CBLB Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the CBLB gene, its protein product, associated diseases, and therapeutic implications.
Gene Information Card
| Symbol | CBLB |
|---|---|
| Full Name | Cbl proto-oncogene B |
| Gene Type | Protein coding |
| Chromosomal Location | 3q13.13 |
| NCBI Gene ID | 868 ncbi.nlm.nih.gov/gene/868 |
| Ensembl ID | ENSG00000114423 |
| UniProt ID | Q13191 |
| OMIM ID | 604491 |
| HGNC ID | 1549 |
| Aliases | Cbl-b, RNF56, Nbla00127 |
Description
The CBLB gene encodes Cbl-b, a RING finger-type E3 ubiquitin ligase that plays a critical role in regulating immune responses. It negatively regulates T cell activation, B cell signaling, and other receptor tyrosine kinase pathways by promoting ubiquitination and degradation of activated receptors and signaling molecules. Cbl-b is essential for maintaining immune tolerance and preventing autoimmunity, and its dysregulation is linked to various cancers and autoimmune diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Autoimmune diseases (e.g., type 1 diabetes, systemic lupus erythematosus) | Loss of Cbl-b function leads to enhanced T cell activation and breakdown of immune tolerance, promoting autoimmunity. | Genetic association studies and mouse models (e.g., Cblb knockout mice develop spontaneous autoimmunity). |
| Cancer (e.g., melanoma, breast cancer, leukemia) | Cbl-b downregulation enhances anti-tumor immunity, but in tumor cells, Cbl-b may promote oncogenic signaling by regulating receptor tyrosine kinases. | Expression studies and functional assays in tumor cell lines and patient samples. |
| Infectious diseases (e.g., viral infections) | Cbl-b modulates antiviral T cell responses; its inhibition can enhance immune clearance. | Preclinical studies with Cblb-deficient mice show improved viral control. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Spleen | 10.2 | Medium |
| Lymph node | 8.5 | Medium |
| Bone marrow | 6.3 | Low |
| Thymus | 5.1 | Low |
| Blood | 4.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Jurkat (T cell leukemia) | 12.5 | High expression; used for T cell signaling studies. |
| Ramos (B cell lymphoma) | 9.8 | Moderate expression; relevant for B cell receptor signaling. |
| HEK293 (embryonic kidney) | 7.2 | Low endogenous expression; commonly used for overexpression studies. |
| MCF7 (breast cancer) | 5.6 | Low expression; potential role in tumor progression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1000C>T (p.Arg334Trp) | Missense | Rare (0.01%) | Loss of function; associated with autoimmune susceptibility. |
| c.1255A>G (p.Ile419Val) | Missense | 0.05% | Uncertain significance; may affect protein stability. |
| c.1771G>A (p.Asp591Asn) | Missense | 0.02% | Potential loss of function; linked to altered T cell activation. |
| c.2200delC (frameshift) | Frameshift | Very rare | Loss of function; predicted to cause truncated protein. |
Mutation functional classification
Loss of Function (LOF)
Most CBLB mutations that are pathogenic are loss-of-function, leading to enhanced immune activation and autoimmunity. These mutations impair the E3 ligase activity or protein stability, reducing ubiquitination of substrates like ZAP70 and PI3K, thereby increasing T cell receptor signaling.
Gain of Function (GOF)
Gain-of-function mutations in CBLB are rare and not well characterized. They could potentially enhance ubiquitination of tumor suppressors, promoting oncogenesis, but evidence is limited.
Dominant Negative (DN)
Some missense mutations may act in a dominant-negative manner, interfering with wild-type Cbl-b function. For example, mutations in the RING finger domain could bind substrates but fail to ubiquitinate them, blocking normal downregulation.
View complete mutation data：
Gene Ontology (GO)
| • Ubiquitin-protein transferase activity | • Zinc ion binding |
| • Signal transducer activity | • Protein binding |
| • Negative regulation of T cell receptor signaling pathway | • Positive regulation of proteasomal ubiquitin-dependent protein catabolic process |
Pathways
• T cell receptor signaling pathway
• B cell receptor signaling pathway
• Fc epsilon receptor signaling pathway
• Ubiquitin mediated proteolysis
• PD-1 signaling
Protein Summary
Cbl-b is a 982-amino acid protein with a molecular weight of ~109 kDa. It contains an N-terminal tyrosine kinase binding (TKB) domain, a RING finger domain, a proline-rich region, and a C-terminal ubiquitin-associated (UBA) domain. The TKB domain mediates substrate recognition, while the RING finger domain provides E3 ligase activity. Cbl-b is primarily cytosolic but translocates to the plasma membrane upon receptor activation. It negatively regulates immune cell signaling by ubiquitinating activated receptor tyrosine kinases and downstream signaling molecules, leading to their degradation. Cbl-b also interacts with adaptor proteins like Grb2 and p85, modulating PI3K and MAPK pathways. Its expression is tightly regulated, and its loss is associated with hyperactive immune responses.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CBLB Knockout HEK293 Cell Line | EDJ-KQ4202 | Human | 868 | Details Get a Quote |
| CBLB Knockout A-549 Cell Line | EDJ-KQ26668 | Human | 868 | Details Get a Quote |
| CBLB Knockout HCT 116 Cell Line | EDJ-KQ26669 | Human | 868 | Details Get a Quote |
| CBLB Knockout HeLa Cell Line | EDJ-KQ26670 | Human | 868 | Details Get a Quote |
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