# CBL (gene)

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene family. CBL gene, a part of the Cbl family, encodes 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 mouse-tropic strain of Murine leukemia virus isolated from the brain of a mouse captured at Lake Casitas, California known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from a mouse into which it was injected. 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 tumor 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,