CBL (gene)
Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

# Discovery
In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.

# Structure
Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:
- N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
- RING finger domain motif: recruits enzymes involved in ubiquitination
- Proline-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions
- C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding
This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.

# Homologues
Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:
- c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
- Cbl-b: ubiquitously expressed, 982 amino acids long.
- Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.
Both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.

# Function

## Ubiquitin ligase
Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.

# Interactions
Cbl gene has been shown to interact with:
- Abl gene,
- ARHGEF7,
- C-Met,
- CD2AP,
- CSF1R.
- CRK,
- CRKL,
- EGFR,<
- FRS2,
- FYN,
- Grb2,
- HCK,
- IGF1R,
- LCP2;,
- NCK1,
- PDGFRA,
- PIK3R1,
- PIK3R2,
- PLCG1,
- PTK2B,
- PTPN11,
- SH2B2,
- SH3KBP1
- SHC1,
- SLA2,
- SORBS1,
- SORBS2,
- SPRY2,
- Syk,
- UBE2L3,
- VAV1,
- YWHAB,
- YWHAQ, and
- ZAP-70,