating CD8(+) T cells.
19815501	Melanoma	Inhibit immunity (T cell function)	We show here that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency. Cbl-b binds and promotes monoubiquitination to CARMA1, a critical signaling molecule in NFkappaB activation.
18759930	Thymoma	Inhibit immunity (T cell function)	Inactivation of Cbl-b also renders mice resistant to both transplanted and spontaneous tumors due to an enhanced anti-tumor immunity of CD8(+) T cells.

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of CBLB in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	Total # shRNA with >= 4-fold: 1	Resistant to T-cell proliferation
24476824	shRNA	melanoma	B16	Secondary screen	Total # shRNA with >= 4-fold: 5	Resistant to T-cell proliferation

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of CBLB in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.176	0.512
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.031	0.981
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.327	0.734
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.211	0.442
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.34	0.879
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.049	0.986
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.356	0.386
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.402	0.773
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.306	0.843
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.298	0.78
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.043	0.483
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.149	0.0427

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of CBLB in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	0	7.1	0.452
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	10	0	10	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	14.8	2.7	12.1	0.0439
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	14.8	3.4	11.4	0.0746
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	9.5	11.8	-2.3	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	0	12.5	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	18.2	-10.5	0.576
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	14.3	-14.3	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	0	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of CBLB. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of CBLB. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by CBLB. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of CBLB. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of CBLB expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between CBLB and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	CBLB
Name	Cbl proto-oncogene B, E3 ubiquitin protein ligase
Aliases	RNF56; Cbl-b; Cas-Br-M (murine) ectropic retroviral transforming sequence b; Cas-Br-M (murine) ecotropic ret ......
Chromosomal Location	3q
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting CBLB collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

Browse CBLB