CBL Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the CBL gene, its protein product, associated diseases, and mutation landscape.
Gene Information Card
| Symbol | CBL |
|---|---|
| Full Name | Cbl proto-oncogene |
| Gene Type | Protein coding |
| Chromosomal Location | 11q23.3 |
| NCBI Gene ID | 867 ncbi.nlm.nih.gov/gene/867 |
| Ensembl ID | ENSG00000110395 |
| UniProt ID | P22681 |
| OMIM ID | 165360 |
| HGNC ID | 1544 |
| Aliases | CBL2, RNF55, c-Cbl |
Description
The CBL gene encodes a RING finger E3 ubiquitin ligase that plays a critical role in regulating signal transduction by targeting activated receptor tyrosine kinases for ubiquitination and degradation. It is involved in multiple cellular processes including cell proliferation, differentiation, and apoptosis. Mutations in CBL are associated with various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia | Germline mutations in CBL lead to dysregulation of RAS signaling, resulting in developmental abnormalities and predisposition to JMML. | OMIM; ClinVar |
| Juvenile myelomonocytic leukemia (JMML) | Somatic or germline CBL mutations cause loss of E3 ubiquitin ligase activity, leading to prolonged activation of growth factor receptors and aberrant myeloid proliferation. | OMIM; COSMIC |
| Acute myeloid leukemia (AML) | Somatic CBL mutations are recurrent in AML, contributing to constitutive activation of FLT3 and other RTKs, promoting leukemogenesis. | COSMIC; ClinVar |
| Chronic myelomonocytic leukemia (CMML) | CBL mutations are found in CMML, leading to dysregulated RAS signaling and myeloproliferation. | COSMIC; ClinVar |
| Other solid tumors | CBL mutations have been reported in various solid tumors, including lung and colorectal cancers, though with lower frequency, contributing to oncogenic signaling. | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | High | High |
| Spleen | High | High |
| Lymph node | High | High |
| Blood | High | High |
| Liver | Medium | Medium |
| Lung | Medium | Medium |
| Kidney | Medium | Medium |
| Brain | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 (leukemia) | High | CML cell line |
| HL-60 (leukemia) | High | AML cell line |
| A-549 (lung carcinoma) | Medium | Lung cancer cell line |
| MCF7 (breast carcinoma) | Medium | Breast cancer cell line |
| Hep-G2 (hepatocellular carcinoma) | Medium | Liver cancer cell line |
| SK-N-SH (neuroblastoma) | Low | Neuroblastoma cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1111T>C (p.Y371H) | Missense | Somatic; recurrent in myeloid malignancies | Loss of E3 ligase activity; gain of function in RAS signaling |
| c.1096C>T (p.R366C) | Missense | Germline; associated with Noonan syndrome-like disorder | Loss of E3 ligase activity; dysregulated RTK signaling |
| c.1222A>G (p.K408E) | Missense | Somatic; found in AML | Loss of E3 ligase activity; enhanced proliferative signaling |
| c.1259G>A (p.C420Y) | Missense | Somatic; reported in CMML | Loss of E3 ligase activity; impaired ubiquitination |
| c.1118A>G (p.Y373C) | Missense | Somatic; in various cancers | Loss of E3 ligase activity; oncogenic |
Mutation functional classification
Loss of Function (LOF)
Most CBL mutations are loss-of-function, impairing E3 ubiquitin ligase activity, leading to reduced degradation of activated receptor tyrosine kinases and sustained signaling.
Gain of Function (GOF)
Some mutations may exhibit gain-of-function effects by enhancing adaptor functions or promoting oncogenic signaling independent of ubiquitination.
Dominant Negative (DN)
Mutant CBL proteins can act in a dominant-negative manner, interfering with wild-type CBL function and further amplifying signaling.
View complete mutation data：
Gene Ontology (GO)
| • ubiquitin-protein transferase activity | • zinc ion binding |
| • protein binding | • signal transducer activity |
| • identical protein binding | • metal ion binding |
| • transferase activity | • protein ubiquitination |
| • negative regulation of cell proliferation | • positive regulation of cell population proliferation |
| • cell surface receptor signaling pathway | • protein catabolic process |
| • regulation of protein stability | • apoptotic process |
| • cell differentiation |
Pathways
• EGFR tyrosine kinase inhibitor resistance
• ErbB signaling pathway
• Endocytosis
• Ubiquitin mediated proteolysis
• RAS signaling pathway
• JAK-STAT signaling pathway
• PI3K-Akt signaling pathway
• MAPK signaling pathway
Protein Summary
The CBL protein is a 906-amino acid multidomain protein that functions as an E3 ubiquitin ligase. It contains a tyrosine kinase binding (TKB) domain, a RING finger domain, a proline-rich region, and a ubiquitin-associated (UBA) domain. CBL negatively regulates signaling by ubiquitinating activated receptor tyrosine kinases (e.g., EGFR, PDGFR, FLT3) and targeting them for lysosomal degradation. It also acts as an adaptor protein in various signaling cascades. Mutations in CBL disrupt its regulatory function, leading to sustained signaling and oncogenesis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CBLN1 Knockout HEK293 Cell Line | EDJ-KQ3519 | Human | 869 | Details Get a Quote |
| CBL Knockout HEK293 Cell Line | EDJ-KQ4198 | Human | 867 | Details Get a Quote |
| CBLB Knockout HEK293 Cell Line | EDJ-KQ4202 | Human | 868 | Details Get a Quote |
| CBLIF Knockout HEK293 Cell Line | EDJ-KQ4711 | Human | 2694 | Details Get a Quote |
| DCBLD2 Knockout HEK293 Cell Line | EDJ-KQ9271 | Human | 131566 | Details Get a Quote |
| CBLN4 Knockout HEK293 Cell Line | EDJ-KQ9793 | Human | 140689 | Details Get a Quote |
| CBLN2 Knockout HEK293 Cell Line | EDJ-KQ9889 | Human | 147381 | Details Get a Quote |
| CBLL2 Knockout HEK293 Cell Line | EDJ-KQ12744 | Human | 158506 | Details Get a Quote |
| CBLN3 Knockout HEK293 Cell Line | EDJ-KQ12745 | Human | 643866 | Details Get a Quote |
| DCBLD1 Knockout HEK293 Cell Line | EDJ-KQ13103 | Human | 285761 | Details Get a Quote |
| CBLN2 Knockout HeLa Cell Line | EDJ-KQ38074 | Human | 147381 | Details Get a Quote |
| CBL Knockout A-549 Cell Line | EDJ-KQ26659 | Human | 867 | Details Get a Quote |
| CBL Knockout HCT 116 Cell Line | EDJ-KQ26660 | Human | 867 | Details Get a Quote |
| CBL Knockout HeLa Cell Line | EDJ-KQ26661 | Human | 867 | Details Get a Quote |
| CBLB Knockout A-549 Cell Line | EDJ-KQ26668 | Human | 868 | Details Get a Quote |
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