Browse CBLB

Summary
SymbolCBLB
NameCbl 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 Location3q
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
 
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
 
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
 
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
SymbolCBLB
NameCbl 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 Location3q
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
 
  Literatures describing the relation between CBLB and anti-tumor immunity in human cancer.
PMID Cancer type Relation to immunity Evidence sentences
28184224Hepatocellular CarcinomaInhibit immunityCbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation.
21248250Lung CarcinomaInhibit 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.
17364027Thymic LymphomaInhibit immunityIn 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.
19815501MelanomaInhibit 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.
18759930ThymomaInhibit 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
SymbolCBLB
NameCbl 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 Location3q
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
  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
29301958CRISPR-Cas9 melanomaB16F10Pmel-1 T cell NA/NS NA/NS
29301958CRISPR-Cas9 melanomaB16F10OT-1 T cell NA/NS NA/NS
28783722CRISPR-Cas9 melanomaMel6242CT-CRISPR NA/NS NA/NS
28723893CRISPR-Cas9 melanomaB16GVAX+Anti-PD1 NA/NS NA/NS
28723893CRISPR-Cas9 melanomaB16GVAX NA/NS NA/NS
25691366RNAiBreast cancerMCF7Luc-CTL assay NA/NS NA/NS
24476824shRNAmelanomaB16Primary screen Total # shRNA with >= 4-fold: 1 Resistant to T-cell proliferation
24476824shRNAmelanomaB16Secondary screen Total # shRNA with >= 4-fold: 5 Resistant to T-cell proliferation
Summary
SymbolCBLB
NameCbl 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 Location3q
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
 
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 Anno
126997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)1412-0.1760.512
226997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)650.0310.981
326997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)87-0.3270.734
428552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 916-0.2110.442
528552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 59-0.340.879
628552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 47-0.0490.986
729033130MelanomaallAnti-PD-1 (nivolumab) 26230.3560.386
829033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 15110.4020.773
929033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 11120.3060.843
1029301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 480.2980.78
1129301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 2001
1229301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 281.0430.483
1329443960Urothelial cancerallAnti-PD-L1 (atezolizumab) 68230-0.1490.0427
> Mutation difference between responders and non-responders
 
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 Anno
125765070Non-small cell lung cancer (NSCLC)allAnti-PD-1 (pembrolizumab) 14177.107.10.452
225765070Non-small cell lung cancer (NSCLC)smokingAnti-PD-1 (pembrolizumab) 103100101
325765070Non-small cell lung cancer (NSCLC)non-smokingAnti-PD-1 (pembrolizumab) 4140001
426359337MelanomaallAnti-CTLA-4 (ipilimumab) 277314.82.712.10.0439
526359337MelanomaBRAFiAnti-CTLA-4 (ipilimumab) 0140001
626359337Melanomanon-BRAFiAnti-CTLA-4 (ipilimumab) 275914.83.411.40.0746
726997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)21179.511.8-2.31
826997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)8612.5012.51
926997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)13117.718.2-10.50.576
1028552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 91606.2-6.21
1128552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590001
1228552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 47014.3-14.31
1329033130MelanomaallAnti-PD-1 (nivolumab) 38272.602.61
1429033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 22130001
1529033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 16146.206.21
1629301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 11130001
1729301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 610001
1829301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 5120001
Summary
SymbolCBLB
NameCbl 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 Location3q
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
 
Summary
SymbolCBLB
NameCbl 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 Location3q
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
 
> Immunostimulator
 
> MHC molecule
 
Summary
SymbolCBLB
NameCbl 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 Location3q
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
 
> Receptor
 
Summary
SymbolCBLB
NameCbl 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 Location3q
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Distribution of CBLB expression across immune and molecular subtypes.
> Immune subtype
> Molecular subtype
> Immune subtype
 
> Molecular subtype
 
Summary
SymbolCBLB
NameCbl 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 Location3q
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Associations between CBLB and clinical features.
> Overall survival analysis
> Cancer stage
> Tumor grade
> Overall survival
 
> Stage
 
> Grade
 
Summary
SymbolCBLB
NameCbl 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 Location3q
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Drugs targeting CBLB collected from DrugBank database.
> Drugs from DrugBank database
 

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